myelin-basic-protein and Brain-Injuries

Biomarkers allow physiological processes to be monitored, in both health and injury. Multiple attempts have been made to use biomarkers in traumatic brain injury (TBI). Identification of such biomarkers could allow improved understanding of the pathological processes involved in TBI, diagnosis, prognostication and development of novel therapies. This review article aims to cover both established and emerging TBI biomarkers along with their benefits and limitations. It then discusses the potential value of TBI biomarkers to military, civilian and sporting populations and the future hopes for developing a role for biomarkers in head injury management.

Topics: Biomarkers; Brain Injuries; Creatine Kinase, BB Form; Cytokines; Glial Fibrillary Acidic Protein; Humans; Intermediate Filaments; L-Lactate Dehydrogenase; Microtubule-Associated Proteins; Myelin Basic Protein; Phosphopyruvate Hydratase; Receptors, Urokinase Plasminogen Activator; S100 Calcium Binding Protein beta Subunit; Spectrin; Ubiquitin Thiolesterase

There is a lack of reliable serum biomarkers for routine use in the diagnostic workup of people with traumatic brain injury. Multiple biomediators and biomarkers have been described in the pertinent literature in recent years; however, only a few candidate molecules have been associated with high sensitivity and high specificity for risk stratification and outcome prediction after traumatic brain injury. This review was designed to provide an overview of the state of the art regarding established serum biomarkers in the field and to outline future directions of investigation.

Topics: Biomarkers; Brain Injuries; Glial Fibrillary Acidic Protein; Humans; Myelin Basic Protein; Phosphopyruvate Hydratase; S100 Calcium Binding Protein beta Subunit; tau Proteins; Ubiquitin Thiolesterase

To define and discuss new developments in the field of pediatric traumatic brain injury (TBI). Review of several recent key studies on therapy since publication of the first U.S. traumatic brain injury guidelines in 2003. In addition, we discuss new developments in the use of biomarkers of brain injury in TBI diagnosis and also discuss recent advances in bedside neuromonitoring that may be helpful in the setting of pediatric brain injury. Important new information on optimal cerebral perfusion pressure management, cerebrospinal fluid drainage, decompressive craniectomy, hypothermia, biomarkers of brain injury along with advances in neuromonitoring are presented. The 2003 guidelines have stimulated important new research. This is reshaping bedside care.

Topics: Biomarkers; Brain Injuries; Child; Child, Preschool; Guidelines as Topic; Humans; Myelin Basic Protein; Pediatrics; Phosphopyruvate Hydratase; Point-of-Care Systems; S100 Proteins; Ultrasonography, Doppler, Transcranial

Emerging data suggest that biomarkers of brain injury have potential utility as diagnostic, prognostic, and therapeutic adjuncts in the setting of traumatic and ischemic brain injury. Two approaches are being used, namely, assessing markers of structural damage and quantifying mediators of the cellular, biochemical, or molecular cascades in secondary injury or repair. Novel proteomic, multiplex, and lipidomic methods are also being applied.. Biochemical markers of neuronal, glial, and axonal damage such as neuron-specific enolase, S100B, and myelin basic protein, respectively, are readily detectable in biological samples such as serum or cerebrospinal fluid and are being studied in patients with ischemic and traumatic brain injury. In addition, a number of studies have demonstrated that novel tools to assess simultaneously multiple biomarkers can provide unique insight such as details on specific molecular participants in cell death cascades, inflammation, or oxidative stress.. Multifaceted cellular, biochemical, and molecular monitoring of proteins and lipids is logical as an adjunct to guiding therapies and improving outcomes in traumatic and ischemic brain injury and we appear to be on the verge of a breakthrough with the use of these markers as diagnostic, prognostic, and monitoring adjuncts, in neurointensive care.

Topics: Biomarkers; Brain Injuries; Brain Ischemia; Decision Making; Humans; Inflammation; Myelin Basic Protein; Nerve Growth Factors; Oxidative Stress; Phosphopyruvate Hydratase; Prognosis; Proteomics; S100 Calcium Binding Protein beta Subunit; S100 Proteins

After head injury, many complex neurochemical events occur locally, at the site of initial injury, and globally, as a result of secondary phenomena. Neurochemical alterations in the cerebrospinal fluid after injury can be utilized to reflect these events. The authors review the role of the cerebrospinal fluid in the treatment of head injury as it relates to the diagnosis, prognosis, and further elucidation of the pathophysiological manifestations of head injury at the cellular and biochemical level.

Topics: Acetylcholine; Brain Edema; Brain Injuries; Calcium; Cerebrospinal Fluid Proteins; Dopamine; Fatty Acids, Unsaturated; Histamine; Humans; Kallikreins; Kinins; Lactates; Lactic Acid; Myelin Basic Protein; Neurotransmitter Agents; Norepinephrine; Potassium; Prostaglandins; Pyruvates; Pyruvic Acid; Serotonin

The objectives of this study were to determine effects of severe traumatic brain injury (TBI) on cerebrospinal fluid (CSF) concentrations of myelin basic protein (MBP) and to assess relationships between clinical variables and CSF MBP concentrations.. We measured serial CSF MBP concentrations in children enrolled in a randomized controlled trial evaluating therapeutic hypothermia (TH) after severe pediatric TBI. Control CSF was obtained from children evaluated, but found not to be having CNS infection. Generalized estimating equation models and Wilcoxon Rank-Sum test were used for comparisons of MBP concentrations.. There were 27 TBI cases and 57 controls. Overall mean (± SEM) TBI case MBP concentrations for 5 days after injury were markedly greater than controls (50.49 ± 6.97 vs. 0.11 ± 0.01 ng/ml, p < 0.01). Mean MBP concentrations were lower in TBI patients <1 year versus >1 year (9.18 ± 1.67 vs. 60.22 ± 8.26 ng/ml, p = 0.03), as well as in cases with abusive head trauma (AHT) versus non-abusive TBI (14.46 ± 3.15 vs. 61.17 ± 8.65 ng/ml, p = 0.03). TH did not affect MBP concentrations.. Mean CSF MBP increases markedly after severe pediatric TBI, but is not affected by TH. Infancy and AHT are associated with low MBP concentrations, suggesting that age-dependent myelination influences MBP concentrations after injury. Given the magnitude of MBP increases, axonal injury likely represents an important therapeutic target in pediatric TBI.

Topics: Age Factors; Biomarkers; Brain Injuries; Child; Child Abuse; Child, Preschool; Diffuse Axonal Injury; Female; Humans; Hypothermia, Induced; Infant; Male; Myelin Basic Protein; Sex Factors; Trauma Severity Indices

In the treatment of severe traumatic brain injury (TBI), the choice of fluid and osmotherapy is important. There are practical and theoretical advantages to the use of hypertonic saline. S100B, neuron-specific enolase (NSE), and myelin-basic protein (MBP) are commonly assessed biomarkers of brain injury with potential utility as diagnostic and prognostic indicators of outcome after TBI, but they have not previously been studied in the context of fluid resuscitation. This randomized controlled trial compared serum concentrations of S100B, NSE, and MBP in adult severe TBI patients resuscitated with 250 mL of 7.5% hypertonic saline plus 6% dextran70 (HSD; n = 31) versus 0.9% normal saline (NS; n = 33), and examined their relationship with neurological outcome at discharge. Blood samples drawn on admission (

Topics: Adult; Analysis of Variance; Biomarkers; Brain Injuries; Dextrans; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Fluid Therapy; Humans; Injury Severity Score; Myelin Basic Protein; Nerve Growth Factors; Phosphopyruvate Hydratase; Regression Analysis; Resuscitation; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Saline Solution, Hypertonic; Treatment Outcome

Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti-inflammatory phenotypes. Toll-like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild-type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4-/-) mice were used to investigate the potential role of TLR4-induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti-inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T

Topics: Animals; Anti-Inflammatory Agents; Brain Injuries; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Myelin Basic Protein; Neuroinflammatory Diseases; Subarachnoid Hemorrhage; Toll-Like Receptor 4; White Matter

In forensic pathology, traumatic brain injury (TBI) is a frequently encountered cause of death. Unfortunately, the statistic autopsy data, risk investigation about injury patterns, and circumstances of TBI are still sparse. Estimates of survival time post-TBI and postmortem diagnosis of TBI are especially important implications in forensic medicine. Neurogranin (Ng) and myelin basic protein (MBP) represent potential biomarkers of TBI. The present study analyzed retrospectively the forensic autopsy records of TBI cases at a university center of medico-legal investigation from 2008 to 2020. Immunohistochemistry and enzyme-linked immunosorbent assays (ELISA) were used to investigate the expression changes of Ng and MBP in the cortical brain injury adjacent tissues and serum, respectively, from cases of TBI at autopsy with different survival times post-TBI. The results show that the major mechanism of death of TBI is assault, and accident was the major manner of death. Ng and MBP are mainly expressed in the cortical nerve cells and the myelin sheath, respectively. The serum levels of Ng and MBP in each TBI group were higher compared with those in the controls. The brain cortical levels of Ng and MBP decreased at first and then steadily increased with extended survival time post-TBI. The immunopositive ratios and serum concentration of Ng and MBP have shown significant differences among control group and all TBI group (p < 0.001). Collectively, the immunohistochemical analyses of Ng and MBP in human brain tissues may be useful to determine the survival time after TBI, and Ng and MBP level in the human blood specimens could be considered as a postmortem diagnostic tools of TBI in forensic practice.

Topics: Autopsy; Biomarkers; Brain Injuries; Brain Injuries, Traumatic; Humans; Myelin Basic Protein; Neurogranin; Retrospective Studies

The objective of this study was to investigate changes in serum biomarkers of acute brain injury, including white matter and astrocyte injury during chronic foetal hypoxaemia. We have previously shown histopathological changes in myelination and neuronal density in fetuses with chronic foetal hypoxaemia at a level consistent with CHD.. Mid-gestation foetal sheep (110 ± 3 days gestation) were cannulated and attached to a pumpless, low-resistance oxygenator circuit, and incubated in a sterile fluid environment mimicking the intrauterine environment. Fetuses were maintained with an oxygen delivery of 20-25 ml/kg/min (normoxemia) or 14-16 ml/kg/min (hypoxaemia). Myelin Basic Protein and Glial Fibrillary Acidic Protein serum levels in the two groups were assessed by ELISA at baseline and at 7, 14, and 21 days of support.. Based on overlapping 95% confidence intervals, there were no statistically significant differences in either Myelin Basic Protein or Glial Fibrillary Acidic Protein serum levels between the normoxemic and hypoxemic groups, at any time point. No statistically significant correlations were observed between oxygen delivery and levels of Myelin Basic Protein and Glial Fibrillary Acidic Protein.. Chronic foetal hypoxaemia during mid-gestation is not associated with elevated serum levels of acute white matter (Myelin Basic Protein) or astrocyte injury (Glial Fibrillary Acidic Protein), in this model. In conjunction with our previously reported findings, our data support the hypothesis that the brain dysmaturity with impaired myelination found in fetuses with chronic hypoxaemia is caused by disruption of normal developmental pathways rather than by direct cellular injury.

Topics: Animals; Biomarkers; Brain Injuries; Female; Fetus; Glial Fibrillary Acidic Protein; Humans; Hypoxia; Myelin Basic Protein; Oxygen; Pregnancy; Sheep

Mild traumatic brain injury (TBI) is a major risk factor for post-traumatic stress disorder (PTSD), and both disorders share common symptoms and neurobiological defects. Relapse after successful treatment, known as long-term fear resurgence, is common in PTSD patients and a major therapeutic hurdle. We induced a mild focal TBI by controlled cortical impact (CCI) in male C57BL/6 J mice and used fear conditioning to assess PTSD-like behaviors and concomitant alterations in the fear circuitry. We found for the first time that mild TBI, and to a lesser extent sham (craniotomy), mice displayed a spontaneous resurgence of conditioned fear when tested for fear extinction memory recall, despite having effectively acquired and extinguished conditioned fear 6 weeks earlier in the same context. Other characteristic symptoms of PTSD are risk-taking behaviors and cognitive deficits. CCI mice displayed risk-taking behaviors, behavioral inflexibility and reductions in processing speed compared to naïve mice. In conjunction with these changes there were alterations in amygdala morphology 3 months post-trauma, and decreased myelin basic protein density at the primary lesion site and in distant secondary sites such as the hippocampus, thalamus, and amygdala, compared to sham mice. Furthermore, activity-dependent brain-derived neurotrophic factor (BDNF) transcripts were decreased in the prefrontal cortex, a key region for fear extinction consolidation, following fear extinction training in both TBI and, to a lesser extent, sham mice. This study shows for the first time that a mild brain injury can generate a spontaneous resurgence of conditioned fear associated with defective BDNF signalling in the prefrontal cortex, PTSD-like behaviors, and have enduring effects on the brain.

Topics: Animals; Brain; Brain Injuries; Conditioning, Classical; Disease Models, Animal; Extinction, Psychological; Fear; Male; Maze Learning; Mental Recall; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Psychomotor Disorders; Risk-Taking; RNA, Messenger; Statistics, Nonparametric; Time Factors

Once excessive, neurological disorders associated with inflammatory conditions will inevitably cause secondary inflammatory damage to brain tissue. Immunosuppressive therapy can reduce the inflammatory state, but resulting infections can expose the patient to greater risk. Using specific immune tolerance organs or tissues from the body, brain antigen immune tolerance treatment can create a minimal immune response to the brain antigens that does not excessively affect the body's immunity. However, commonly used immune tolerance treatment approaches, such as those involving the nasal, gastrointestinal mucosa, thymus or liver portal vein injections, affect the clinical conversion of the therapy due to uncertain drug absorption, or inconvenient routes of administration. If hepatic portal intravenous injections of brain antigens could be replaced by normal peripheral venous infusion, the convenience of immune tolerance treatment could certainly be greatly increased. We attempted to encapsulate brain antigens with minimally immunogenic nanomaterials, to control the sizes of nanoparticles within the range of liver Kupffer cell phagocytosis and to coat the antigens with a coating material that had an affinity for liver cells. We injected these liver drug-loaded nanomaterials via peripheral intravenous injection. With the use of microparticles with liver characteristics, the brain antigens were transported into the liver out of the detection of immune armies in the blood. This approach has been demonstrated in rat models of surgical brain injury. It has been proven that the immune tolerance of brain antigens can be accomplished by peripheral intravenous infusion to achieve the effect of treating brain trauma after operations, which simplifies the clinical operation and could elicit substantial improvements in the future.

Topics: Animals; Brain Injuries; Cells, Cultured; Cytophagocytosis; Disease Models, Animal; Humans; Immune Tolerance; Inflammation; Injections, Intravenous; Kupffer Cells; Liver; Mice; Mice, Nude; Myelin Basic Protein; Nanoparticles; Neurodegenerative Diseases; Particle Size; T-Lymphocytes

Unexpected neurological morbidity in Pediatric Intensive Care Units (PICUs) remains high and is difficult to detect proactively. Brain-specific biomarkers represent a novel approach for early detection of neurological injury. We sought to determine whether serum concentrations of neuron-specific enolase (NSE), myelin basic protein (MBP), and S100B, specific for neurons, oligodendrocytes, and glia, respectively, were predictive of neurological morbidity in critically ill children.. Serum was prospectively collected on days 1-7 from diagnostically diverse PICU patients (n = 103). Unfavorable neurological outcome at hospital discharge was defined as Pediatric Cerebral Performance Category (PCPC) score of 3-6 with a deterioration from baseline. NSE, MBP, and S100B concentrations were measured by enzyme-linked immunosorbent assay.. Peak biomarker levels were greater in patients with unfavorable versus favorable neurological outcome [NSE 39.4 ± 44.1 vs. 12.2 ± 22.9 ng/ml (P = 0.005), MBP 9.1 ± 11.5 vs. 0.6 ± 1.3 ng/ml (P = 0.003), S100B 130 ± 232 vs. 34 ± 70 pg/ml (P = 0.04), respectively; mean ± SD]. Peak levels were each independently associated with unfavorable neurological outcome when controlling for presence of primary neurologic admission diagnosis and poor baseline PCPC using logistic regression analysis (NSE, P = 0.04; MBP, P = 0.004; S100B, P = 0.04), and had the following receiver operating characteristics: NSE 0.75 (0.58, 0.92), MBP 0.81 (0.66, 0.94), and S100B 0.80 (0.67, 0.93) (area under the curve [95% confidence intervals]).. Prospectively collected brain-specific serum biomarkers predict unfavorable neurological outcome in critically ill children. Serum biomarkers used in conjunction with clinical data could be used to generate models predicting early detection of neurological injury, allowing for more timely diagnostic and therapeutic interventions, potentially reducing neurological morbidity in the PICU.

Topics: Biomarkers; Brain Injuries; Child; Child, Preschool; Female; Humans; Infant; Intensive Care Units, Pediatric; Male; Myelin Basic Protein; Phosphopyruvate Hydratase; Pilot Projects; Prospective Studies; S100 Calcium Binding Protein beta Subunit

Periventricular white matter injury (PWMI) is very common in survivors of premature birth, and the final outcomes are a reduction in myelinated neurons leading to white matter hypomyelination. How and (or) why the oligodendrocyte lineage develops abnormally and myelination is reduced is a hot topic in the field. This study focuses on the effect of intrauterine inflammation on the proliferation of oligodendrocyte lineage cells and the underlying mechanisms. Lipopolysaccharide (LPS) (300 μg/kg) was intraperitoneally injected into pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish a rat model of intrauterine infection-induced white matter injury. Corpus callosum tissues were collected at postnatal day 14 (P14) to quantify the number of oligodendrocytes, the number and proliferation of oligodendrocyte precursor cells (OPCs), and the expression of myelin proteins (MBP and PLP). Furthermore, the expression of Wnt and Notch signaling-related proteins was analyzed. The results showed that the number of oligodendrocytes in the corpus callosum tissues of LPS-treated rats was reduced, and the expression levels of myelinating proteins were down-regulated. Further analysis showed that the Notch signaling pathway was down-regulated in the LPStreated group. These results indicate that intrauterine LPS may inhibit the proliferation of OPCs by down-regulating the Notch rather than the Wnt signaling pathway, leading to hypomyelination of white matter.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Cell Lineage; Cell Proliferation; Corpus Callosum; Female; Gene Expression Regulation, Developmental; Humans; Infections; Leukoencephalopathies; Lipopolysaccharides; Myelin Basic Protein; Myelin Proteolipid Protein; Oligodendrocyte Precursor Cells; Pregnancy; Rats; Receptors, Notch; Signal Transduction

In rodent models of traumatic brain injury (TBI), both Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) levels increase early after injury to return later to basal levels. We have developed and characterized a rat mild fluid percussion model of TBI (mLFP injury) that results in righting reflex response times (RRRTs) that are less than those characteristic of moderate to severe LFP injury and yet increase IL-1α/β and TNFα levels. Here we report that blockade of IL-1α/β and TNFα binding to IL-1R and TNFR1, respectively, reduced neuropathology in parietal cortex, hippocampus, and thalamus and improved outcome. IL-1β binding to the type I IL-1 receptor (IL-1R1) can be blocked by a recombinant form of the endogenous IL-1R antagonist IL-1Ra (Kineret). TNFα binding to the TNF receptor (TNFR) can be blocked by the recombinant fusion protein etanercept, made up of a TNFR2 peptide fused to an Fc portion of human IgG1. There was no benefit from the combined blockades compared with individual blockades or after repeated treatments for 11 days after injury compared with one treatment at 1 hr after injury, when measured at 6 hr or 18 days, based on changes in neuropathology. There was also no further enhancement of blockade benefits after 18 days. Given that both Kineret and etanercept given singly or in combination showed similar beneficial effects and that TNFα also has a gliotransmitter role regulating AMPA receptor traffic, thus confounding effects of a TNFα blockade, we chose to focus on a single treatment with Kineret.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Brain Injuries; Calcium-Binding Proteins; Disease Models, Animal; Etanercept; Gene Expression Regulation; Interleukin 1 Receptor Antagonist Protein; Male; Microfilament Proteins; Microtubule-Associated Proteins; Motor Activity; Myelin Basic Protein; Myelin Sheath; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Receptors, Cytokine; Reflex; Time Factors

Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies.

Topics: Animals; Animals, Newborn; Apoptosis; Axons; Brain Injuries; Calcium-Binding Proteins; Calpain; Caspases; Enzyme Activation; Erythropoietin; Female; Hypoxia-Ischemia, Brain; Membrane Proteins; Myelin Basic Protein; Rats, Sprague-Dawley

Intra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.. Pregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.. Intra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.. Intra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury.

Topics: Animals; Brain Injuries; Calcium-Binding Proteins; Candida albicans; Candidiasis; Caspase 3; Disease Models, Animal; DNA-Binding Proteins; Encephalitis; Enzyme-Linked Immunosorbent Assay; Female; Fluoresceins; Granulocyte Colony-Stimulating Factor; Interleukin-3; Interleukin-6; Ki-67 Antigen; Male; Microfilament Proteins; Myelin Basic Protein; Nerve Tissue Proteins; Pregnancy; Prenatal Exposure Delayed Effects; Recombinant Fusion Proteins; Sheep

Macrophages are involved in demyelination in many brain diseases. However, the role of macrophages in the recovery phase of the ischemic brain is unknown. The present study aims to explore the role of macrophages in the ischemic brain injury and tissue repair following a 90-min transient middle cerebral artery occlusion in mice.. Clodronate liposomes were injected into mice to deplete periphery macrophages. These mice subsequently underwent middle cerebral artery occlusion. F4/80(+) and CD68(+) cells were examined in the mouse spleen and brain to confirm macrophage depletion at 14 days after middle cerebral artery occlusion. Modified neurological severity scores were used to evaluate the behavioral function between 1 and 14 days after middle cerebral artery occlusion. MBP, Iba1, and CD31 immunostaining were performed to determine myelin lesion, microglia activation, and microvessel density.. Clodronate liposomes depleted 80 % of the macrophages in the mouse spleen and reduced macrophage infiltration in the mouse brain. Macrophage depletion reduced the myelin damage in the ipsilateral striatum and microglia activation in both the ipsilateral cortex and striatum, enhanced the microvessel density in the peri-infarct region, attenuated brain atrophy, and promoted neurological recovery following middle cerebral artery occlusion.. Our results suggested that macrophage depletion is a potential intervention that can promote tissue repair and remodeling after brain ischemia, reduce demyelination and microglia activation, and enhance focal microvessel density.

Topics: Analysis of Variance; Animals; Antigens, CD; Bone Density Conservation Agents; Brain; Brain Injuries; Calcium-Binding Proteins; Clodronic Acid; Disease Models, Animal; Flow Cytometry; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Macrophages; Male; Mice; Mice, Inbred ICR; Microfilament Proteins; Microglia; Microvessels; Myelin Basic Protein; Time Factors

Chemotherapy-induced cognitive impairment, also known as 'chemobrain', is now widely recognized as a frequent adverse side effect of cancer treatment that often persists into survivorship. There are no drugs available to prevent or treat chemotherapy-induced cognitive deficits. The aim of this study was to establish a mouse model of cisplatin-induced cognitive deficits and to determine the potential preventive effects of the anti-diabetic drug metformin.. Treatment of C57/BL6J mice with cisplatin (cumulative dose 34.5 mg/kg) impaired performance in the novel object and place recognition task as well as in the social discrimination task indicating cognitive deficits. Co-administration of metformin prevented these cisplatin-induced cognitive impairments. At the structural level, we demonstrate that cisplatin reduces coherency of white matter fibers in the cingulate cortex. Moreover, the number of dendritic spines and neuronal arborizations as quantified on Golgi-stained brains was reduced after cisplatin treatment. Co-administration of metformin prevented all of these structural abnormalities in cisplatin-treated mice. In contrast to what has been reported in other models of chemobrain, we do not have evidence for persistent microglial or astrocyte activation in the brains of cisplatin-treated mice. Finally, we show that co-administration of metformin also protects against cisplatin-induced peripheral neuropathy.. In summary, we show here for the first time that treatment of mice with cisplatin induces cognitive deficits that are associated with structural abnormalities in the brain. Moreover, we present the first evidence that the widely used and safe anti-diabetic drug metformin protects against these deleterious effects of cancer treatment. In view of the ongoing clinical trials to examine the potential efficacy of metformin as add-on therapy in patients treated for cancer, these findings should allow rapid clinical translation.

Topics: Animals; Behavior, Animal; Brain; Brain Injuries; Cisplatin; Cognition Disorders; Disease Models, Animal; Female; Hyperalgesia; Hypoglycemic Agents; Metformin; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Pyramidal Cells

Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg) at the onset of hyperoxia (24 hours, 80% oxygen) in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity.

Topics: Animals; Animals, Newborn; Behavior, Animal; Brain Injuries; Cell Survival; Cognition; Diffusion Tensor Imaging; Disease Models, Animal; Down-Regulation; Erythropoietin; Hyperoxia; Immunohistochemistry; Microscopy, Confocal; Mitochondria; Myelin Basic Protein; Neuregulin-1; Neuronal Plasticity; Neuropilin-1; Neuroprotective Agents; Oligodendroglia; Rats; Rats, Wistar; Synaptophysin; White Matter

Surgical brain injury (SBI) defines complications induced by intracranial surgery, such as cerebral edema and other secondary injuries. In our study, intrathymic and hepatic portal vein injection of allogeneic myelin basic protein (MBP) or autogeneic brain cell suspensions were administered to a standard SBI model. Serum pro-inflammatory IL-2, anti-inflammatory IL-4 concentrations and the CD4(+)T/CD8(+)T ratio were measured at 1, 3, 7, 14 and 21 d after surgery to verify the establishment of immune tolerance. Furthermore, we confirmed neuroprotective effects by evaluating neurological scores at 1, 3, 7, 14 and 21 d after SBI. Anti-Fas ligand (FasL) immunohistochemistry and TUNEL assays of brain sections were tested at 21 d after surgery. Intrathymic injections of MBP or autogeneic brain cell suspensions functioned by both suppressing secondary inflammatory reactions and improving prognoses, whereas hepatic portal vein injections of autogeneic brain cell suspensions exerted a better effect than MBP. Intrathymic and hepatic portal vein injections of MBP had equal effects on reducing secondary inflammation and improving prognoses. Otherwise, hepatic portal vein injections of autogeneic brain cell suspensions had better outcomes than intrathymic injections of autogeneic brain cell suspensions. Moreover, the benefit of injecting antigens into the thymus was outweighed by hepatic portal vein injections.

Topics: Animals; Antigens; Brain; Brain Injuries; Cytokines; Fas Ligand Protein; Immune Tolerance; Injections, Intravenous; Interleukin-2; Interleukin-4; Liver; Male; Myelin Basic Protein; Portal Vein; Postoperative Complications; Rats, Sprague-Dawley

Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low-protein-diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth-restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition-induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth-restricted human infants. GLIA 2016;64:2306-2320.

Topics: Adenomatous Polyposis Coli Protein; Animals; Animals, Newborn; Antigens; Antigens, CD; Brain; Brain Injuries; Cytokines; Female; Fetal Growth Retardation; Gene Expression; Lipopolysaccharides; Microglia; Myelin Basic Protein; Neural Pathways; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Pregnancy; Proteoglycans; Rats; Rats, Sprague-Dawley; Transcriptome

To study the relationship between the levels of erythropoietin (EPO) in serum and brain injury in preterm infants.. Three hundred and four preterm infants (gestational age: 28-34 weeks) born between October 2014 and September 2015 were enrolled in this study. Brain injury was diagnosed using cerebral ultrasound and MRI. The levels of EPO, S100 protein, neuron-specific enolase (NSE) and myelin basic protein (MBP) in serum were detected using ELISA. To compare the incidence of brain injury in different serum EPO levels in preterm infants, and the relationship between brain injury and serum EPO levels was analyzed.. The incidence rate of brain injury in preterm infants was 41.1% (125/304). The incidence rate of brain injury in the low EPO level group was significantly higher than that in the middle-high EPO level groups (P<0.01). The serum levels of S100 protein, NSE, and MBP in the brain injury groups were significantly higher than in the control group (P<0.01). The serum EPO levels were negatively correlated with serum S100 protein concentration and NSE levels (P<0.05). According to the multiple logistic regression analysis, low gestational age, low birth weight, asphyxia, prolonged mechanical ventilation, anemia and low serum EPO levels were the risk factor for brain injury in preterm infants.. There is a higher incidence rate of brain injury in preterm infants with lower serum EPO levels. The serum EPO levels may be correlated with brain injury in preterm infants.

Topics: Brain Injuries; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Male; Myelin Basic Protein

This study highlights the possible pathological role of MMP-12 in the context of ischemic stroke. Male rats were subjected to a two-hour middle cerebral artery occlusion (MCAO) procedure. MMP-12 shRNA expressing plasmid formulation was administered to these rats twenty-four hours after reperfusion. The results showed a predominant upregulation of MMP-12 (approximately 47, 58, 143, and 265 folds on days 1, 3, 5, 7 post-ischemia, respectively) in MCAO subjected rats. MMP-12 expression was localized to neurons, oligodendrocytes and microglia, but not astrocytes. Transcriptional inactivation of MMP-12 significantly reduced the infarct size. The percent infarct size was reduced from 62.87±4.13 to 34.67±5.39 after MMP-12 knockdown compared to untreated MCAO subjected rats. Expression of myelin basic protein was increased, and activity of MMP-9 was reduced in ischemic rat brains after MMP-12 knockdown. Furthermore, a significant reduction in the extent of apoptosis was noticed after MMP-12 knockdown. TNFα expression in the ipsilateral regions of MCAO-subjected rats was reduced after MMP-12 knockdown in addition to the reduced protein expression of apoptotic molecules that are downstream to TNFα signaling. Specific knockdown of MMP-12 after focal cerebral ischemia offers neuroprotection that could be mediated via reduced MMP-9 activation and myelin degradation as well as inhibition of apoptosis.

Topics: Animals; Apoptosis; Brain Injuries; Brain Ischemia; Cell Line, Tumor; Gene Knockdown Techniques; Gene Silencing; Male; Matrix Metalloproteinase 12; Matrix Metalloproteinase 9; Myelin Basic Protein; Neurons; Plasmids; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reperfusion; RNA, Small Interfering; Substrate Specificity; Transcription, Genetic; Tumor Necrosis Factor-alpha; Up-Regulation

Diffuse axonal injury is an extremely common type of traumatic brain injury encountered in motor vehicle crashes, sports injuries, and in combat. Although many cases of diffuse axonal injury result in chronic disability, there are no current treatments for this condition. Its basic lesion, traumatic axonal injury, has been aggressively modeled in primate and rodent animal models. The inexorable axonal and perikaryal degeneration and dysmyelination often encountered in traumatic axonal injury calls for regenerative therapies, including therapies based on stem cells and precursors. Here we explore the proof of concept that treatments based on transplants of human oligodendrocyte progenitor cells can replace or remodel myelin and, eventually, contribute to axonal regeneration in traumatic axonal injury.. We derived human oligodendrocyte progenitor cells from the human embryonic stem cell line H9, purified and characterized them. We then transplanted these human oligodendrocyte progenitor cells into the deep sensorimotor cortex next to the corpus callosum of nude rats subjected to traumatic axonal injury based on the impact acceleration model of Marmarou. We explored the time course and spatial distribution of differentiation and structural integration of these cells in rat forebrain.. At the time of transplantation, over 90 % of human oligodendrocyte progenitor cells expressed A2B5, PDGFR, NG2, O4, Olig2 and Sox10, a profile consistent with their progenitor or early oligodendrocyte status. After transplantation, these cells survived well and migrated massively via the corpus callosum in both injured and uninjured brains. Human oligodendrocyte progenitor cells displayed a striking preference for white matter tracts and were contained almost exclusively in the corpus callosum and external capsule, the striatopallidal striae, and cortical layer 6. Over 3 months, human oligodendrocyte progenitor cells progressively matured into myelin basic protein(+) and adenomatous polyposis coli protein(+) oligodendrocytes. The injured environment in the corpus callosum of impact acceleration subjects tended to favor maturation of human oligodendrocyte progenitor cells. Electron microscopy revealed that mature transplant-derived oligodendrocytes ensheathed host axons with spiral wraps intimately associated with myelin sheaths.. Our findings suggest that, instead of differentiating locally, human oligodendrocyte progenitor cells migrate massively along white matter tracts and differentiate extensively into ensheathing oligodendrocytes. These features make them appealing candidates for cellular therapies of diffuse axonal injury aiming at myelin remodeling and axonal protection or regeneration.

Topics: Animals; Brain; Brain Injuries; Cell Differentiation; Cell Line; Cell Movement; Cell Survival; Disease Models, Animal; Human Embryonic Stem Cells; Humans; Immunohistochemistry; Male; Microscopy, Electron; Myelin Basic Protein; Oligodendroglia; Rats; Rats, Nude; Receptor, Platelet-Derived Growth Factor alpha; Stem Cell Transplantation; Stem Cells

Despite advances in neonatal care, hypoxic-ischemic brain injury is still a serious clinical problem, which is responsible for many cases of perinatal mortality, cerebral palsy, motor impairment and cognitive deficits. Resveratrol, a natural polyphenol with important anti-oxidant and anti-inflammatory properties, is present in grapevines, peanuts and pomegranates. The aim of the present work was to evaluate the possible neuroprotective effect of resveratrol when administered before or immediately after a hypoxic-ischemic brain event in neonatal rats by analyzing brain damage, the mitochondrial status and long-term cognitive impairment. Our results indicate that pretreatment with resveratrol protects against brain damage, reducing infarct volume, preserving myelination and minimizing the astroglial reactive response. Moreover its neuroprotective effect was found to be long lasting, as behavioral outcomes were significantly improved at adulthood. We speculate that one of the mechanisms for this neuroprotection may be related to the maintenance of the mitochondrial inner membrane integrity and potential, and to the reduction of reactive oxygen species. Curiously, none of these protective features was observed when resveratrol was administered immediately after hypoxia-ischemia.

Topics: Animals; Animals, Newborn; Astrocytes; Behavior, Animal; Brain; Brain Injuries; Cognition Disorders; Disease Models, Animal; Female; Hypoxia-Ischemia, Brain; Male; Membrane Potential, Mitochondrial; Mitochondria; Myelin Basic Protein; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Resveratrol; Stilbenes

Morbidity and mortality in children with cardiac arrest largely result from neurologic injury. Serum biomarkers of brain injury can potentially measure injury to neurons (neuron-specific enolase), astrocytes (S100b), and axons (myelin basic protein). We hypothesized that serum biomarkers can be used to classify outcome from pediatric cardiac arrest.. Prospective observational study.. Single tertiary pediatric hospital.. Forty-three children with cardiac arrest.. None.. We measured serum neuron-specific enolase, S100b, and myelin basic protein on days 1-4 and 7 after cardiac arrest. We recorded demographics, details of the cardiac arrest and resuscitation, and Pediatric Cerebral Performance Category at hospital discharge and 6 months. We analyzed the association of biomarker levels at 24, 48, and 72 hours with favorable (Pediatric Cerebral Performance Category 1-3) or unfavorable (Pediatric Cerebral Performance Category 4-6) outcome and mortality. Forty-three children (49% female; mean age of 5.9 ± 6.3) were enrolled and 17 (40%) died. Serum S100b concentrations peaked earliest, followed by neuron-specific enolase and finally myelin basic protein. Serum neuron-specific enolase and S100b concentrations were increased in the unfavorable versus favorable outcome group and in subjects who died at all time points (all p < 0.05). Serum myelin basic protein at 24 and 72 hours correctly classified survival but not good versus poor outcome. Using best specificity, serum S100b and neuron-specific enolase had optimal positive and negative predictive values at 24 hours to classify both favorable versus unfavorable outcome and survival, whereas serum myelin basic protein's best accuracy occurred at 48 hours. Receiver operator curves for serum S100b and neuron-specific enolase to classify favorable versus unfavorable outcome at 6 months were superior to clinical variables.. Preliminary data show that serum S100b, neuron-specific enolase, and myelin basic protein may aid in outcome classification of children surviving cardiac arrest.

Topics: Biomarkers; Brain Injuries; Cardiopulmonary Resuscitation; Child; Child, Preschool; Female; Heart Arrest; Hospital Mortality; Hospitals, Pediatric; Humans; Intensive Care Units, Pediatric; Male; Myelin Basic Protein; Nerve Growth Factors; Phosphopyruvate Hydratase; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Assessment; S100 Calcium Binding Protein beta Subunit; Sensitivity and Specificity; Severity of Illness Index; Survival Analysis; Treatment Outcome

Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) are present in some neuromyelitis optica patients who lack antibodies against aquaporin-4 (AQP4-IgG). The effects of neuromyelitis optica MOG-IgG in the central nervous system have not been investigated in vivo. We microinjected MOG-IgG, obtained from patients with neuromyelitis optica, into mouse brains and compared the results with AQP4-IgG.. MOG-IgG caused myelin changes and altered the expression of axonal proteins that are essential for action potential firing, but did not produce inflammation, axonal loss, neuronal or astrocyte death. These changes were independent of complement and recovered within two weeks. By contrast, AQP4-IgG produced complement-mediated myelin loss, neuronal and astrocyte death with limited recovery at two weeks.. These differences mirror the better outcomes for MOG-IgG compared with AQP4-IgG patients and raise the possibility that MOG-IgG contributes to pathology in some neuromyelitis optica patients.

Topics: Animals; Aquaporin 4; Astrocytes; Brain Injuries; Cell Adhesion Molecules, Neuronal; Humans; Immunoglobulin G; Mice; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Nerve Tissue Proteins; Neuromyelitis Optica; Neurons; Sodium Channels; Time Factors

Dietary supplementation with omega-3 (ω-3) fatty acids is a safe, economical mean of preventive medicine that has shown protection against several neurologic disorders. The present study tested the hypothesis that this method is protective against controlled cortical impact (CCI). Indeed, mice fed with ω-3 polyunsaturated fatty acid (PUFA)-enriched diet for 2 months exhibited attenuated short and long-term behavioral deficits due to CCI. Although ω-3 PUFAs did not decrease cortical lesion volume, these fatty acids did protect against hippocampal neuronal loss after CCI and reduced pro-inflammatory response. Interestingly, ω-3 PUFAs prevented the loss of myelin basic protein (MPB), preserved the integrity of the myelin sheath, and maintained the nerve fiber conductivity in the CCI model. ω-3 PUFAs also directly protected oligodendrocyte cultures from excitotoxicity and blunted the microglial activation-induced death of oligodendrocytes in microglia/oligodendrocyte cocultures. In sum, ω-3 PUFAs elicit multifaceted protection against behavioral dysfunction, hippocampal neuronal loss, inflammation, and loss of myelination and impulse conductivity. The present report is the first demonstration that ω-3 PUFAs protect against white matter injury in vivo and in vitro. The protective impact of ω-3 PUFAs supports the clinical use of this dietary supplement as a prophylaxis against traumatic brain injury and other nervous system disorders.

Topics: Animals; Behavior, Animal; Brain Injuries; Cerebral Cortex; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Hippocampus; Male; Mice; Myelin Basic Protein; Neurons; Oligodendroglia

Nearly two million people suffer traumatic brain injury in the US each year. These injuries alter adversely the metabolism of myelin, a major lipid material in brain, both in people and in experimental injuries of animals. A newly discovered and severe human neuropathy from copper deficiency provides evidence that some people in the US are malnourished in copper. As it is well known among copper cognoscenti that it is impossible to synthesize myelin if copper nutriture is inadequate, it seems reasonable to assume that repair will be poor in this situation. Copper status of patients should be evaluated and experiments with injured animals should be repeated with graded doses of copper to determine if copper metabolism is important in this illness.

Topics: Biosynthetic Pathways; Brain Injuries; Copper; Humans; Models, Biological; Myelin Basic Protein; Myelin Sheath

Schwannosis is a condition characterized by a benign proliferation of Schwann cells and an incomplete myelination of central nervous system axons following different chronic stimuli. It. has been mainly observed in the spinal cord. Various hypotheses have been put forward with respect to the appearance of Schwann cells inside the central nervous system since they exclusively populate the peripheral nervous system. According to these hypotheses, schwannosis seems to be either the result of aberrant migration under certain conditions, especially in response to spinal cord injury, or as a developmental abnormality in form of ectopia during ontogenesis.We report, for the first time, on the multifocal occurrence of this rare nosological entity in the brain stem. Furthermore we compare the histological and immunohistochemical profile of schwannosis to that of an intracerebral schwannoma taken from our archive.

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; Adult; Brain Injuries; Brain Stem; Cell Proliferation; Humans; Ki-67 Antigen; Male; Myelin Basic Protein; Neurofilament Proteins; S100 Proteins; Schwann Cells

The biology of cerebral white matter injury has been woefully understudied, in part because of the difficulty of reliably modeling this type of injury in rodents. Periventricular leukomalacia (PVL) is the predominant form of brain injury and the most common cause of cerebral palsy in premature infants. PVL is characterized by predominant white matter injury. No specific therapy for PVL is presently available, because the pathogenesis is not well understood. Here we report that two types of mouse PVL models have been created by hypoxia-ischemia with or without systemic coadministration of lipopolysaccharide (LPS). LPS coadministration exacerbated hypoxic-ischemic white matter injury and led to enhanced microglial activation and astrogliosis. Drug trials with the antiinflammatory agent minocycline, the antiexcitotoxic agent NBQX, and the antioxidant agent edaravone showed various degrees of protection in the two models, indicating that excitotoxic, oxidative, and inflammatory forms of injury are involved in the pathogenesis of injury to immature white matter. We then applied immunoelectron microscopy to reveal fine structural changes in the injured white matter and found that synapses between axons and oligodendroglial precursor cells (OPCs) are quickly and profoundly damaged. Hypoxia-ischemia caused a drastic decrease in the number of postsynaptic densities associated with the glutamatergic axon-OPC synapses defined by the expression of vesicular glutamate transporters, vGluT1 and vGluT2, on axon terminals that formed contacts with OPCs in the periventricular white matter, resulted in selective shrinkage of the postsynaptic OPCs contacted by vGluT2 labeled synapses, and led to excitotoxicity mediated by GluR2-lacking, Ca(2+) -permeable AMPA receptors. Overall, the present study provides novel mechanistic insights into the pathogenesis of PVL and reveals that axon-glia synapses are highly vulnerable to white matter injury in the developing brain. More broadly, the study of white matter development and injury has general implications for a variety of neurological diseases, including PVL, stroke, spinal cord injury, and multiple sclerosis.

Topics: Animals; Animals, Newborn; Antigens; Brain Injuries; Carotid Artery Diseases; Disease Models, Animal; Excitatory Amino Acid Antagonists; Functional Laterality; Glial Fibrillary Acidic Protein; Hypoxia-Ischemia, Brain; Leukoencephalopathies; Luminescent Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Minocycline; Myelin Basic Protein; Nerve Fibers, Myelinated; Neuroglia; Polysaccharides; Proteoglycans; Quinoxalines; Receptors, AMPA; Synapses; Vesicular Glutamate Transport Protein 1; Vesicular Glutamate Transport Protein 2

Intracranial surgery causes cortical injury from incisions, hemorrhage, retraction, and electrocautery. The term "surgical brain injury" (SBI) has been developed to categorize this injury inherent to the procedure. Neuroinflammation plays a significant role in SBI. Traditional antiinflammatory therapies are often limited by their immunosuppressive side effects and poor CNS penetration. This study uses mucosal tolerance to develop an immune system that is tolerant to brain myelin basic protein (MBP) so that inflammation can be suppressed in a timely and site-specific manner following surgical disruption of the blood-brain barrier.. A standard SBI model using CD57 mice was used. Nasopharyngeal mucosa was exposed to vehicle, ovalbumin, or MBP to develop mucosal tolerance to these antigens. Immunological tolerance to MBP was confirmed in vivo through hypersensitivity testing. Neurological scores, cerebral edema, and interleukin (IL)-1β and transforming growth factor (TGF)-β1 cytokine levels were measured 48 hours postoperatively.. Hypersensitivity testing confirmed the development of immune tolerance to MBP. Myelin basic protein-tolerant mice demonstrated reduced neurological injury, less cerebral edema, decreased levels of IL-1β, and increased levels of TGFβ1 following SBI.. Developing preoperative immunological tolerance to brain antigens through mucosal tolerance provides neuroprotection, reduces brain edema, and modulates neuroinflammation following SBI.

Topics: Animals; Brain; Brain Edema; Brain Injuries; Cytokines; Encephalitis; Immune Tolerance; Immunity, Mucosal; Mice; Myelin Basic Protein

After stroke and brain injury, cortical gray matter recovery involves mechanisms of neurovascular matrix remodeling. In white matter, however, the mechanisms of recovery remain unclear. In this study, we demonstrate that oligodendrocytes secrete matrix metalloproteinase-9 (MMP-9), which accelerates the angiogenic response after white matter injury. In primary oligodendrocyte cultures, treatment with the proinflammatory cytokine interleukin-1β (IL-1β) induced an upregulation and secretion of MMP-9. Conditioned media from IL-1β-stimulated oligodendrocytes significantly amplified matrigel tube formation in brain endothelial cells, indicating that MMP-9 from oligodendrocytes can promote angiogenesis in vitro. Next, we asked whether similar signals and substrates operate after white matter injury in vivo. Focal white matter injury and demyelination was induced in mice via stereotactic injection of lysophosphatidylcholine into corpus callosum. Western blot analysis showed that IL-1β expression was increased in damaged white matter. Immunostaining demonstrated MMP-9 signals in myelin-associated oligodendrocytic basic protein-positive oligodendrocytes. Treatment with an IL-1β-neutralizing antibody suppressed the MMP-9 response in oligodendrocytes. Finally, we confirmed that the broad spectrum MMP inhibitor GM6001 inhibited angiogenesis around the injury area in this white matter injury model. In gray matter, a neurovascular niche promotes cortical recovery after brain injury. Our study suggests that an analogous oligovascular niche may mediate recovery in white matter.

Topics: Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Brain Injuries; Cell Communication; Cells, Cultured; Cerebral Cortex; Culture Media, Conditioned; Dipeptides; Disease Models, Animal; Endothelium; In Vitro Techniques; Interleukin-1beta; L-Lactate Dehydrogenase; Male; Myelin Basic Protein; Nerve Tissue Proteins; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Platelet Endothelial Cell Adhesion Molecule-1; Protease Inhibitors; Rats; Rats, Sprague-Dawley

Our previous studies showed that the intracerebral injection of apotransferrin (aTf) attenuates white matter damage and accelerates the remyelination process in a neonatal rat model of cerebral hypoxia-ischemia (HI) injury. However, the intracerebral injection of aTf might not be practical for clinical treatments. Therefore, the development of less invasive techniques capable of delivering aTf to the central nervous system would clearly aid in its effective clinical use. In this work, we have determined whether intranasal (iN) administration of human aTf provides neuroprotection to the neonatal mouse brain following a cerebral hypoxic-ischemic event. Apotransferrin was infused into the naris of neonatal mice and the HI insult was induced by right common carotid artery ligation followed by exposure to low oxygen concentration. Our results showed that aTf was successfully delivered into the neonatal HI brain and detected in the olfactory bulb, forebrain and posterior brain 30 min after inhalation. This treatment successfully reduced white matter damage, neuronal loss and astrogliosis in different brain regions and enhanced the proliferation and survival of oligodendroglial progenitor cells (OPCs) in the subventricular zone and corpus callosum (CC). Additionally, using an in vitro hypoxic model, we demonstrated that aTf prevents oligodendrocyte progenitor cell death by promoting their differentiation. In summary, these data suggest that iN administration of aTf has the potential to be used for clinical treatment to protect myelin and to induce remyelination in demyelinating hypoxic-ischemic events in the neonatal brain.

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; Administration, Intranasal; Age Factors; Animals; Animals, Newborn; Antigens; Apoproteins; Autophagy-Related Proteins; Brain Injuries; Bromodeoxyuridine; Caspase 3; Cell Death; Cell Proliferation; Cells, Cultured; Cerebral Cortex; Colchicine; Corpus Callosum; Cytochalasin B; Female; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Hypoxia; Hypoxia-Ischemia, Brain; Intermediate Filament Proteins; Intracellular Signaling Peptides and Proteins; Lateral Ventricles; Male; Mice; Mice, Transgenic; Myelin Basic Protein; Nerve Fibers, Myelinated; Nerve Tissue Proteins; Nestin; Neurogenesis; Neuroprotective Agents; Oligodendroglia; Platelet-Derived Growth Factor; Proteoglycans; SOXB1 Transcription Factors; Time Factors; Transferrin

A peripheral indicator of the presence and magnitude of brain injury has been a sought-after tool by clinicians. We measured neuron-specific enolase (NSE), myelin basic protein (MBP), and S100B, prior to and after scaled cortical impact in immature pigs, to determine if these purported markers increase after injury, correlate with the resulting lesion volume, and if these relationships vary with maturation. Scaled cortical impact resulted in increased lesion volume with increasing age. Concentrations of NSE, but not S100B or MBP, increased after injury in all age groups. The high variability of S100B concentrations prior to injury may have precluded detection of an increase due to injury. Total serum markers were estimated, accounting for the allometric growth of blood volume, and resulted in a positive correlation of both NSE and S100B with lesion volume. Even with allometric scaling of blood volume and a uniform mechanism of injury, NSE had only a fair to poor predictive value. In a clinical setting, where the types of injuries are varied, more investigation is required to yield a panel of serum markers that can reliably predict the extent of injury. Allometric scaling may improve estimation of serum marker release in pediatric populations.

Topics: Aging; Algorithms; Animals; Biomarkers; Blood Volume; Body Weight; Brain Injuries; Cerebral Cortex; Enzyme-Linked Immunosorbent Assay; Female; Male; Myelin Basic Protein; Nerve Growth Factors; Phosphopyruvate Hydratase; Predictive Value of Tests; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Swine

Genetic regulation of autoimmune neuroinflammation is a well known phenomenon, but genetic influences on inflammation following traumatic nerve injuries have received little attention. In this study we examined the inflammatory response in a rat traumatic brain injury (TBI) model, with a particular focus on major histocompatibility class II (MHC II) presentation, in two inbred rat strains that have been extensively characterized in experimental autoimmune encephalomyelitis (EAE); DA and PVG. In addition, MHC and Vra4 congenic strains on these backgrounds were studied to give information on MHC and non-MHC gene contribution. Thus, allelic differences in Vra4, harboring the Ciita gene, was found to regulate expression of the invariant chain at the mRNA level, with a much smaller effect exerted by the MHC locus itself. Notably, however, at the protein level the MHC congenic PVG-RT1(av1) strain displayed much stronger MHCII(+) presentation, as shown both by immunolabeling and flow cytometry, than the PVG strain, dwarfing the effect of Ciita. The PVG-RT1(av1) strain had significantly more T-cell influx than both DA and PVG, suggesting regulation both by MHC and non-MHC genes. Finally, in terms of outcome, the EAE susceptible DA strain displayed a significantly smaller resulting lesion volume than the resistant PVG-RT1(av1) strain. These results provide additional support for a role of adaptive immune response after neurotrauma and demonstrate that outcome is significantly affected by host genetic factors.

Topics: Animals; Brain; Brain Injuries; Flow Cytometry; Genes, MHC Class II; Inflammation; Major Histocompatibility Complex; Male; Myelin Basic Protein; Peptide Fragments; Rats; Rats, Inbred Strains; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes

Neural crest stem cells (NCSCs) give rise to the neurons and glia of the peripheral nervous system (PNS). NCSC-like cells can be isolated from multiple peripheral organs and maintained in neurosphere culture. Combining in vitro culture and transplantation, we show that expanded embryonic NCSC-like cells lose PNS traits and are reprogrammed to generate CNS cell types. When transplanted into the embryonic or adult mouse CNS, they differentiate predominantly into cells of the oligodendrocyte lineage without any signs of tumor formation. NCSC-derived oligodendrocytes generate CNS myelin and contribute to the repair of the myelin deficiency in shiverer mice. These results demonstrate a reprogramming of PNS progenitors to CNS fates without genetic modification and imply that PNS cells could be a potential source for cell-based CNS therapy.

Topics: Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Brain Injuries; Cell Differentiation; Cell Movement; Cells, Cultured; Disease Models, Animal; Embryo, Mammalian; Female; Ganglia, Spinal; Gene Expression Regulation, Developmental; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Nerve Tissue Proteins; Neural Stem Cells; Neurofilament Proteins; O Antigens; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Stem Cell Transplantation; Transfection; Tubulin

After intracerebral hemorrhage (ICH), hemoglobin (Hb) that is released from erythrocytes within the brain hematoma is highly cytotoxic and leads to severe brain edema and direct neuronal damage. Therefore, neutralization of Hb could represent an important target for reducing the secondary injury after ICH. Haptoglobin (Hp), an endogenous Hb-binding protein in blood plasma, is found in this study to be upregulated in the hematoma-affected brain after ICH. Both in vivo and in vitro studies indicate that Hp upregulation is primarily mediated by oligodendrocytes. Hp acts as a secretory protein capable of neutralizing the cell-free Hb. We also found in an "ICH-like" injury that Hp-KO mice show the most severe brain injury and neurological deficits, whereas Hp-Tg mice are the most resistant to ICH injury, suggesting that a higher Hp level is associated with the increased resistance of animals to hemolytic product-mediated brain injury after ICH. We conclude that brain-derived Hp plays a cytoprotective role after ICH, and Hp may represent a new potential therapeutic target for management of ICH.

Topics: Animals; Brain Injuries; Cells, Cultured; Cerebral Hemorrhage; Cytoprotection; Disease Models, Animal; Embryo, Mammalian; Gene Expression Regulation; Haptoglobins; L-Lactate Dehydrogenase; Mice; Mice, Knockout; Myelin Basic Protein; Neuroglia; Neurologic Examination; Neurons; Rats; Rats, Sprague-Dawley

Intracranial surgery causes brain damage from cortical incisions, intraoperative hemorrhage, retraction, and electrocautery; collectively these injuries have recently been coined surgical brain injury (SBI). Inflammation following SBI contributes to neuronal damage. This study develops T-cells that are immunologically tolerant to brain antigen via the exposure of myelin basic protein (MBP) to airway mucosa. We hypothesize that these T-cells will migrate to the site of corticotomy, secrete immunosuppressive cytokines, such as TGFβ1, reduce inflammation, and improve neurological outcomes following SBI. A standard model for SBI was used for this experiment. C57 mice were divided into six groups: SHAM+Vehicle, SHAM+Ovalbumin, SHAM+MBP, SBI+Vehicle, SBI+OVA, and SBI+MBP. Induction of mucosal tolerance to vehicle, ovalbumin, or MBP was performed prior to SBI. Neurological scores and TBFβ1 cytokine levels were measured 48 h postoperatively. Mice receiving craniotomy demonstrated a reduction in neurological score. Animals tolerized to MBP (SBI+MBP) had better postoperative neurological scores than SBI+Vehicle and SBI+OVA. SBI inhibited the cerebral expression TGFβ1 in PBS and OVA treated groups, whereas MBP treated-animals preserved preoperative levels. Mucosal tolerance to MBP leads to significant improvement in neurological outcome that is associated with the preservation of endogenous levels of brain TGFβ1.

Topics: Analysis of Variance; Animals; Brain; Brain Injuries; Craniotomy; Disease Models, Animal; Drug Tolerance; Inflammation; Mice; Mice, Inbred C57BL; Mucous Membrane; Myelin Basic Protein; Neurologic Examination; Ovalbumin; Transforming Growth Factor beta1; Treatment Outcome

Diffusion tensor imaging is highly sensitive to the microstructural integrity of the brain and has uncovered significant abnormalities following traumatic brain injury not appreciated through other methods. It is hoped that this increased sensitivity will aid in the detection and prognostication in patients with traumatic injury. However, the pathological substrates of such changes are poorly understood. Specifically, decreases in fractional anisotropy derived from diffusion tensor imaging are consistent with axonal injury, myelin injury or both in white matter fibres. In contrast, in both humans and animal models, increases in fractional anisotropy have been suggested to reflect axonal regeneration and plasticity, but the direct histological evidence for such changes remains tenuous. We developed a method to quantify the anisotropy of stained histological sections using Fourier analysis, and applied the method to a rat controlled cortical impact model to identify the specific pathological features that give rise to the diffusion tensor imaging changes in subacute to chronic traumatic brain injury. A multiple linear regression was performed to relate the histological measurements to the measured diffusion tensor changes. The results show that anisotropy was significantly increased (P < 0.001) in the perilesioned cortex following injury. Cortical anisotropy was independently associated (standardized β = 0.62, P = 0.04) with the coherent organization of reactive astrocytes (i.e. gliosis) and was not attributed to axons. By comparison, a decrease in white matter anisotropy (P < 0.001) was significantly related to demyelination (β = 0.75, P = 0.0015) and to a lesser extent, axonal degeneration (β = -0.48, P = 0.043). Gliosis within the lesioned cortex also influenced diffusion tensor tractography, highlighting the fact that spurious tracts in the injured brain may not necessarily reflect continuous axons and may instead depict glial scarring. The current study demonstrates a novel method to relate pathology to diffusion tensor imaging findings, elucidates the underlying mechanisms of anisotropy changes following traumatic brain injury and significantly impacts the clinical interpretation of diffusion tensor imaging findings in the injured brain.

Topics: Analysis of Variance; Animals; Anisotropy; Brain Injuries; Brain Mapping; Diffusion Tensor Imaging; Disease Models, Animal; Female; Fourier Analysis; Glial Fibrillary Acidic Protein; Gliosis; Linear Models; Microtubule-Associated Proteins; Myelin Basic Protein; Neurofilament Proteins; Rats; Rats, Wistar; Statistics as Topic

A microscopic immunological study of cerebral spinal fluid (CSF) of 100 patients with traumatic brain injury (TBI) of different severity was carried out in the 1st, 10th and 21st days after trauma. The content of antibodies to basic myelin protein (BMP) and phospholipids (PL) significantly differed from that in the control group (patients with soft tissue head injuries without TBI) and was significantly higher in patients with severe TBI. The level of antibodies to BMP in the CSF was strongly correlated with scores on the Glasgow Coma Scale in the 1st day after TBI and the degree of recovery of neurological status in the 21st day. The level of antibodies to PL was strongly correlated with the severity of cytosis, content of CSF erythrocytes and proteins. The correlation between antibodies to BMP and antibodies to PL was weak. The different diagnostic value of antibodies to BMP and to PL in the most acute period of TBI was found. In conclusion, content of antibodies to BMP may be used as a marker of TBI severity and outcome while the significant elevation of antibodies to PL indicates the severity of vascular complications of trauma.

Topics: Adolescent; Adult; Aged; Antibodies, Antiphospholipid; Autoantibodies; Biomarkers; Brain Injuries; Child; Female; Glasgow Coma Scale; Humans; Male; Middle Aged; Myelin Basic Protein; Prognosis; Trauma Severity Indices; Young Adult

To determine the sensitivity of T2*-weighted gradient-echo (T2*GRE) and inversion recovery turbo-field-echo (TFE) sequences for cortical multiple sclerosis lesions at 7 T.. Autopsied brain tissue from individuals with multiple sclerosis was scanned with 3-dimensional T2*GRE and 3-dimensional inversion recovery white matter-attenuated TFE sequences at 7 T. Cortical lesions visible with either sequence were scored for each anatomical lesion type. Imaged brain tissue was then processed for immunohistochemical analysis, and cortical lesions were identified by labeling with antibody against myelin basic protein and CD68 for microglia. Magnetic resonance images were matched with corresponding histological sections and scored retrospectively to determine the sensitivity for each cortical lesion type. Main Outcome Measure Cortical lesion detection by 3-dimensional T2*GRE and white matter-attenuated TFE sequences.. The 3-dimensional T2*GRE and white matter-attenuated TFE sequences retrospectively detected 93% and 82% of all cortical lesions, respectively (with varying sensitivities for different lesion types). Lesion visibility was primarily determined by size as all undetected lesions were smaller than 1.1 mm at their smallest diameter. The T2*GRE images showed hypointense rings in some cortical lesions that corresponded with increased density of activated microglia.. Three-dimensional T2*GRE and white matter-attenuated TFE sequences at a 7-T field strength detect most cortical lesions in postmortem multiple sclerosis tissue. This study indicates the potential of T2*GRE and white matter-attenuated TFE sequences in ultra-high-field magnetic resonance imaging for cortical lesion detection in patients with multiple sclerosis.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain Injuries; Cerebral Cortex; Female; Humans; Image Processing, Computer-Assisted; Iron; Magnetic Resonance Imaging; Male; Microglia; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Postmortem Changes; Prospective Studies; Time Factors

Traumatic brain injury (TBI) and hypoxic ischemic encephalopathy (HIE) are leading causes of morbidity and mortality in children. Several studies over the past several years have evaluated the use of serum biomarkers to predict outcome after pediatric brain injury. These studies have all used simple point estimates such as initial and peak biomarker concentrations to predict outcome. However, this approach does not recognize patterns of change over time. Trajectory analysis is a type of analysis which can capture variance in biomarker concentrations over time and has been used with success in the social sciences. We used trajectory analysis to evaluate the ability of the serum concentrations of 3 brain-specific biomarkers - S100B, neuron-specific enolase (NSE) and myelin basic protein (MBP) - to predict poor outcome (Glasgow Outcome Scale scores 3-5) after pediatric TBI and HIE. Clinical and biomarker data from 100 children with TBI or HIE were evaluated. For each biomarker, we validated 2-, 3- and 4-group models for outcome prediction, using sensitivity and specificity. For S100B, the 3-group model predicted poor outcome with a sensitivity of 59% and specificity of 100%. For NSE, the 3-group model predicted poor outcome with a sensitivity of 48% and specificity of 98%. For MBP, the 3-group model predicted poor outcome with a sensitivity of 73% and specificity of 61%. Thus, when the models predicted a poor outcome, there was a very high probability of a poor outcome. In contrast, 17% of subjects with a poor outcome were predicted to have a good outcome by all 3 biomarker trajectories. These data suggest that trajectory analysis of biomarker data may provide a useful approach for predicting outcome after pediatric brain injury.

Topics: Biomarkers; Brain Injuries; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; Glasgow Outcome Scale; Humans; Hypoxia, Brain; Male; Models, Statistical; Myelin Basic Protein; Nerve Growth Factors; Phosphopyruvate Hydratase; Recovery of Function; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Sensitivity and Specificity; Time

To study the histopathologic changes of primary brain stem injury and to investigate their significance in the diagnosis of primary brain stem injury.. Sixty-five autopsy cases died of primary brain stem injury and other diseases were enrolled into this study. The cases were subdivided into brain stem injury group (n = 25) and control group (including 20 cases died of cardiovascular disease and 20 cases died of non-cardiovascular diseases). The brain stem tissue sections were stained with hematoxylin-eosin and silver impregnation techniques. Immunohisto chemical study for glial fibrillary acidic protein, neurofilament, amyloid-beta and myelin basic protein was carried out. The widest cross diameters of 10 axons highlighted by immunostaining were measured in each low power field (x 100) through light miscroscopy in all the cases studied.. In comparing with that of the control group, there were differences in the degree of contusion lesion, reactive astrocytosis, edema and pathologic changes of neuronal cells present in the brain stem injury group and was statistically significant (P < 0.05). The axons locating in the brain stem injury group showed a distinctive histology by the appearance of significantly larger diameters (P < 0.05).. Primary brain stem injury demonstrates certain distinctive histopathologic changes and measurement of axonal diameters provides an additional quantitative index useful in autopsy diagnosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Axons; Brain Injuries; Brain Stem; Female; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Male; Middle Aged; Myelin Basic Protein; Neurofilament Proteins; Young Adult

The aim of this study was to study the effects of resveratrol on severe acute pancreatitis (SAP)-induced brain injury.. Ninety-six male Sprague-Dawley rats were randomly divided into 4 equal groups: sham operation, SAP, resveratrol-treated (RES), and dexamethasone-treated. Each group was evaluated at 3, 6, and 12 hours. Levels of serum myelin basic protein and zonula occludens 1 (Zo-1) were determined by enzyme-linked immunosorbent assay. The brain and pancreatic tissues were examined using electron microscopy. Expressions of Bax, Bcl-2, and caspase-3 were observed using immunohistochemistry, reverse transcriptase polymerase chain reaction, and Western blotting. Cytochrome c was detected using Western blotting alone.. Myelin basic protein and Zo-1 levels of the RES group were lower than the SAP group at all time points (P < 0.05). The RES group had significantly improved pathologic brain, increase in Bcl-2 expression, and decrease in Bax and caspases-3 expressions compared with the SAP group.. The degradation of Zo-1 is involved in the pathophysiology of brain injury in SAP; MBP can be used as a marker of brain injury in SAP. The protective effect of resveratrol might be associated with the up-regulation of Bcl-2 and down-regulation of Bax and caspase-3.

Topics: Animals; bcl-2-Associated X Protein; Blotting, Western; Brain; Brain Injuries; Caspase 3; Cytochromes c; Enzyme-Linked Immunosorbent Assay; Male; Membrane Proteins; Microscopy, Electron; Myelin Basic Protein; Neuroprotective Agents; Pancreas; Pancreatitis, Acute Necrotizing; Phosphoproteins; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Time Factors; Vasodilator Agents; Zonula Occludens-1 Protein

Preterm infants exposed to inflammation are at increased risk of white matter injury and/or cerebral palsy. To investigate the effect of chronic inflammation on the developing white matter, we administered low-dose lipopolysaccharide once a day from postnatal days 3 to 11, examined white matter changes at postnatal day 12, and monitored serum levels of insulin-like growth factor 1 and insulin-like factor binding protein-3. A single injection of lipopolysaccharide decreased the serum insulin-like growth factor 1 level but not the insulin-like factor binding protein-3 level. At postnatal day 12, quantification of immunohistochemical staining for axonal, myelin, and oligodendrocyte markers revealed impaired myelination in subcortical white matter. In addition, brain gray matter volume decreased and spleen and liver weight increased at postnatal day 12. These data suggest chronic subclinical inflammation hampers development of white and gray matter in early life, which may be associated with insulin-like growth factor 1 deficiency.

Topics: Animals; Animals, Newborn; Brain Injuries; Central Nervous System; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Inflammation; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor I; Interleukin-6; Liver; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Myelin Basic Protein; Neurofilament Proteins; Organ Size; Polysaccharides; Pregnancy; Spleen

To investigate the relations between anti-myelin basic protein antibody (anti-MBP) variation and myelinoclasis in the brain stem following brain trauma.. In rat models of brain trauma, MBP content and anti-MBP titer in the blood were measured using enzyme-linked immunosorbent assay (ELISA) at different time points after brain trauma, and the degree of myelinoclasis in the brain stem slices was assessed with osmic acid staining.. Early after brain trauma, MBP content in the blood increased followed by significant reduction 10 days later. Four days after the trauma, anti-MBP titer was markedly increased, accompanied by obvious exacerbation of myelinoclasis in the brain stem, both reaching the highest levels on day 10, at the point of which anti-MBP titer increased by 4 folds and the number of myelinoclasis by 10 folds compared with the control group. Anti-MBP titer and brain stem myelinolysis both lowered 30 days later. Correlation analysis showed an intimate positive correlation between anti-MBP titer and the degree of myelinoclasis.. After brain trauma, MBP is released as a specific antigen into the blood to stimulate the immune system for anti-MBP production, and the antibody is intimately related to the brain stem myelinoclasis.

Topics: Animals; Antibodies; Brain Injuries; Brain Stem; Demyelinating Autoimmune Diseases, CNS; Female; Male; Myelin Basic Protein; Nerve Tissue Proteins; Random Allocation; Rats; Rats, Sprague-Dawley; Transcription Factors

An increasing amount of data provides support for the hypothesis that periventricular leukomalacia (PVL) results from pre- or perinatal hypoxia occurring and is a major cause of cerebral palsy. In this work, anoxic and hypoxic-ischemic brain injuries were observed by us, after injection of neurotoxin 3-nitropropionic acid (3-NP) in a neonatal rat model on postnatal day 5 (P5). 3-NP-induced brain injury was examined in fixed brain sections at 24h (P6), 48h (P7), 72h (P8), and 9 days (P14) after 3-NP injection, respectively. Injection with 3-NP results in pathological injuries including white matter lesions, cerebral cortex destruction, callose thinness, and cerebral ventricle expansion. Numbers of immature oligodendrocytes turned to less in the model of 3-NP. Furthermore myeline basic protein expression became significantly lower after 3-NP was injected. Pathological changes after injection of 3-NP appeared also significantly among rats of postnatal day 5. The effect of the 3-NP neurotoxicity paradigm was evaluated in this study to further investigate the underlying pathology associated with PVL, which may yield a potential desirable model for clinic experiments.

Topics: Age Factors; Animals; Animals, Newborn; Brain Injuries; Injections, Intraventricular; Myelin Basic Protein; Neurotoxins; Nitro Compounds; Oligodendroglia; Propionates; Rats; Rats, Sprague-Dawley; Time Factors

Experimental studies of intracerebral hemorrhage (ICH) have focused on neuron death, with little or no information on axonal and myelin damage outside the hematoma. Because development of effective therapies will require an understanding of white matter injury, we examined white matter injury and its spatial and temporal relationship with microglial/macrophage activation in a collagenase model of rat striatal ICH. The hematoma and parenchyma surrounding the hematoma were assessed in young and aged animals at 6 h, 1, 3 and 28 days after ICH onset. Demyelination occurred inside and at the edge of the hematoma; regions where we have shown substantial neuron death. In contrast, there was axonal damage without demyelination at the edge of the hematoma, and by 3 days this damage had spread to the surrounding parenchyma, a region where we have shown there is no neuron death. Because the axonal damage preceded infiltration of activated microglia into the white matter tracts (seen at 3 days), our results support the hypothesis that these cells respond to, rather than perpetrate the damage. Importantly, axonal damage was worse in aged animals, which provides a plausible explanation for the poorer functional recovery of older animals after ICH, despite a similar loss of grey matter. Our findings support strategies that target white matter injury to reduce neurological impairment after ICH.

Topics: Age Factors; Aging; Amyloid beta-Protein Precursor; Animals; Brain Injuries; Cerebral Hemorrhage; Demyelinating Diseases; Disease Models, Animal; Male; Microglia; Myelin Basic Protein; Nerve Fibers, Myelinated; Neuritis; Rats; Rats, Sprague-Dawley; Stroke

The mechanisms underlying the formation of the glial scar after injury are poorly understood. In this report, we demonstrate that after cortical injury Olig2 is upregulated in reactive astrocytes coincident with proliferation of these cells. Short-term lineage tracing studies with glial subtype-restricted transgenic reporter lines indicate that Olig2-expressing cells in the astroglial but not the oligodendroglial lineage are the essential source of reactive astrocytes. In addition, cortical Olig2 ablation results in a decrease in proliferation of reactive astrocytes in response to injury. Cell-type-specific mutagenesis indicates that Olig2 ablation in GFAP+ astrocytes and their precursors rather than in neuronal or oligodendroglial cells is responsible for the reduction of reactive astrocyte proliferation. Thus, our studies suggest that Olig2 is critical for postinjury gliosis.

Topics: Analysis of Variance; Animals; Astrocytes; Basic Helix-Loop-Helix Transcription Factors; Brain Injuries; Cell Lineage; Cell Proliferation; Cerebral Cortex; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Intermediate Filament Proteins; Mice; Mice, Mutant Strains; Myelin Basic Protein; Nerve Tissue Proteins; Nestin; Oligodendrocyte Transcription Factor 2; Receptor, Platelet-Derived Growth Factor alpha

Neurotrauma, as in the case of traumatic brain injury, promotes protease over-activation characterized by the select fragmentation of brain proteins. The resulting polypeptides are indicators of biochemical processes, which can be used to study post-injury dynamics and may also be developed into biomarkers. To this end, we devised a novel mass spectrometry approach to characterize post-injury calpain proteolytic processing of myelin basic protein (MBP), a biomarker of brain injury that denotes white matter damage and recovery. Our approach exceeds conventional immunological assays in its deconvolution of multiple protein isoforms, its absolute quantification of proteolytic fragments and its polypeptide selectivity. We quantified and characterized post-injury proteolytic processing of all MBP isoforms identified in adult rat cortex. Further, the translation of calpain-cleaved MBP into CSF was verified following brain injury. We ascertained that the exon-6 sequence of MBP resulted in a characteristic shift in gel migration for intact and fragmented protein alike. We also found evidence for a second post-TBI cleavage event within exon-2 and for the dimerization of the post-TBI 4.3 kDa fragment. Ultimately, the novel methodology described here can be used to study MBP dynamics and other similar proteolytic events of relevance to brain injury and other CNS processes.

Topics: Amino Acid Sequence; Animals; Brain Injuries; Calpain; Cysteine Endopeptidases; Hydrolysis; Male; Molecular Sequence Data; Myelin Basic Protein; Protein Isoforms; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Time Factors

Hypoxic-ischemic brain injury is regulated in part by neurotransmitter and chemokine signaling via G-protein-coupled receptors (GPCRs). GPCR-kinase 2 (GRK2) protects these receptors against overstimulation by inducing desensitization. Neonatal hypoxic-ischemic brain damage is preceded by a reduction in cerebral GRK2 expression. We determined the functional importance of GRK2 in hypoxic-ischemic brain damage. Nine-day-old wild-type and GRK2(+/-) mice with a approximately 50% reduction in GRK2 protein were exposed to unilateral carotid artery occlusion and hypoxia. In GRK2(+/-) animals, gray and white matter damage was aggravated at 3 weeks after hypoxia-ischemia. In addition, cerebral neutrophil infiltration was increased in GRK2(+/-) animals. Neutrophil depletion reduced brain damage, but neuronal loss was still more pronounced in GRK2(+/-) animals. Onset of neuronal loss was advanced in GRK2(+/-) animals regardless of neutrophil depletion. White matter injury was advanced in GRK2(+/-) animals and was not affected by neutrophil depletion. Activation/infiltration of microglia/macrophages was stronger in GRK2(+/-) brains but only occurred 24 h after hypoxia-ischemia and is therefore not the primary cause of increased damage. During hypoxia, cerebral blood flow was reduced to the same extent in both genotypes. In vitro, GRK2(+/-) hippocampal slices and cerebellar granular neurons were more sensitive to glutamate-induced death. We propose the novel concept that the kinase GRK2 regulates onset and magnitude of hypoxic-ischemic brain damage. Increased gray and white matter damage in GRK2(+/-) animals was not dependent on infiltrating neutrophils and occurred before microglia/macrophage activation was detected. Collectively, our data suggest that cerebral GRK2 has an important endogenous neuroprotective role in ischemic cerebral damage.

Topics: Animals; Animals, Newborn; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Brain Injuries; G-Protein-Coupled Receptor Kinase 2; Gene Expression Regulation, Developmental; Glutamic Acid; Hypoxia-Ischemia, Brain; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Neuroglia; Neurons; Neutrophil Infiltration; Peroxidase; Regional Blood Flow; Subcellular Fractions; Time Factors

Traumatic brain injury (TBI) in infants and toddlers is frequently explained by child abuse. This study compared 6-month outcome in children with inflicted TBI (iTBI) or non-inflicted TBI (nTBI) who were injured before 3 years of age, and assessed the relationship between outcome and serum concentrations of neuron-specific enolase (NSE), S100B, and myelin-basic protein (MBP). Children with iTBI (n = 15) or nTBI (n = 15) of varying severity were assessed 6 months after injury using the Glasgow Outcome Scale (GOS), Vinel and Adaptive Behavior Scale (VABS), and an intelligence quotient (IQ) measure. Serum concentrations of NSE, S100B, and MBP were measured soon after injury and every 12 h, for up to 5 days. Groups were matched by ethnicity, gender, socioeconomic status, and injury severity. Student's t-tests, analysis of covariance, or nonparametric tests assessed between-group differences for GOS, IQ, and biomarkers; correlation coefficients assessed relationships between outcome and biochemical markers. Functional and cognitive tests showed significant between-group differences (p < or = 0.05); the iTBI group performed more poorly (GOS, 2.00 +/- 1.00 vs.1.23 +/- 0.60; VABS, 95.92 +/- 14.05 vs. 115.80 +/- 20.02; IQ, 69.00 +/- 20.85 vs. 97.33 +/- 23.66). Significant between-group differences (iTBI vs. nTBI) were found for time to peak NSE (66.48 +/- 53.56 vs.8.11 +/- 11.58), S100B (43.30 +/- 51.41 vs. 8.21 +/- 8.29), and MBP (77.66 +/- 56.77 vs. 21.63 +/- 28.39). Time to peak concentrations were significantly correlated with outcome measures. Children with iTBI are at risk for poorer outcome. Acute measurement of NSE, S100B, and MBP serum concentrations may provide a quantitative predictor of outcome after TBI in young children. Outcome may be due to the mechanism of iTBI, cumulative effects of unreported TBI, and/or other unidentified risk factors.

Topics: Biomarkers; Brain Injuries; Child; Child Abuse; Child Behavior; Child, Preschool; Cognition; Cross-Sectional Studies; Female; Glasgow Coma Scale; Humans; Infant; Intelligence Tests; Longitudinal Studies; Male; Myelin Basic Protein; Nerve Growth Factors; Neuropsychological Tests; Phosphopyruvate Hydratase; Predictive Value of Tests; Prospective Studies; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Treatment Outcome

A proliferation of stem/progenitor cells is observed after brain injury. We examined the regional and temporal profile of mitotically active cells to determine whether traumatic brain injury (TBI) would increase neurogenesis in selective brain regions.. Male Sprague-Dawley rats received injections (IP) of 5-bromo-deoxyuridine (BrdU), a compound used to detect mitotic cells, before and after fluid-percussion brain injury. At 3 hr, 1, 2, 3, 7, and 14 days after moderate fluid percussion, brains were processed for immunocytochemical and confocal analysis. Sections were double-labeled for markers selective for neurons (NeuN), astrocytes (GFAP), olidgodendrocytes (CNPase and MBP) and macrophage/microglia (ED1).. At 3 hr post-trauma, the majority of BrdU labeled cells were associated with the subventricular zone of the traumatized hemisphere. At later time points, a significant increase in BrdU positive cells was observed throughout the traumatized cerebral cortex, hippocampus, white matter structures, and some contralateral regions. BrdU labeled cells were observed as late as 14 days post-injury. Double-label studies with confocal microscopy demonstrated that cell phenotypes including astrocytes, macrophage/microglia, oligodendrocytes, and neurons were BrdU positive with the majority of cells appearing glial in nature. Evidence for neurogenesis was seen in the granular cell layer of the hippocampus.. These findings indicate that TBI stimulates widespread cellular proliferation for days after injury and results in focal neurogenesis in the dentate gyrus of the hippocampus. These cellular responses to injury may participate in brain repair and functional recovery.

Topics: Analysis of Variance; Animals; Brain; Brain Injuries; Bromodeoxyuridine; Cell Count; Cell Proliferation; Disease Models, Animal; Ectodysplasins; Glial Fibrillary Acidic Protein; Male; Myelin Basic Protein; Neurons; Organogenesis; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; Time Factors

Predicting outcome after pediatric traumatic brain injury (TBI) is important for providing information to families and prescribing rehabilitation services. The study objective was to assess whether biomarkers concentrations obtained at the time of injury are associated with outcome. Serial serum concentrations of neuron-specific enolase (NSE), S100B and myelin basic protein (MBP) were measured in 152 children with acute TBI. Outcome was assessed with the Glasgow Outcome Scale (GOS) score and/or GOS-Extended Pediatric (GOS-E Peds). Spearman's rank correlation and binary logistic regression assessed the relationship between biomarker concentrations and outcome. For all biomarkers and time points, higher biomarker concentrations were associated with worse outcome. Initial and peak NSE concentrations and initial MBP concentrations were more strongly correlated with outcome in children < or =4 years compared with those >4 years of age. Using binary logistic regression to evaluate the simultaneous affect of all biomarkers on outcome, there was significant overall model fit predicting a dichotomous GOS from biomarker concentrations with a 77% correct classification rate and a negative and positive predictive value of 97% and 75%, respectively. We conclude that NSE, S100B, and MBP concentrations obtained at the time of TBI may be useful in predicting outcome. Future studies should focus on assessing the differential benefit of biomarkers compared with clinical variables and in assessing a continuous rather than categorical outcome variable.

Topics: Age Factors; Biomarkers; Brain Injuries; Child; Child, Preschool; Female; Glasgow Coma Scale; Humans; Infant; Infant, Newborn; Male; Myelin Basic Protein; Nerve Growth Factors; Phosphopyruvate Hydratase; Predictive Value of Tests; Prognosis; S100 Calcium Binding Protein beta Subunit; S100 Proteins

Inflicted traumatic brain injury (iTBI) is the leading cause of death from TBI in infants. Misdiagnosis of iTBI is common and results in increased morbidity and mortality. Biomarkers may be able to assist in screening infants who are at high risk for iTBI and whose injury might otherwise be missed. We investigated whether serum and/or cerebrospinal fluid (CSF) concentrations of neuron-specific enolase (NSE), S100B, and myelin-basic protein (MBP) are sensitive and specific for iTBI in high-risk infants.. A prospective case-control study was conducted of 98 well-appearing infants who presented with nonspecific symptoms and no history of trauma. Serum or CSF was collected. NSE, S100B, and MBP concentrations were measured by enzyme-linked immunosorbent assay. Abnormal marker concentrations were defined a priori. Patients were followed for 12 months to assess for subsequent abuse.. Fourteen patients received a clinical diagnosis of iTBI. Using preestablished cutoffs, NSE was 77% sensitive and 66% specific and MBP was 36% sensitive and 100% specific for iTBI. S100B was neither sensitive nor specific for iTBI. Five patients who were not identified with iTBI at enrollment were identified at follow-up as being possible victims of abuse; 4 had an increased NSE concentration at enrollment.. Serum and/or CSF concentrations of NSE and MBP may be useful as a screening test to identify infants who are at increased risk for iTBI and may benefit from additional evaluation with a head computed tomography scan. S100B is neither sensitive nor specific for iTBI in this study population. The ability to identify iTBI that might otherwise be missed has important implications for decreasing the morbidity and the mortality from iTBI.

Topics: Biomarkers; Brain Injuries; Child Abuse; Female; Humans; Infant; Male; Myelin Basic Protein; Phosphopyruvate Hydratase; S100 Proteins; Sensitivity and Specificity

Neonatal and congenital hydrocephalus are common problems in humans. Hydrocephalus was induced in 1-day-old rats by injection of kaolin into the cisterna magna. At 7 and 21 days, magnetic resonance (MR) imaging was used to assess ventricle size, then brains were subjected to histopathological and biochemical analyses. Hydrocephalic pups did not exhibit delays in righting or negative geotaxis reflexes during the first week. At 7 days, there was variable ventricular enlargement with periventricular white matter edema, axon damage, reactive astrogliosis, and accumulation of macrophages in severe but not mild hydrocephalus. Cellular proliferation in the subependymal zone was significantly reduced. The cortical subplate neuron layer was disrupted. In rats allowed to survive to 21 days, weight was significantly lower in severely hydrocephalic rats. They also exhibited impaired memory in the Morris water maze test. Despite abnormal posture, there was minimal quantitative impairment of walking ability on a rotating cylinder. At 21 days, histological studies showed reduced corpus callosum thickness, fewer mature oligodendrocytes, damaged axons, and astroglial/microglial reaction. Reduced myelin basic protein, increased glial fibrillary acidic protein, and stable synaptophysin content were demonstrated by immunochemical methods. In conclusion, impairment in cognition and motor skills corresponds to ventricular enlargement and white matter destruction. Quantitative measures of weight, memory, ventricle size, and myelin, and glial proteins in this neonatal model of hydrocephalus will be useful tools for assessment of experimental therapeutic interventions.

Topics: Age Factors; Animals; Animals, Newborn; Antidiarrheals; Behavior, Animal; Blotting, Western; Body Weight; Brain Injuries; Cerebral Ventricles; Enzyme-Linked Immunosorbent Assay; Hydrocephalus; Immunohistochemistry; Kaolin; Ki-67 Antigen; Magnetic Resonance Imaging; Myelin Basic Protein; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley; Time Factors; Walking

In order to study whether patients with schizophrenia have cerebral injury, neuron-specific enolase (NSE) and myelin basic protein (MBP)in cerebrospinal fluid (CSF) of 33 patients with first episode schizophrenia and 9 from the control group were determined by double antibody sandwich enzyme immunoassay method. The results showed that there was significant difference in the NSE contents between the experimental group and control group (P<0.01). The NSE contents in CSF in the experimental group were positively correlated with MBP in schizophrenia patients (P< 0. 05). These findings suggested that patients with schizophrenia had cerebral injury.

Topics: Adolescent; Adult; Biomarkers; Brain Injuries; Female; Humans; Immunoassay; Male; Myelin Basic Protein; Phosphopyruvate Hydratase; Schizophrenia

Axonal injury is one of the key features of traumatic brain injury (TBI), yet little is known about the integrity of the myelin sheath. We report that the 21.5 and 18.5-kDa myelin basic protein (MBP) isoforms degrade into N-terminal fragments (of 10 and 8 kDa) in the ipsilateral hippocampus and cortex between 2 h and 3 days after controlled cortical impact (in a rat model of TBI), but exhibit no degradation contralaterally. Using N-terminal microsequencing and mass spectrometry, we identified a novel in vivo MBP cleavage site between Phe114 and Lys115. A MBP C-terminal fragment-specific antibody was then raised and shown to specifically detect MBP fragments in affected brain regions following TBI. In vitro naive brain lysate and purified MBP digestion showed that MBP is sensitive to calpain, producing the characteristic MBP fragments observed in TBI. We hypothesize that TBI-mediated axonal injury causes secondary structural damage to the adjacent myelin membrane, instigating MBP degradation. This could initiate myelin sheath instability and demyelination, which might further promote axonal vulnerability.

Topics: Amino Acid Sequence; Animals; Brain Injuries; Calpain; Disease Models, Animal; Hydrolysis; Male; Molecular Sequence Data; Molecular Weight; Myelin Basic Protein; Peptide Hydrolases; Protein Isoforms; Rats; Rats, Sprague-Dawley

Inflicted traumatic brain injury (iTBI) involves a combination of mechanical trauma and hypoxemia. Serum biomarker concentrations may provide objective information about their relative importance to the pathophysiology of iTBI. We compared the time course of neuron-specific enolase (NSE), S100B and myelin basic protein after pediatric hypoxic-ischemic brain injury, iTBI and noninflicted TBI (nTBI). The time to reach peak concentrations of all three biomarkers was shorter after nTBI. Initial and peak S100B, initial and peak myelin basic protein and peak NSE concentrations were no different between the three groups. Initial NSE concentration was highest after nTBI. These results suggest that the biochemical response of the brain to iTBI is distinct from the response to nTBI and shares temporal similarities with hypoxic-ischemic brain injury. This may have important implications for the treatment and prognosis of children with iTBI.

Topics: Age Factors; Aging; Biomarkers; Brain; Brain Injuries; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Male; Myelin Basic Protein; Nerve Growth Factors; Nerve Tissue Proteins; Phosphopyruvate Hydratase; Predictive Value of Tests; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Time Factors; Up-Regulation

Preferential brain white matter injury and hypomyelination induced by intracerebral administration of the endotoxin lipopolysaccharide (LPS) in the neonatal rat brain has been characterized as associated with the activation of microglia. To examine whether inhibition of microglial activation might provide protection against LPS-induced brain injury and behavioral deficits, minocycline (45 mg/kg) was administered intraperitoneally 12 hr before and immediately after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rats and then every 24 hr for 3 days. Brain injury and myelination were examined on postnatal day 21 and the tests for neurobehavioral toxicity were carried out from P3 to P21. LPS administration resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, loss of oligodendrocytes and tyrosine hydroxylase neurons, damage to axons and dendrites, and impaired myelination as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. LPS administration also significantly affected physical development (body weight) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, and responses in the elevated plus-maze and passive avoidance task. Treatment with minocycline significantly attenuated the LPS-induced brain injury and improved neurobehavioral performance. The protective effect of minocycline was associated with its ability to attenuate LPS-induced microglial activation. These results suggest that inhibition of microglial activation by minocycline may have long-term protective effects in the neonatal brain on infection-induced brain injury and associated neurologic dysfunction in the rat.

Topics: Age Factors; Animals; Animals, Newborn; Avoidance Learning; Behavior, Animal; Brain; Brain Injuries; CD11b Antigen; Cell Count; Gait; Gene Expression Regulation, Developmental; Immunohistochemistry; Lateral Ventricles; Lectins; Lipopolysaccharides; Maze Learning; Microtubule-Associated Proteins; Minocycline; Motor Activity; Myelin Basic Protein; Nervous System Diseases; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Reflex; Staining and Labeling; Tyrosine 3-Monooxygenase

Misdiagnosis of inflicted traumatic brain injury (iTBI) is common. Serum biomarkers may be able to assist in the detection of iTBIs that would otherwise be missed. The authors investigated whether serum concentrations of biomarkers were increased after noninflicted (n)TBI and iTBI in pediatric cases of varying severity.. This prospective, case-control study involved 100 patients (56 with nTBI, 44 with iTBI) and 64 controls. Blood was collected in patients within 12 hours of injury; a subset had serial samples. A single sample was collected from controls. Serum neuron-specific enolase (NSE), S100B, and myelin basic protein concentrations were measured. Abnormal concentrations were defined using receiver-operator characteristic (ROC) curves. The sensitivity and specificity of initial NSE and S100B and peak myelin basic protein concentrations for identifying TBI at ROC curve-defined cutoffs were 71 and 64% (NSE), 77 and 72% (S100B), and 44 and 96% (myelin basic protein), respectively. Eighty-six percent of patients having suffered iTBI had one or more biomarkers increased, including 82% of children with iTBI and a Glasgow Coma Scale score of 15, and two children with iTBI who were initially misdiagnosed. Children with iTBI had a later peak concentration of all three biomarkers and were more likely to have increased myelin basic protein levels at admission compared with patients with nTBI.. Serum NSE, S100B, or myelin basic protein are increased in the majority of children with acute nTBI and iTBI, including well-appearing children with iTBI in whom the diagnosis might otherwise have been missed. Differences in the time course of NSE, S100B, and myelin basic protein after nTBI and iTBI may provide insight into the pathophysiology of iTBI. These serum markers should be prospectively evaluated in a target population of infants.

Topics: Biomarkers; Brain Injuries; Case-Control Studies; Child; Child Abuse; Child, Preschool; Female; Glasgow Coma Scale; Humans; Infant; Infant, Newborn; Injury Severity Score; Male; Myelin Basic Protein; Nerve Growth Factors; Phosphopyruvate Hydratase; Prospective Studies; S100 Calcium Binding Protein beta Subunit; S100 Proteins

To examine the possible role of inflammatory cytokines in mediating neonatal brain injury, we investigated effects of intracerebral injection of IL-1beta (IL-1beta) or tumor necrosis factor-alpha (TNFalpha) on brain injury in the neonatal rat. A stereotaxic intracerebral injection of IL-1beta or TNFalpha (10 ng per pup) was performed in postnatal day 5 (P5) SD rats. Although no necrosis of neurons was found, increased astrogliosis, as indicated by GFAP positive staining was observed 24 and 72 h following the injection of IL-1beta or TNFalpha. IL-1beta induced apoptotic cell death in the rat brain 24 h after the injection, as indicated by increases in positive TUNEL staining and caspase-3 activity, and apoptotic cell death was partially blocked by systemic administration of NBQX, an antagonist of the AMPA glutamate receptor. IL-1beta also significantly reduced the number of developing oligodendrocytes (OLs) 24 h after the injection and this impairment was not prevented by NBQX. On the contrary, TNFalpha induced a much smaller increase in the number of TUNEL positive cells and did not reduce the number of developing OLs. By P8, myelin basic protein (MBP) was clearly detected in the control rat brain, while MBP positive staining was very weak, if any, in the IL-1beta treated rat brain. MBP expression in the TNFalpha treated rat brain was less affected. The overall results indicate that IL-1beta may directly cause injuries to developing OLs and impair myelination in the neonatal rat brain and TNFalpha may have different roles in mediating brain injury.

Topics: Animals; Animals, Newborn; Apoptosis; Brain Injuries; Caspase 3; Caspases; Cerebral Cortex; Excitatory Amino Acid Antagonists; Humans; In Situ Nick-End Labeling; Infant; Inflammation; Interleukin-1; Myelin Basic Protein; Oligodendroglia; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Tumor Necrosis Factor-alpha

Myelin-specific encephalitogenic T cells, when passively transferred into rats or mice, cause an experimental autoimmune disease. Previous studies by our group have shown that (a) the same cells also significantly reduce post-traumatic degeneration in these animals after injury to the central nervous system, (b) this beneficial autoimmunity is a physiological response, and (c) animals differ in their ability to resist injurious conditions, and the ability to resist post-traumatic degeneration correlates with resistance to the development of an autoimmune disease. Here we show that optic nerve neurons in both resistant and susceptible rat strains can be protected from secondary degeneration after crush injury by immunization with myelin basic protein emulsified in complete or incomplete Freund's adjuvant. We provide evidence that potentially destructive autoimmunity (causing autoimmune disease) and beneficial autoimmunity (causing improved neuronal survival) both result from activity of the same myelin-specific, proinflammatory Th1 cells. We further show that following passive transfer of such Th1 cells, the expression of their beneficial potential depends on the activity of an additional T cell (CD4(+)) population. By identifying the additional cellular component of autoimmune neuroprotection, we may be able to take meaningful steps toward achieving neuroprotection without risk of accompanying autoimmune disease.

Topics: Animals; Autoimmunity; Brain Injuries; CD4-Positive T-Lymphocytes; Cell Survival; Female; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Myelin Basic Protein; Myelin Proteins; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Th1 Cells; Vaccination; X-Rays

This study analyzes how the antigen specificity, the subtype, and the activation state of T cells modulate their recently discovered neuroprotective potential. We assessed the prevention from neuronal damage in organotypic entorhinal-hippocampal slice cultures after co-culture with Th1 and Th2 cells either specific for myelin basic protein (MBP) or ovalbumin (OVA). We found that MBP-specific Th2 cells were the most effective in preventing central nervous system (CNS) tissue from secondary injury. This neuroprotective T cell effect appears to be mediated by soluble factors. After stimulation with phorbol myristate acetate and ionomycin, all T cells were most effective in preventing neuronal death. Our data show that the T cell subtype and activation state are important features in determining the neuroprotective potential of these cells.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Cell Survival; Chemotaxis, Leukocyte; Contact Inhibition; Cytokines; Epitopes; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Nerve Degeneration; Neurons; Ovalbumin; Tetradecanoylphorbol Acetate; Th1 Cells; Th2 Cells

Proteases are involved in a variety of processes including demyelination after injury to the central nervous system. Neuropsin is a serine protease, which is constitutively expressed in the neurons of the limbic system. In the present study, intrahippocampal kainate injection and enucleation were performed on adult mice. Neuropsin mRNA and protein expression was detected by in situ hybridization and immunohistochemistry. Double in situ hybridization confirmed that the mRNA expression was induced in oligodendrocytes. One day after kainate injection to the hippocampus, neuropsin mRNA was expressed, peaking 4-8 days postoperatively and disappearing at 14 days. Immunohistochemistry and immunoelectron microscopy revealed that neuropsin was expressed in the cell body of oligodendrocytes and myelin. To see if neuropsin degrades myelin protein, purified myelin was incubated with recombinant neuropsin. A decrease in the intensity of the bands of myelin basic protein was observed. These results indicate that neuropsin is involved in demyelination.

Topics: Animals; Axons; Brain Injuries; Excitatory Amino Acid Agonists; Eye Enucleation; Hippocampus; Immunohistochemistry; Kainic Acid; Kallikreins; Mice; Myelin Basic Protein; Nerve Degeneration; Oligodendroglia; Optic Nerve; Pyramidal Cells; RNA, Messenger; Serine Endopeptidases

Topics: Animals; Autoantigens; Autoimmunity; Brain Injuries; Humans; Immunization; Mice; Myelin Basic Protein; Rats; Stroke

Expression of 18 genes was examined at 8 different time points between 1 h and 28 days following cryogenic rat brain injury. The genes include thymidine kinase (TK), p53 tumor suppressor, c-fos, renin, myelin basic protein (MBP), proteolipid protein (PLP), transferrin, transferrin receptor, platelet-derived growth factor A (PDGF A), platelet-derived growth factor B (PDGF B), platelet-derived growth factor receptor alpha (PDGF alpha receptor), platelet-derived growth factor receptor beta (PDGF beta receptor), glial fibrillary acidic protein (GFAP), transforming growth factor-beta 1 (TGF-beta 1), basic fibroblast growth factor (bFGF), fibroblast growth factor receptor-1 (FGF-R1), insulin-like growth factor-1 (IGF-1), and somatostatin. Time courses of gene expression were determined for RNAs derived from hippocampus and cortex. Genes were divided into categories based upon those in which statistically significant changes in expression were first observed at or before 24 h (early genes) and those in which changes were first observed at or after 72 h (late genes). In the present model, many genes demonstrate elevated RNA levels in the cortex prior to hippocampus, following injury. RNAs transcribed from late genes tend to be elevated concurrently in cortex and hippocampus.

Topics: Animals; Brain Injuries; Cerebral Cortex; Cold Temperature; Freezing; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Growth Substances; Hippocampus; Myelin Basic Protein; Nerve Tissue Proteins; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Growth Factor; Renin; RNA, Messenger; Time Factors; Transferrin; Tumor Suppressor Protein p53; Wound Healing

Neuron-specific enolase (NSE) and myelin basic protein (MBP) in the peripheral venous blood (PVB) have been reported to be sensitive markers for judging the prognosis of patients with head injury. However, to our knowledge, the levels of NSE and MBP in the internal jugular venous blood (IJVB) have never been studied.. In 25 patients with acute head injury, blood samples were taken from the internal jugular vein and the peripheral vein at the same time before any medical or surgical procedure was performed. The levels of NSE and MBP in the both venous blood samples were measured. The time interval between injury and sampling was 1.5-8.0 hours (mean 4.3 hours). The levels of NSE and MBP in the IJVB were compared to those in the PVB. The relationship between the clinical outcome and the serum levels of those was evaluated.. The levels of NSE and MBP in the IJVB were almost equal to those in the PVB. The levels of NSE and MBP were significantly higher in the patients who died than in those who survived. In the survivors, the levels of NSE and MBP in the IJVB were 17.6 +/- 11.4 ng/ml and 1.4 +/- 1.5 ng/ml, whereas in the patients who died, both levels were elevated to 51.3 +/- 27.3 ng/ml (p < 0.005) and to 11.3 +/- 9.5 ng/ml (p < 0.01), respectively.. The assay of serum NSE and MBP levels provides a reliable laboratory indicator of the degree of brain damage and allows early prediction of the prognosis in patients with acute head injury.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Brain Injuries; Female; Glasgow Coma Scale; Humans; Jugular Veins; Male; Middle Aged; Myelin Basic Protein; Phosphopyruvate Hydratase; Regression Analysis

We have used sections of adult mouse brain to determine whether antibodies specific for oligodendroglia (anti-carbonic anhydrase II, CA II; anti-galactocerebroside, GC; anti-myelin basic protein, MBP) and astroglia (anti-glial fibrillary acidic protein, GFAP; anti-S 100 protein) are suitable for quantitative studies of the proliferation and subsequent differentiation of these cells. Unlesioned adult mice received a single injection of 3H-thymidine (TdR) and were killed between 1 h and 70 days later. Quantitative evaluations of autoradiographs of 2-microns-thick serial sections stained immunocytochemically with the antibodies mentioned above or with Richardson's method for histological control led to the following conclusions. Anti-GC and anti-MBP stained only the oligodendrocytic processes and, thus, cannot be used in well-myelinated brain areas. Anti-CA II stained only a portion of the differentiated oligodendrocytes, but no proliferating cells. Anti-S 100 protein recognized all the astrocytes, but also many (interfascicular) oligodendrocytes. Anti-GFAP stained only a few astrocytes in the unlesioned mouse; all astrocytes may become GFAP-immunopositive only after wounding the brain. Thus, in contrast to in vitro studies, immunocytochemical studies with these antibodies on sections of adult animals cannot be recommended for the quantitative analysis of cell proliferation. In addition, our results show that differentiated glial cells proliferate in adult mice. Astro- and oligodendrocytes divide with the same cell cycle parameters and mode of proliferation up to about 1 month after 3H-TdR injection. In contrast to oligodendrocytes, some astrocytes might re-enter the cycle after a few weeks of quiescence.

Topics: Animals; Artifacts; Astrocytes; Autoradiography; Biomarkers; Brain; Brain Injuries; Carbonic Anhydrases; Cell Cycle; Cell Division; DNA Replication; Galactosylceramidase; Glial Fibrillary Acidic Protein; Immunoenzyme Techniques; Male; Mice; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Oligodendroglia; S100 Proteins; Thymidine; Tritium

Cellular immune responses to brain antigens in patients with head injury were studied by applying the leukocyte adherence inhibition (LAI) assay. The investigation was conducted in three phases. 1) In the initial phase, evaluation of a series of 22 test and 25 control cases obtained at random during a 2- to 6-week time frame following a traumatic event indicated significant non-adherence of leukocytes (NAL) in 77% of the test group and 20% of the control group in the presence of brain antigen. 2) In a second phase, larger test population was divided into four groups of different posttraumatic intervals. This study measured NAL in the presence of normal heart of normal brain antigen. Assays revealed an initial significant NAL in the presence of both antigens; however, after the first week following injury the majority of cases manifested significant NAL only with brain antigen. These values of NAL persisted over a 6- to 8-week period. 3) As a final phase of investigation, analysis of a sequential series of assays in 12 patients over a 90-day period indicated significant NAL in the presence of brain antigen within the first week of injury, this was followed by a drop in NAL in most of the cases. Studies at 7 to 60 days posttrauma demonstrated significant NAL with brain antigen alone, with a subsequent drop by 90 days. These observations are interpreted to represent sensitization of leukocyte subgroups to brain proteins that are immunologically recognized following the traumatic event.

Topics: Antibody Formation; Antigens; Autoantigens; Brain; Brain Injuries; Encephalomyelitis; Humans; Immunity, Cellular; Leukocyte Adherence Inhibition Test; Myelin Basic Protein; Time Factors

Topics: Brain Injuries; Coma; Humans; Myelin Basic Protein; Prognosis; Psychological Tests; Radioimmunoassay

Serum levels of myelin basic protein (M.B.P.), a nervous-system-specific protein, were measured in 157 patients after head injury and related both to the type of brain damage and to the clinical outcome assessed three months after injury. Mean concentrations of M.B.P. in patients with severe intracerebral damage, with or without associated extracerebral haematoma, were significantly raised at the time of admission and remained high for two weeks after injury. In patients with extracerebral haematoma not associated with severe intracerebral damage mean M.B.P. values rose four to six days after injury and were significantly raised only in patients with poor eventual outcome. Mean serum-M.B.P. concentrations in patients with a good outcome after injury were similar to those in controls. In patients with a poor outcome the mean M.B.P. levels between two and six days after injury were significantly higher than in those with a good outcome. The assay of serum-M.B.P. may be valuable in assessment of severity of brain damage in patients after head injury and in prediction of outcome.

Topics: Blood-Brain Barrier; Brain Diseases; Brain Injuries; Brain Neoplasms; Cerebrovascular Disorders; Craniocerebral Trauma; Hematoma; Humans; Myelin Basic Protein; Prognosis

Topics: Animals; Asparaginase; Brain; Brain Chemistry; Brain Injuries; Encephalomyelitis, Autoimmune, Experimental; Escherichia coli; Freund's Adjuvant; Immune Sera; Immunization; Immunization, Passive; Male; Myelin Basic Protein; Pertussis Vaccine; Rats; Rats, Inbred Lew; Spinal Cord