myelin-basic-protein and Stroke

Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Autoantigens; Autoimmunity; Glatiramer Acetate; Humans; Immunization, Passive; Immunologic Factors; Immunomodulation; Myelin Basic Protein; Nerve Regeneration; Neurodegenerative Diseases; Neuroprotection; Parkinson Disease; Peptide Fragments; Peptides; Proteostasis Deficiencies; Spinal Cord Injuries; Stroke

A blood test that quantified the extent of brain damage following ischaemic stroke might be a useful surrogate outcome measure in trials of acute stroke treatments. Measures of neuronal and glial damage, such as neuron-specific enolase (NSE), glial fibrillary acidic protein, tau-protein, myelin-basic protein and S100-β are potential candidate biomarkers.. We systematically reviewed the relevant literature to find studies that correlated blood levels of neuronal and glial damage markers with imaging measures of infarct volume.. We identified studies with a comprehensive search of databases and the reference lists of relevant studies. We included studies that: (1) measured the highest level, or area under the curve (AUC) over time of markers of cerebral damage, (2) calculated infarct volume, and (3) correlated the two measures.. Seventeen studies met the criteria for the systematic review. There were sufficient data to provide summary estimates for S100-β and NSE. The peak level and AUC over time of both markers correlated with subacute infarct volume. Measurements of S100-β later than 24 h after stroke were better correlated with subacute infarct size than earlier measurements. However, scan times varied, and none was later than 8 days after stroke.. Peak and AUC levels of NSE and S100-β levels correlated with subacute infarct volume. Correlations of S100-β with infarct volume were stronger when measured after 24 h than closer to admission. Exploratory studies within clinical trials are necessary before blood markers of cerebral tissue damage can be recommended as surrogate endpoints.

Topics: Biomarkers; Brain; Brain Ischemia; Glial Fibrillary Acidic Protein; Humans; Magnetic Resonance Imaging; Myelin Basic Protein; Nerve Growth Factors; Nerve Tissue Proteins; Neuroglia; Neurons; Phosphopyruvate Hydratase; Predictive Value of Tests; Prognosis; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Stroke; tau Proteins; Time Factors; Tomography, X-Ray Computed

Ischemic stroke is associated with altered systemic immune responses both early after the onset and in the recovery phase. Interleukin (IL)-10, a Th2 related cytokine, has multiple effects on different cell types, including T and B lymphocytes, monocytes, neutrophils and mast cells. IL-4 is another Th2 cytokine that inhibits the synthesis of pro-inflammatory cytokines by Th1 clones. We used enzyme-linked immunospot assays to detect and enumerate blood mononuclear cells (MNC) secreting IL-10 and IL-4 spontaneously as well as after stimulation with myelin basic protein (MBP), considered to be an autoantigen of possible pathogenic importance in, for example, multiple sclerosis, to evaluate the involvement of anti-inflammatory cytokines in ischemic stroke. All patients with ischemic stroke and cerebral hemorrhage had strongly elevated numbers of IL-10 secreting blood MNC compared with healthy individuals. Numbers of MBP-reactive IL-10 secreting blood MNC were also elevated in a proportion of the patients with stroke and hemorrhage. Levels of IL-4 secreting blood MNC did not differ in ischemic stroke versus healthy individuals. The anti-inflammatory IL-10 could play a pivotal role in ischemic stroke as well as cerebral hemorrhage.

Topics: Acute-Phase Reaction; Cerebrovascular Disorders; Enzyme-Linked Immunosorbent Assay; Humans; In Vitro Techniques; Interleukin-10; Interleukin-4; Monocytes; Myelin Basic Protein; Stimulation, Chemical; Stroke

Ischemic stroke often causes motor and cognitive deficits. Deregulated glia gap junction communication, which is reflected by increased protein levels of glial fibrillary acidic protein (GFAP) and connexin 43 (Cx43), has been observed in ischemic hippocampus and has been associated with cognitive impairment in animal stroke models. Here, we tested the hypothesis that reactive astrocytes-mediated loss of synaptophysin (SYP) and CREB-regulated transcription coactivator 1 (CRTC1) contribute to dysfunction in glia gap junction communication and memory impairment after ischemic stroke. Male Sprague-Dawley rats were subjected to a 90-min middle cerebral artery occlusion (MCAO) with 7-day reperfusion. Fluorocitrate (1 nmol), the reversible inhibitor of the astrocytic tricarboxylic acid cycle, was injected into the right lateral ventricle of MCAO rats once every 2 days starting immediately before reperfusion. The Morris water maze was used to assess memory in conjunction with western blotting and immunostaining to detect protein expression and distribution in the hippocampus. Our results showed that ischemic stroke caused significant memory impairment accompanied by increased protein levels of GFAP and Cx43 in hippocampal tissue. In addition, the levels of several key memory-related important proteins including SYP, CRTC1, myelin basic protein and high-mobility group-box-1 were significantly reduced in the hippocampal tissue. Of note, inhibition of reactive astrocytes with fluorocitrate was shown to significantly reverse the above noted changes induced by ischemic stroke. Taken together, our findings demonstrate that inhibiting reactive astrocytes with fluorocitrate immediately before reperfusion may protect against ischemic stroke-induced memory impairment through the upregulation of CRTC1 and SYP.

Topics: Animals; Astrocytes; Brain Ischemia; Citrates; Connexin 43; Glial Fibrillary Acidic Protein; Hippocampus; HMGB1 Protein; Learning; Male; Memory Disorders; Motor Activity; Myelin Basic Protein; Rats, Sprague-Dawley; Stroke; Synaptophysin; Transcription Factors; Up-Regulation

Cognitive impairment is a common outcome for stroke survivors. Growth hormone (GH) could represent a potential therapeutic option as this peptide hormone has been shown to improve cognition in various clinical conditions. In this study, we evaluated the effects of peripheral administration of GH at 48 hours poststroke for 28 days on cognitive function and the underlying mechanisms.. Experimental stroke was induced by photothrombotic occlusion in young adult mice. We assessed the associative memory cognitive domain using mouse touchscreen platform for paired-associate learning task. We also evaluated neural tissue loss, neurotrophic factors, and markers of neuroplasticity and cerebrovascular remodeling using biochemical and histology analyses.. Our results show that GH-treated stroked mice made a significant improvement on the paired-associate learning task relative to non-GH-treated mice at the end of the study. Furthermore, we observed reduction of neural tissue loss in GH-treated stroked mice. We identified that GH treatment resulted in significantly higher levels of neurotrophic factors (IGF-1 [insulin-like growth factor-1] and VEGF [vascular endothelial growth factor]) in both the circulatory and peri-infarct regions. GH treatment in stroked mice not only promoted protein levels and density of presynaptic marker (SYN-1 [synapsin-1]) and marker of myelination (MBP [myelin basic protein]) but also increased the density and area coverage of 2 major vasculature markers (CD31 and collagen-IV), within the peri-infarct region.. These findings provide compelling preclinical evidence for the usage of GH as a potential therapeutic tool in the recovery phase of patients after stroke.

Topics: Animals; Association Learning; Brain; Cerebrovascular Circulation; Cognition; Collagen Type IV; Growth Hormone; Insulin-Like Growth Factor I; Male; Mice; Myelin Basic Protein; Neuronal Plasticity; Platelet Endothelial Cell Adhesion Molecule-1; Random Allocation; Stroke; Synapsins; Vascular Endothelial Growth Factor A; Vascular Remodeling; Weight Gain

The positive correlation between therapeutic exercise and memory recovery in cases of ischemia has been extensively studied; however, long-term exercise begun after ischemic neuronal death as a chronic neurorestorative strategy has not yet been thoroughly examined.. The purpose of this study is to investigate possible mechanisms by which exercise ameliorates ischemia-induced memory impairment in the aged gerbil hippocampus after transient cerebral ischemia.. Treadmill exercise was begun 5 days after ischemia-reperfusion (I-R) and lasted for 1 or 4 weeks. The animals were sacrificed 31 days after the induction of ischemia. Changes in short-term memory, as well as the hippocampal expression of markers of cell proliferation, neuroblast differentiation, neurogenesis, myelin and microvessel repair, and growth factors were examined by immunohistochemistry and/or western blots.. Four weeks of exercise facilitated memory recovery despite neuronal damage in the stratum pyramidale (SP) of the hippocampal CA1 region and in the polymorphic layer (PoL) of the dentate gyrus (DG) after I-R. Long-term exercise enhanced cell proliferation and neuroblast differentiation in a time-dependent manner, and newly generated mature cells were found in the granule cell layer of the DG, but not in the SP of the CA1 region or in the PoL of the DG. In addition, long-term exercise ameliorated ischemia-induced damage of myelin and microvessels, which was correlated with increased BDNF expression in the CA1 region and the DG.. These results suggest that long-term treadmill exercise after I-R can restore memory function through replacement of multiple damaged structures in the ischemic aged hippocampus.

Topics: Animals; Avoidance Learning; Brain Ischemia; Bromodeoxyuridine; Disease Models, Animal; Exercise Test; Exercise Therapy; Gerbillinae; Glucose Transport Proteins, Facilitative; Male; Memory Disorders; Microvessels; Myelin Basic Protein; Myelin Sheath; Nerve Tissue Proteins; Neurogenesis; Stroke; Stroke Rehabilitation; Time Factors

B lymphocytes cause post-stroke cognitive decline in mice. We therefore evaluated the association between autoantibodies and post-stroke cognitive decline in a prospectively collected human cohort. The mini-mental state exam (MMSE) was administered 30, 90, 180, and 365days after stroke. Antibody titers to myelin basic protein (MBP), proteolipid protein, and several non-specific proteins were determined. Among 58 subjects with initial MMSE≥20 and at least 2 MMSE examinations in the year after stroke, cognitive decline (MMSE decrease ≥2) occurred in 10 (17%) subjects. In multivariate analysis, MBP antibody titers were the only independent predictor of cognitive decline (OR=9.02 [1.18, 68.90]; P=0.03).

Topics: Adult; Aged; Autoantibodies; Cognition Disorders; Cohort Studies; Female; Gene Expression Regulation; Humans; Male; Mental Status Schedule; Middle Aged; Myelin Basic Protein; Myelin Proteolipid Protein; Neuropsychological Tests; Stroke

Infections are common following stroke and associated with worse outcome. Using an animal model of pneumonia, we assessed the effect of infection and its treatment on the immune response and stroke outcome.. Lewis rats were subjected to transient cerebral ischemia and survived for 4weeks. One day after stroke animals were exposed to aerosolized Staphylococcus aureus, Pseudomonas aeruginosa or saline. Antibiotics (ceftiofur or enrofloxacin) were started immediately after exposure or delayed for 3days. Behavioral tests were performed weekly. ELISPOT assays were done on lymphocytes from spleen and brain to assess autoimmune responses to myelin basic protein (MBP).. Among animals that received immediate antibiotic therapy, infection was associated with worse outcome in ceftiofur but not enrofloxacin treated animals. (The outcome with immediate enrofloxacin therapy was so impaired that further worsening may have been difficult to detect.) A delay in antibiotic therapy was associated with better outcomes in both ceftiofur and enrofloxacin treated animals. Infection was associated with an increased likelihood of developing Th1(+) responses to MBP in non-infarcted brain (OR=2.94 [1.07, 8.12]; P=0.04), and Th1(+) responses to MBP in spleen and non-infarcted brain were independently associated with a decreased likelihood of stroke recovery (OR=0.16 [0.05, 0.51; P=0.002 and OR=0.32 [0.12, 0.84]; P=0.02, respectively).. Infection worsens stroke outcome in ceftiofur treated animals and increases Th1 responses to MBP. These data may help explain how infection worsens stroke outcome and suggest that treatment of infection may contribute to this outcome.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Body Temperature; Body Weight; Cephalosporins; Cytokines; Disease Models, Animal; Enrofloxacin; Fluoroquinolones; Lymphocytes; Male; Myelin Basic Protein; Nervous System Diseases; Pneumonia; Rats; Rats, Inbred Lew; Staphylococcus aureus; Statistics, Nonparametric; Stroke

Whether and when auto-reactivity after stroke occurs is still a matter of debate. By using overlapping 15mer peptide pools consisting of myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) we show increased frequencies of immunodominant MOG- and MBP T cell responses in acute ischemic stroke which were associated with reduced frequencies of naïve T cells as well as CD8+ TEMRA cells. Auto-reactive CNS antigen-specific T cells responses as well as alterations of T cell subpopulations normalized in long-term follow up after stroke. Our findings suggest that stroke-induced immunodepression might function as an adaptive mechanism in order to inhibit harmful and long-lasting CNS antigen-specific immune responses.

Topics: Adult; Aged; Aged, 80 and over; Autoimmunity; Brain Ischemia; Enzyme-Linked Immunospot Assay; Female; Flow Cytometry; Follow-Up Studies; Humans; Immunologic Memory; Interferon-gamma; Male; Middle Aged; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Neuroimmunomodulation; Stroke; T-Lymphocyte Subsets

White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 h after 60 min of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment-facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

Topics: Animals; Antigens, CD; Calcium-Binding Proteins; Cell Proliferation; Cerebrovascular Circulation; Corpus Callosum; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Ischemic Attack, Transient; Leukoencephalopathies; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Myelin Basic Protein; Nerve Tissue Proteins; Nervous System Diseases; Stroke; Time Factors

Stroke is a leading cause of death and neurological disability worldwide and striatal ischemic stroke is frequent in humans due to obstruction of middle cerebral artery. Several pathological events underlie damage progression and a comprehensive description of the pathological features following experimental stroke in both acute and chronic survival times is a necessary step for further functional studies. Here, we explored the patterns of microglial activation, astrocytosis, oligodendrocyte damage, myelin impairment, and Nogo-A immunoreactivity between 3 and 30 postlesion days (PLDs) after experimental striatal stroke in adult rats induced by microinjections of endothelin-1 (ET-1). The focal ischemia induced tissue loss concomitant with intense microglia activation between 3 and 14 PLDs (maximum at 7 PLDs), decreasing afterward. Astrocytosis was maximum around 7 PLDs. Oligodendrocyte damage and Nogo-A upregulation were higher at 3 PLDs. Myelin impairment was maximum between 7 and 14 PLDs. Nogo-A expression was higher in the first week in comparison to control. The results add important histopathological features of ET-1 induced stroke in subacute and chronic survival times. In addition, the establishment of the temporal evolution of these neuropathological events is an important step for future studies seeking suitable neuroprotective drugs targeting neuroinflammation and white matter damage.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Disease Models, Animal; Endothelin-1; Immunohistochemistry; Male; Microglia; Microscopy; Myelin Basic Protein; Nogo Proteins; Oligodendroglia; Rats; Rats, Wistar; Stroke; Up-Regulation; White Matter

Translational research is beginning to reveal the importance of trophic factors as a therapy for cellular brain repair. The purpose of this study was to analyze whether brain-derived neurotrophic factor (BDNF) administration could mediate oligodendrogenesis and remyelination after white matter injury in subcortical stroke.. Ischemia was induced in rats by injection of endothelin-1. At 24 hours, 0.4 μg/kg of BDNF or saline was intravenously administered to the treatment and control groups, respectively. Functional evaluation, MRI, and fiber tract integrity on tractography images were analyzed. Proliferation (KI-67) and white matter repair markers (A2B5, 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase], adenomatous polyposis coli [APC], platelet-derived growth factor receptor alpha [PDGFR-α], oligodendrocyte marker O4 [O4], oligodendrocyte transcription factor [Olig-2], and myelin basic protein [MBP]) were analyzed at 7 and 28 days.. The BDNF-treated animals showed less functional deficit at 28 days after treatment than the controls (P<0.05). Although T2-MRI did not show differences in lesion size at 7 and 28 days between groups, diffusion tensor imaging tractography analysis revealed significantly better tract connectivity at 28 days in the BDNF group than in the controls (P<0.05). Increased proliferation of oligodendrocyte progenitors was observed in treated animals at 7 days (P<0.05). Finally, the levels of white matter repair markers (A2B5, CNPase, and O4 at 7 days; Olig-2 and MBP at 28 days) were higher in the BDNF group than in the controls (P<0.05).. BDNF administration exerted better functional outcome, oligodendrogenesis, remyelination, and fiber connectivity than controls in rats subjected to subcortical damage in ischemic stroke.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adenomatous Polyposis Coli Protein; Animals; Basic Helix-Loop-Helix Transcription Factors; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Cell Differentiation; Diffusion Tensor Imaging; Magnetic Resonance Imaging; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Rats; Receptor, Platelet-Derived Growth Factor alpha; Stroke; White Matter

Despite its high incidence, nerve fiber (axon and myelin) damage after cerebral infarct has not yet been extensively investigated. The aim of this study was to investigate white matter repair after adipose-derived mesenchymal stem cell (ADMSC) administration in an experimental model of subcortical stroke. Furthermore, we aimed to analyze the ADMSC secretome and whether this could be implicated in this repair function.. An animal model of subcortical ischemic stroke with white matter affectation was induced in rats by injection of endothelin-1. At 24 hours, 2 × 10(6) ADMSC were administered intravenously to the treatment group. Functional evaluation, lesion size, fiber tract integrity, cell death, proliferation, white matter repair markers (Olig-2, NF, and MBP) and NogoA were all studied after sacrifice (7 days and 28 days). ADMSC migration and implantation in the brain as well as proteomics analysis and functions of the secretome were also analyzed.. Neither ADMSC migration nor implantation to the brain was observed after ADMSC administration. In contrast, ADMSC implantation was detected in peripheral organs. The treatment group showed a smaller functional deficit, smaller lesion area, less cell death, more oligodendrocyte proliferation, more white matter connectivity and higher amounts of myelin formation. The treated animals also showed higher levels of white matter-associated markers in the injured area than the control group. Proteomics analysis of the ADMSC secretome identified 2,416 proteins, not all of them previously described to be involved in brain plasticity.. White matter integrity in subcortical stroke is in part restored by ADMSC treatment; this is mediated by repair molecular factors implicated in axonal sprouting, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery after stroke.

Topics: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Movement; Cell Proliferation; Diffusion Tensor Imaging; Disease Models, Animal; Endothelin-1; Magnetic Resonance Imaging; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myelin Basic Protein; Myelin Proteins; Nerve Tissue Proteins; Nogo Proteins; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Proteome; Proteomics; Rats; Rats, Sprague-Dawley; Recovery of Function; Stroke; White Matter

In this study we examined Th1 and Th17 immune responses to rat myelin basic protein (MBP), bovine MBP, human MBP, MBP 68-86, MBP 63-81 and ovalbumin in Lewis rats to determine which MBP antigen is recognized following ischemic brain injury. Responses were compared to animals immunized to rat MBP. Data show that immune responses following immunization with rat MBP are promiscuous with cross reaction to MBP from other species. After stroke, few animals develop Th1 or Th17 responses to MBP, but when those responses occur, especially Th1 responses to rat MBP in the brain, they are predictive of worse stroke outcome.

Topics: Animals; Autoimmunity; Brain; Cattle; Humans; Myelin Basic Protein; Rats; Rats, Inbred Lew; Stroke; Th1 Cells; Th17 Cells

Thymosin β4 (Tβ4) is a 5K actin binding peptide. Tβ4 improves neurological outcome in a rat model of embolic stroke and research is now focused on optimizing its dose for clinical trials. The purpose of this study was to perform a dose-response study of Tβ4 to determine the optimal dose of neurological improvement in a rat model of embolic stroke.. Male Wistar rats were subjected to embolic middle cerebral artery occlusion (MCAo). Rats were divided into 4 groups of 10 animals/group: control, 2, 12 and 18 mg/kg. Tβ4 was administered intraperitoneally 24h after MCAo and then every 3 days for 4 additional doses in a randomized controlled fashion. Neurological tests were performed after MCAo and before treatment and up to 8 weeks after treatment. The rats were sacrificed 56 days after MCAo and lesion volumes measured. Generalized estimating equation was used to compare the treatment effect on long term functional recovery at day 56. A quartic regression model was used for an optimal dose determination.. Tβ4 significantly improved neurological outcome at dose of 2 and 12 mg/kg at day 14 and extended to day 56 (p-values <0.05). The higher dose of 18 mg/kg did not show significant improvement. The estimated optimal dose of 3.75 mg/kg would provide optimal neurological improvement.. This study shown that Tβ4 significantly improved the long term neurological functional recovery at day 56 after MCAo with an optimal dose of 3.75 mg/kg. These results provide preclinical data for human clinical trials.

Topics: Acute Disease; Adenomatous Polyposis Coli; Animals; Brain; Bromodeoxyuridine; Disease Models, Animal; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Male; Myelin Basic Protein; Neuroimaging; Neurologic Examination; Rats; Stroke; Thymosin; Time Factors; Treatment Outcome; Versicans

Hypertension is associated with cerebral small vessel disease (SVD) and with diffuse white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). We tested whether stroke-prone spontaneously hypertensive rats (SHRSP), a model of chronic hypertension, exhibit WMH. Male SHRSP (age 10 months) without stroke symptoms were compared with age-matched male WKY rats. Stroke-prone spontaneously hypertensive rats exhibited no WMH on MRI scans (T2, T2*, diffusion tensor imaging) and no neuropathological lesions. While leptomeningeal arteries exhibited fibrohyaline wall thickening, with decreased smooth muscle actin relative to WKY, deep penetrating arterioles within the caudate nuclei had no vasculopathy. We conclude that WMH are not an obligate feature of stroke-free SHRSP aged up to 10 months.

Topics: Animals; Brain; Cerebral Arteries; Hypertension; Leukoencephalopathies; Male; Myelin Basic Protein; Rats; Rats, Inbred SHR; Stroke

In stroke, a common cause of neurological disability in adults is that the myelin sheaths are lost through the injury or death of mature oligodendrocytes, and the failure of remyelination may be often due to insufficient proliferation and differentiation of oligodendroglial progenitors. In the current study, we used middle cerebral artery occlusion (MCAO) to induced transient focal cerebral ischemia, and found that WIN55, 212-2 augmented actively proliferating oligodendrocytes measured by CC1 immunoreactive cells within the peri-infarct areas. To establish whether these effects were associated with changes in myelin formation, we analyzed the expression of myelin basic protein (MBP) and myelin ultrastructure. We found that WIN55, 212-2 showed more extensive remyelination than vehicle at 14 days post injection (dpi). The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway may be involved in OPCs differentiation. To determine the regulatory effect of WIN55, 212-2 post-treatment on phospho-ERK 1/2 (p-ERK 1/2) after ischemia/reperfusion, Western blot analysis was performed. We found that WIN55, 212-2 regulated the phosphorylation level of the ERK 1/2 to promote OPCs survival and differentiation. Notably, cannabinoid receptor 1 is coupled to the activation of the ERK cascade. Following rimonabant combined treatment, the effect of WIN55, 212-2 on regulating the phosphorylation level of the ERK 1/2 was reversed, and the effect of accelerated myelin formation was partially inhibited. Together, we first found that WIN55, 212-2 promoted OPCs differentiation and remyelination through regulation of the level of the p-ERK 1/2 via cannabinoid receptor 1.

Topics: Animals; Antimetabolites; Benzoxazines; Blotting, Western; Brain Ischemia; Bromodeoxyuridine; Cannabinoid Receptor Antagonists; Cell Differentiation; Cell Survival; Demyelinating Diseases; Immunohistochemistry; Indicators and Reagents; Male; MAP Kinase Signaling System; Microscopy, Electron; Morpholines; Myelin Basic Protein; Myelin Sheath; Naphthalenes; Oligodendroglia; Phosphorylation; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Stroke

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitors administered prior to or immediately after experimental stroke confer acute neuroprotection. However, it remains unclear if delayed treatment with a PTEN inhibitor improves long-term functional recovery after stroke. We addressed the issue in this study. Adult male mice were subjected to 1h of middle cerebral artery occlusion (MCAO) followed by treatment with a well-established PTEN inhibitor BPV or saline daily for 14 days, starting at 24h after MCAO. Functional recovery was assessed with behavioral tests and acute infarct volumes were analyzed histologically. Delayed BPV treatment did not reduce infarction during the acute phase, but significantly improved long-term functional recovery after MCAO. Since PTEN is a critical intrinsic inhibitory factor in axonal regeneration, we further examined BPV effects on axonal densities following MCAO using bielschowsky silver staining and immunohistochemistry with antibodies against myelin basic protein. Delayed BPV treatment significantly increased axon densities in the ischemic brain at 14 days after MCAO. Moreover, PTEN expression persistently remained high in the ischemic brain over 14 days after MCAO, and BPV treatment increased post-ischemic activation of Akt and mTOR in the ischemic brain. Akt and mTOR activation are the well-established cascades downstream to PTEN inhibition and have been shown to contribute to post-injury axonal regrowth in response to PTEN inhibition. Consistently, in an in vitro neuronal ischemia model, BPV enhanced axonal outgrowth of primary cortical neurons after oxygen-glucose deprivation and the enhancing effects were abolished by Akt/mTOR inhibition. In conclusion, delayed BPV treatment improved functional recovery from experimental stroke possibly via enhancing axonal growth and Akt/mTOR activation contributed to BPV-enhanced post-stroke axon growth.

Topics: Animals; Axons; Behavior, Animal; Brain; Brain Ischemia; Disease Models, Animal; Enzyme Inhibitors; Male; Mice; Myelin Basic Protein; Neurons; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Recovery of Function; Stroke; TOR Serine-Threonine Kinases; Vanadium Compounds

Antibodies to brain antigens are present in stroke survivors. In this study, we assessed autoantibody responses to white matter antigens, their correlation to white matter disease and stroke outcome. Antibody titers (immunoglobulin G [igG]) to myelin basic protein (MBP), proteolipid protein (PLP) and tetanus toxoid (TT) were available at one or more time points for 112 subjects with ischemic stroke. In comparison to the control subjects (N=40), there was a global decrease in IgG titers to TT early after stroke. Patients with white matter disease on magnetic resonance imaging had elevated titers of antibodies to both MBP and PLP at 30days after stroke, and anti-MBP antibodies were associated with worse outcome. The potential pathologic consequences of antibodies to white matter, especially MBP, is deserving of further investigation.

Topics: Aged; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoglobulin G; Male; Middle Aged; Myelin Basic Protein; Myelin Proteolipid Protein; Stroke

Ischemic injury to the central nervous system causes cellular activation and disintegration, leading to release of cell-type-specific proteins into the cerebrospinal fluid (CSF). We investigated CSF concentrations of myelin basic protein (MBP), glial fibrillary astrocytic protein (GFAP), the calcium-binding protein S100B, and neuron-specific enolase (NSE) in acute ischemic stroke patients and their relation to initial stroke severity, stroke location, and long-term stroke outcome.. CSF concentrations of MBP, GFAP, S100B, and NSE were assessed in 89 stroke patients on admission (mean 8.7 h after stroke onset) and in 35 controls. We evaluated the relation between CSF concentrations and (a) stroke severity (NIH Stroke Scale [NIHSS] score on admission, infarct volume), (b) stroke location, and (c) stroke outcome (modified Rankin Scale [mRS] score at month 3).. MBP concentration was significantly higher in subcortical than in cortical infarcts (median MBP, 1.18 vs 0.66 microg/L, P < 0.001). GFAP and S100B concentrations correlated with the NIHSS score on admission (GFAP, R = 0.35, P = 0.001; S100B, R = 0.29, P = 0.006), infarct volume (GFAP, R = 0.34, P = 0.001; S100B, R = 0.28, P = 0.008), and mRS score at month 3 (R = 0.42, P < 0.001 and R = 0.28, P = 0.007). Concentrations of NSE did not correlate with stroke characteristics.. MBP, GFAP, S100B, and NSE display relevant differences in cellular and subcellular origins, which are reflected in their relation to stroke characteristics. MBP is a marker for infarct location. GFAP and S100B correlate with stroke severity and outcome.

Topics: Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Female; Glial Fibrillary Acidic Protein; Humans; Male; Middle Aged; Myelin Basic Protein; Nerve Growth Factors; Phosphopyruvate Hydratase; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Stroke

Anamnestic recall of stroke-related deficits is a common clinical observation, especially during periods of systemic infection. The pathophysiology of this transient re-emergence of neurological dysfunction is unknown.. Male Lewis rats underwent 3 hours middle cerebral artery occlusion and were treated with lipopolysaccharide or saline at the time of reperfusion. The delayed-type hypersensitivity (DTH) response to myelin basic protein was examined 28 days after middle cerebral artery occlusion. Changes in behavioral outcomes were assessed after DTH testing and repeat administration of lipopolysaccharide or saline at 34 days. At the time of euthanasia (36 days), the immunologic response of splenocytes to myelin basic protein, neuron-specific enolase, and proteolipid protein was determined by enzyme-linked immunospot assay and the number of lymphocytes in the brain determined by immunocytochemistry.. Animals treated with lipopolysaccharide at middle cerebral artery occlusion had a greater DTH response to myelin basic protein than animals treated with saline. Among those animals that had fully recovered on a given behavioral test before DTH testing, those treated with lipopolysaccharide at middle cerebral artery occlusion displayed more neurological deterioration after DTH testing and had more CD8(+) lymphocytes within the ischemic core of the brain. Furthermore, the Th1 immune response to brain antigens in the spleen was more robust among those animals that deteriorated after DTH testing and there were more CD4(+) lymphocytes in the penumbral region of animals with a Th1 response to myelin basic protein.. Our data suggest that an immune response to the brain contributes to the phenomenon of anamnestic recall of stroke-related deficits after an infection. The contribution of the immune response to this phenomenon deserves further investigation.

Topics: Amnesia; Animals; Brain; Hypersensitivity, Delayed; Immune System; Infarction, Middle Cerebral Artery; Lipopolysaccharides; Male; Models, Animal; Myelin Basic Protein; Nervous System Diseases; Rats; Rats, Inbred Lew; Stroke; Th1 Cells; 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

Animals subjected to an inflammatory insult at the time of stroke are predisposed to the development of an inflammatory autoimmune response to brain. This response is associated with worse neurological outcome. Because induction of immunologic tolerance to brain antigens before stroke onset is associated with improved outcome, we sought to determine whether this paradigm could prevent the deleterious autoimmune response to brain provoked by an inflammatory stimulus at the time of ischemia.. Male Lewis rats were tolerized to myelin basic protein (MBP) or ovalbumin by intranasal administration before middle cerebral artery occlusion. At the time of reperfusion, all animals received lipopolysaccharide (1 mg/kg intraperitoneal). Behavioral tests were performed at set time intervals.. One month after middle cerebral artery occlusion, lymphocytes from the spleens of MBP-tolerized animals were less likely to evidence an autoimmune response and more likely to evidence a regulatory response (Treg) toward MBP than those from ovalbumin-tolerized animals. Animals that had an inflammatory response toward MBP (a Th1 response) performed worse on behavioral tests than those that did not. Fractalkine, a surrogate marker of inflammation, was elevated in animals with a Th1 response to MBP.. These data extend our previous findings and suggest that deleterious autoimmunity to brain antigens can be prevented by prophylactically inducing regulatory T-cell responses to those antigens.

Topics: Administration, Intranasal; Animals; Autoimmune Diseases of the Nervous System; Autoimmunity; Biomarkers; Chemokine CX3CL1; Encephalitis; Immune Tolerance; Immunity, Cellular; Immunotherapy; Infarction, Middle Cerebral Artery; Male; Myelin Basic Protein; Ovalbumin; Rats; Rats, Inbred Lew; Stroke; T-Lymphocytes, Regulatory; Treatment Outcome

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

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Phosphopyruvate Hydratase; S100 Proteins; Stroke