losartan-potassium and Encephalitis

Highly expressed Erythropoietin Receptor (EPO-R) has been detected in several nonhematopoietic hypoxic cells, including cells from different brain areas in response to many different types of cell injury. In brain, hypoxia-ischemia (HI) can induce a wide spectrum of biologic responses, where inflammation and apoptosis are the main protagonists. Inflammation, as a primary brain insult, can induce a chronic hypoxic condition, producing the continuous cycle of inflammation-hypoxia that increases the apoptotic-cell number. It has also been demonstrated that administration of erythropoietin (EPO) prevented the neuronal death induced by HI, as well as the induction of lipid peroxidation in the hippocampus in a rodent model of Alzheimer's disease. Anti-apoptotic, anti-inflammatory, anti-oxidant, and/or cell-proliferative effects of EPO, have been observed in all type of cells expressing EPO-R, resulting in a potential tool for neuroprotection, neuroreparation, or neurogenesis of brain damaged areas. The nasal route is an alternative way of drugs administration that has been successfully exploited for bypassing the blood brain barrier, and subsequently delivering EPO and other molecules to central nervous system. Intranasal administration of EPO could be a new therapeutic opportunity in several brain damages that includes hypoxia, inflammation, neurodegenerative process, and apoptosis.

Topics: Administration, Intranasal; Animals; Blood-Brain Barrier; Encephalitis; Erythropoietin; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Receptors, Erythropoietin

Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50-75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.

Topics: Acute Disease; Animals; Autoimmune Diseases; Brain; Brain Ischemia; Cerebral Cortex; Encephalitis; Epoetin Alfa; Erythropoietin; Humans; Kainic Acid; Neuroprotective Agents; Recombinant Proteins; Stroke; Wounds, Nonpenetrating

Parkinson's disease (PD) is the second most common neurodegenerative disease, presenting with midbrain dopaminergic neurons degeneration. A number of studies suggest that microglial activation may have a role in PD. It has emerged that inflammation-derived oxidative stress and cytokine-dependent toxicity may contribute to nigrostriatal pathway degeneration and exacerbate the progression of the disease in patients with idiopathic PD. Cell therapies have long been considered a feasible regenerative approach to compensate for the loss of specific cell populations such as the one that occurs in PD. We recently demonstrated that erythropoietin-releasing neural precursors cells (Er-NPCs) administered to MPTP-intoxicated animals survive after transplantation in the recipient's damaged brain, differentiate, and rescue degenerating striatal dopaminergic neurons. Here, we aimed to investigate the potential anti-inflammatory actions of Er-NPCs infused in an MPTP experimental model of PD.. The degeneration of dopaminergic neurons was caused by MPTP administration in C57BL/6 male mice. 2.5 × 10. Er-NPC administration promoted a rapid anti-inflammatory effect that was already evident 24 h after transplant with a decrease of pro-inflammatory and increase of anti-inflammatory cytokines mRNA expression levels. This effect was maintained until the end of the observational period, 2 weeks post-transplant. Here, we show that Er-NPCs transplant reduces macrophage infiltration, directly counteracting the M1-like pro-inflammatory response of murine-activated microglia, which corresponds to the decrease of CD68 and CD86 markers, and induces M2-like pro-regeneration traits, as indicated by the increase of CD206 and IL-10 expression. Moreover, we also show that this activity is mediated by Er-NPCs-derived erythropoietin (EPO) since the co-injection of cells with anti-EPO antibodies neutralizes the anti-inflammatory effect of the Er-NPCs treatment.. This study shows the anti-inflammatory actions exerted by Er-NPCs, and we suggest that these cells may represent good candidates for cellular therapy to counteract neuroinflammation in neurodegenerative disorders.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Coculture Techniques; Corpus Striatum; Cytokines; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Encephalitis; Erythropoietin; Green Fluorescent Proteins; Male; Mice; Mice, Inbred C57BL; Muscle Strength; Neural Stem Cells; Parkinsonian Disorders; Recovery of Function; Smell; Tyrosine 3-Monooxygenase

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive cognitive dysfunction and memory loss. There is deposition of amyloid plaques in the brain and subsequent neuronal loss. Neuroinflammation plays a key role in the pathogenesis of AD. There is still no effective curative therapy for these patients. One promising strategy involves the stimulation of endogenous stem cells. This study investigated the therapeutic effect of erythropoietin (EPO) in neurogenesis, and proved its manipulation of the endogenous mesenchymal stem cells in model of lipopolysaccharide (LPS)-induced neuroinflammation.. Forty five adult male mice were divided equally into 3 groups: Group I (control), group II (LPS untreated group): mice were injected with single dose of lipopolysaccharide (LPS) 0.8 mg/kg intraperitoneally (ip) to induce neuroinflammation, group III (EPO treated group): in addition to (LPS) mice were further injected with EPO in dose of 40 μg/kg of body weight three times weekly for 5 consecutive weeks. Groups were tested for their locomotor activity and memory using open field test and Y-maze. Cerebral specimens were subjected to histological and morphometric studies. Glial fibrillary acidic protein (GFAP) and mesenchymal stem cell marker CD44 were assessed using immunostaining. Gene expression of brain derived neurotrophic factor (BDNF) was examined in brain tissue.. LPS decreased locomotor activity and percentage of correct choices in Y-maze test. Cerebral sections of LPS treated mice showed increased percentage area of dark nuclei and amyloid plaques. Multiple GFAP positive astrocytes were detected in affected cerebral sections. In addition, decrease BDNF gene expression was noted. On the other hand, EPO treated group, showed improvement in locomotor and cognitive function. Examination of the cerebral sections showed multiple neurons exhibiting less dark nuclei and less amyloid plaques in comparison to the untreated group. GFAP positive astrocytes were also reduced. Cerebral sections of the EPO treated group showed multiple branched and spindle CD44 positive cells inside and around blood vessels more than in LPS group. This immunostaining was negative in the control group. EPO administration increased BDNF gene expression.. This study proved that EPO provides excellent neuroprotective and neurotrophic effects in vivo model of LPS induced neuroinflammation. It enhances brain tissue regeneration via stimulation of endogenous mesenchymal stem cells proliferation and their migration to the site of inflammation. EPO also up regulates cerebral BDNF expression and production, which might contributes to EPO mediated neurogenesis. It also attenuates reactive gliosis thus reduces neuroinflammation. These encouraging results obtained with the use of EPO proved that it may be a promising candidate for future clinical application and treatment of neurodegenerative diseases.

Topics: Analysis of Variance; Animals; Brain-Derived Neurotrophic Factor; Cell Movement; Disease Models, Animal; Encephalitis; Erythropoietin; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hyaluronan Receptors; Lipopolysaccharides; Locomotion; Male; Maze Learning; Mice; Neuroprotective Agents; RNA, Messenger; Stem Cells

We performed high-dose erythropoietin therapy (hEPO) for acute encephalopathy or encephalitis (AE), and evaluated its safety and efficacy.. We performed hEPO in AE patients with widespread lesions demonstrated by diffusion-weighted imaging, and prospectively investigated changes in hemoglobin levels, adverse events, changes in images, and developmental quotients.. All four patients showed neither an increase in the hemoglobin level nor adverse event possibly related to hEPO. One patient with acute encephalitis showed resolution of the lesion and normal developmental quotient. Two patients who had acute encephalopathy with febrile convulsive status epilepticus showed mild cerebral atrophy in the recovery phase;one had a normal developmental quotient. The patient with acute necrotizing encephalopathy including a brainstem lesion avoided acute-phase death.. Two patients showed no sequelae despite images indicating widespread abnormality. hEPO could be performed safely in patients with AE, however further trials are necessary concerning its efficacy.

Topics: Acute Disease; Child, Preschool; Diffusion Magnetic Resonance Imaging; Electroencephalography; Encephalitis; Erythropoietin; Female; Humans; Infant; Male; Treatment Outcome

The cytokine hormone erythropoietin (EPO) and the chemokine CCL3 are known to be produced in the brain under various pathological conditions. In this study, we investigated whether EPO and CCL3 influence on each other during neuroinflammation. We showed that EPO could reduce lipopolysaccharide (LPS)-induced CCL3 mRNA expression in rat cerebellar neuron-enriched preparations (real-time RT-PCR). Whereas administration of EPO or CCL3 respectively mediated neuroprotective properties after LPS treatment, the combinations of both molecules resulted in increased caspase 3/7 activity. Thus, it seems that - probably depending on particular conditions - EPO and CCL3 may cancel each other's functional properties.

Topics: Animals; Caspase 3; Caspase 7; Cerebellum; Chemokine CCL3; Encephalitis; Erythropoietin; Gene Expression; Lipopolysaccharides; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; RNA, Messenger

Erythropoietin (EPO) suppresses epileptic seizures, but the mechanism is unclear. The search for novel targets in the therapy of epilepsy has focused recently on brain inflammation since brain inflammation and the associated blood-brain barrier (BBB) damage appears to be an integral part of epilepsy pathophysiology. We examined the effects of EPO on proinflammatory mediators in brain and serum in PTZ-induced generalized seizure model. The inflammation markers (IL-1β, TNF-α, IL-6, IL-10), BBB and neuron damage markers (S100B, Neuron specific enolase; NSE, respectively) in serum and brain of Sprague-Dawley male rats were examined with the ELISA method. Nitric oxide synthase (NOS) isoforms were investigated immunohistochemically in hippocampus. EPO treatment 4 h and 24 h before PTZ administration had diverse effects. EPO treatment 4 h before PTZ administration elongated the seizure latency, decreased the inflammation and damage markers in serum and brain significantly, whereas EPO treatment 24 h before PTZ administration lowered inflammation and damage markers to control levels and decreased the seizure stage. PTZ-induced seizures increased inducible NOS (iNOS) activity and decreased endothelial NOS (eNOS) activity in hippocampus. Both EPO pretreatments reversed these effects. These findings, i.e., decreased iNOS activity and increased eNOS activity by EPO suggest the first time that the favorable effect of EPO pretreatment on inflammatory mediators triggered by PTZ-induced seizures. This can provide further insight into epilepsy treatment and new prophylactic strategies against epilepsy risk.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Convulsants; Cytokines; Drug Administration Schedule; Encephalitis; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Hippocampus; Male; Pentylenetetrazole; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein beta Subunit; Seizures; Time Factors

Blast injuries are an increasing problem in military conflicts and terrorist incidents. Blast-induced traumatic brain injury has risen to prominence and represents a specific form of primary brain injury, with sufficiently different physical attributes (and possibly biological consequences) to be classified separately. There is increasing interest in the role of blast in initiating inflammatory responses, which may be linked to the pathological processes seen clinically. Terminally anaesthetised rats were exposed to a blast wave directed at the cranium, using a bench-top blast wave generator. Control animals were not exposed to blast. Animals were killed after 8 h, and the brains examined for evidence of an inflammatory response. Compared to controls, erythropoietin, endothelial integrins, ICAM and sVCAM, and the pro-inflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1) were significantly elevated. Other pro-inflammatory cytokines, including MIP-1α, were also detectable, but levels did not permit accurate quantification. Six inflammatory genes examined by qRT-PCR exhibited a biologically significant increase in activity in the blast-exposed animals. These included genes supporting chemokines responsible for monocyte recruitment, including MCP-1, and chemokines influencing T cell movement. Brain injury is usually accompanied by pathological neuro-inflammation. This study shows that blast brain injury is no exception, and the data provide important mechanistic clues regarding the drivers of such inflammation. Whilst this effect alone is unlikely to be responsible for the totality of consequences of blast brain injury, it suggests a mechanism that may be priming the cerebral inflammatory response and rendering cerebral tissue more susceptible to the deleterious effects of systemic inflammatory reactions.

Topics: Animals; Blast Injuries; Brain Injuries; Cell Adhesion Molecules; Chemokine CCL2; Chemotaxis, Leukocyte; Cytokines; Encephalitis; Endothelium, Vascular; Erythropoietin; Gene Expression Regulation; Hemodynamics; Integrins; Male; Random Allocation; Rats; Rats, Wistar; T-Lymphocytes

Intrauterine infection and inflammation have been linked to preterm birth and brain damage. We hypothesized that recombinant human erythropoietin (rhEPO) would ameliorate brain damage in anovine model of fetal inflammation. At 107 +/- 1 day of gestational age (DGA), chronically catheterized fetal sheep received on 3 consecutive days 1) an intravenous bolus dose of lipopolysaccharide ([LPS] approximately 0.9 microg/kg; n = 8); 2) an intravenous bolus dose of LPS, followed at 1 hour by 5,000 IU/kg of rhEPO (LPS + rhEPO, n = 8); or 3) rhEPO (n = 5). Untreated fetuses (n = 8) served as controls. Fetal physiological parameters were monitored, and fetal brains and optic nerves were histologically examined at 116 +/- 1 DGA. Exposure to LPS, but not to rhEPO alone or saline, resulted in fetal hypoxemia, hypotension (p < 0.05), brain damage, including white matter injury, and reductions in numbers of myelinating oligodendrocytes in the corticospinal tract and myelinated axons in the optic nerve (p < 0.05 for both). Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but reduced brain injury and was beneficial to myelination in the corticospinal tract and the optic nerve. This is the first study in a long-gestation species to demonstrate the neuroprotective potential of rhEPO in reducing fetal brain and optic nerve injury after LPS exposure.

Topics: Animals; Brain; Brain Damage, Chronic; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Endotoxins; Erythropoietin; Female; Fetal Diseases; Fetal Hypoxia; Injections, Intravenous; Lipopolysaccharides; Nerve Fibers, Myelinated; Neuroprotective Agents; Optic Nerve; Pregnancy; Sheep, Domestic; Treatment Outcome

The impact of epoetin beta (recombinant human erythropoietin) on brain infarction area (BIA) and neurological status in a rat model of acute ischemic stroke (IS) induced by distal left internal carotid artery occlusion was investigated.. Adult male Sprague-Dawley rats (n = 30) were categorized into group 2 (IS only) and group 3 (IS plus intraperitoneal erythropoietin 5000 IU/kg at 0, 12, and 24 hours after IS). Healthy Sprague-Dawley rats (n = 10) served as group 1.. Analysis of brain tissues showed larger BIA in group 2 than in group 3 (P < 0.001). Corner test identified highest frequency of left turn in group 2 (P < 0.05). The mRNA expressions of Bax, caspase 3, interleukin 18, toll-like receptor 4, and plasminogen activator inhibitor 1 were highest, whereas Bcl-2 was lowest in group 2 (P < 0.05). Lower CXCR4 and stromal cell-derived factor 1 expressions were noted in group 2 than in group 3 (P < 0.01). Immunohistofluorescence staining showed lower expressions of CXCR4, stromal cell-derived factor 1, von Willebrand factor, and doublecortin with higher number of apoptotic nuclei in group 2 than in group 3 (P < 0.001). Immunohistochemical staining demonstrated lower cellular proliferation and number of small vessels with higher glial fibrillary acid protein expression in group 2 than in group 3 (P < 0.01).. Erythropoietin significantly limited BIA and improved sensorimotor dysfunction after acute IS.

Topics: Acute Disease; Animals; Apoptosis; Brain Infarction; Brain Ischemia; Disease Models, Animal; Doublecortin Protein; Encephalitis; Erythropoietin; Hematinics; Humans; Male; Neovascularization, Physiologic; Neurogenesis; Oxidative Stress; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Recovery of Function

This study sought to determine the bio-availability of recombinant human erythropoietin (EPO) in the brain and blood and its effects on the cerebral concentrations of the inflammatory mediators interleukin-1beta (IL-1beta) and macrophage-inflammation protein-2 (MIP-2) following lateral fluid percussion brain injury (FPI) in the rat. After induction of moderate FPI (1.6-1.8 atm), EPO was injected intraperitoneally (IP) or intravenously (IV) at doses of 1000-5000 U/kg in a randomized and blinded manner. Animals were then sacrificed at time points (4, 8, 12, 24 h) post-trauma, and the brain concentrations of EPO, IL-1beta, and MIP-2 were determined. EPO administration leads to a dose-dependent increase in the brain concentration of the drug; however, this could only be detected at doses of 3000 and 5000 U/kg. The cerebral concentration peaked in the first 4 h following trauma. EPO concentrations were significantly higher and decreased more slowly in the traumatized cortex compared to the contralateral side (p<0.0125). IV EPO (5000 U/kg) produced slightly higher concentrations of EPO than same doses injected IP; however, this was not significant. At a dose of 5000 U/kg, EPO significantly reduced the increase in IL-1beta at 8 and 12 h in both cortical sides. It also reduced the increase in MIP-2 but only after 8 h, on the contralateral side and after 12 h on the ipsilateral side. Our results suggest that EPO crosses the blood-brain barrier (BBB) by 4 h after trauma and is localized primarily in the traumatized cortex. Further, it has biological efficacy at 8 h on several inflammatory proteins, yet must be employed at high doses to cross the BBB.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Injuries; Chemokine CXCL2; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Administration Schedule; Encephalitis; Erythropoietin; Functional Laterality; Humans; Injections, Intraperitoneal; Injections, Intravenous; Interleukin-1beta; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Time Factors

Erythropoietin (EPO) has recently been shown to have a neuroprotective effect in animal models of traumatic brain injury (TBI). However, the precise mechanisms remain unclear. Cerebral inflammation plays an important role in the pathogenesis of secondary brain injury after TBI. We, therefore, tried to analyze how recombinant human erythropoietin (rhEPO) might effect the inflammation-related factors common to TBI: nuclear factor kappa B (NF-kappaB), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) in a rat TBI model. Male rats were given 0 or 5000 units/kg injections of rhEPO 1h post-injury and on days 1, 2 and 3 after surgery. Brain samples were extracted at 3 days after trauma. We measured NF-kappaB by electrophoretic mobility shift assay (EMSA); IL-1beta, TNF-alpha and IL-6 by enzyme-linked immunosorbent assay (ELISA); ICAM-1 by immunohistochemistry; brain edema by wet/dry method; blood-brain barrier (BBB) permeability by Evans blue extravasation and cortical apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method. We found that NF-kappaB, pro-inflammatory cytokines and ICAM-1 were increased in all injured animals. In animals given rhEPO post-TBI, NF-kappaB, IL-1beta, TNF-alpha and ICAM-1 were decreased in comparison to vehicle-treated animals. Measures of IL-6 showed no change after rhEPO treatment. Administration of rhEPO reduced brain edema, BBB permeability and apoptotic cells in the injured brain. In conclusion, post-TBI rhEPO administration may attenuate inflammatory response in the injured rat brain, and this may be one mechanism by which rhEPO improves outcome following TBI.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Blood-Brain Barrier; Brain Edema; Brain Injuries; Cerebral Cortex; Cytoprotection; Disease Models, Animal; Encephalitis; Erythropoietin; Humans; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Male; Neuroprotective Agents; NF-kappa B; Rats; Rats, Wistar; Recombinant Proteins; Treatment Outcome; Tumor Necrosis Factor-alpha

Erythropoietin (EPO), a pleiotropic cytokine involved in erythropoiesis, is tissue-protective in ischemic, traumatic, toxic and inflammatory injuries. In this study, we investigated the effect of EPO in experimental intracerebral hemorrhage (ICH). Two hours after inducing ICH via the stereotaxic infusion of collagenase, recombinant human EPO (500 or 5000 IU/kg, ICH + EPO group) or PBS (ICH + vehicle group) was administered intraperitoneally, then once daily afterwards for 1 or 3 days. ICH + EPO showed the better functional recovery in both rotarod and modified limb placing tests. The brain water content was decreased in ICH + EPO dose-dependently, as compared with ICH + vehicle. The effect of EPO on the brain water content was inhibited by N(omega)-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg). Mean hemorrhage volume was also decreased in ICH + EPO. EPO reduced the numbers of TUNEL +, myeloperoxidase + or OX-42 + cells in the perihematomal area. In addition, EPO reduced the mRNA level of TNF-alpha, Fas and Fas-L, as well as the activities of caspase-8, 9 and 3. EPO treatment showed up-regulations of endothelial nitric oxide synthase (eNOS) and p-eNOS, pAkt, pSTAT3 and pERK levels. These data suggests that EPO treatment in ICH induces better functional recovery with reducing perihematomal inflammation and apoptosis, coupled with activations of eNOS, STAT3 and ERK.

Topics: Animals; Apoptosis; Biomarkers; Body Water; Brain; Brain Edema; Cell Death; Cerebral Hemorrhage; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Enzyme Activation; Enzyme Inhibitors; Erythropoietin; Male; Nerve Degeneration; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Recovery of Function; Signal Transduction; STAT3 Transcription Factor; Treatment Outcome

Using immunohistochemistry, expression of erythropoietin (EPO), a hypoxia-inducible neuroprotective factor, and its receptor (EPOR) were investigated in human brain tissue after ischemia/hypoxia. Autopsy brains of neuropathologically normal subjects were compared to those with ischemic infarcts or hypoxic damage. In normal brain, weak EPO/EPOR immunoreactivity was mainly neuronal. In fresh infarcts, EPO immunoreactivity appeared in vascular endothelium, EPOR in microvessels and neuronal fibers. In older infarcts reactive astrocytes exhibited EPO/EPOR immunoreactivity. Acute hypoxic brain damage was associated with vascular EPO expression, older hypoxic damage with EPO/EPOR immunoreactivity in reactive astrocytes. The pronounced up-regulation of EPO/EPOR in human ischemic/hypoxic brains underlines their role as an endogenous neuroprotective system and suggests a novel therapeutic potential in cerebrovascular disease for EPO, a clinically well-characterized and safe compound.

Topics: Adult; Aged; Astrocytes; Brain; Encephalitis; Endothelium, Vascular; Erythropoietin; Female; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein; Humans; Hypoxia-Ischemia, Brain; Male; Middle Aged; Nerve Degeneration; Neurofilament Proteins; Neurons; Receptors, Erythropoietin; von Willebrand Factor