endothelin-1 and Encephalitis

Cerebral vasospasm lingers as the leading preventable cause of death and disability in patients who experience aneurysmal subarachnoid hemorrhage. Despite the potentially devastating consequences of cerebral vasospasm, the mechanisms behind it are incompletely understood. Nitric oxide, endothelin-1, bilirubin oxidation products and inflammation appear to figure prominently in its pathogenesis. Therapies directed at many of these mechanisms are currently under investigation and hold significant promise for an ultimate solution to this substantial problem.

Topics: Anti-Inflammatory Agents; Bilirubin; Calcium Channel Blockers; Cerebral Angiography; Encephalitis; Endothelin-1; Fibrinolytic Agents; Heme Oxygenase (Decyclizing); Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracranial Aneurysm; Magnesium; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Subarachnoid Hemorrhage; Time Factors; Vasospasm, Intracranial

Brain plasticity following focal cerebral ischaemia has been observed in both stroke survivors and in preclinical models of stroke. Endogenous neurovascular adaptation is at present incompletely understood yet its potentiation may improve long-term functional outcome. We employed longitudinal MRI, intracranial array electrophysiology, Montoya Staircase testing, and immunofluorescence to examine function of brain vessels, neurons, and glia in addition to forelimb skilled reaching during the subacute stage of ischemic injury progression. Focal ischemic stroke (~100mm

Topics: Animals; Brain; Brain Ischemia; Brain Waves; Encephalitis; Endothelin-1; Hypercapnia; Magnetic Resonance Imaging; Male; Motor Skills; Neuroglia; Neurons; Physical Stimulation; Rats, Sprague-Dawley; Recovery of Function; Sensorimotor Cortex; Somatosensory Cortex; Stroke; Touch Perception; Vascular Remodeling

Blood-brain-barrier (BBB) disruption, inflammation and thrombosis are important steps in the pathophysiology of acute ischemic stroke but are still inaccessible to therapeutic interventions. Rolipram specifically inhibits the enzyme phosphodiesterase (PDE) 4 thereby preventing the inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Rolipram has been shown to relief inflammation and BBB damage in a variety of neurological disorders. We investigated the therapeutic potential of rolipram in a model of brain ischemia/reperfusion injury in mice. Treatment with 10mg/kg rolipram, but not 2 mg/kg rolipram, 2 h after 60 min of transient middle cerebral artery occlusion (tMCAO) reduced infarct volumes by 50% and significantly improved clinical scores on day 1 compared with vehicle-treated controls. Rolipram maintained BBB function upon stroke as indicated by preserved expression of the tight junction proteins occludin and claudin-5. Accordingly, the formation of vascular brain edema was strongly attenuated in mice receiving rolipram. Moreover, rolipram reduced the invasion of neutrophils as well as the expression of the proinflammatory cytokines IL-1β and TNFα but increased the levels of TGFβ-1. Finally, rolipram exerted antithrombotic effects upon stroke and fewer neurons in the rolipram group underwent apoptosis. Rolipram is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Brain Injuries; Cytokines; Disease Models, Animal; Encephalitis; Endothelin-1; Hemodynamics; Infarction, Middle Cerebral Artery; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Occludin; Phosphodiesterase 4 Inhibitors; Rolipram; Stroke; Thrombosis

We reported previously that amoeboid microglial cells (AMC) in the developing brain exhibited endothelins (ETs) expression which diminished with advancing age and was undetected in microglia in the more mature brain. This study sought to explore if microglia in the adult would be induced to express ETs in altered conditions. By immunofluorescence microscopy, ETs and endothelin (ET)-B receptor were undetected in microglial cells in sham-operated and normal control rats. However, in adult rats subjected to middle cerebral artery occlusion (MCAO), lectin labeled activated microglia which occurred in large numbers in the marginal zones in the ischemic cortex at 3 days and 1 week intensely expressed ETs specifically endothelin (ET)-1 and ET-B receptor; ET-3 and ET-A receptor were absent in these cells. By RT-PCR and ELISA, ET-1 and -3 mRNA and protein expression level was progressively increased in the ischemic cerebral cortex after MCAO compared with the controls. ET-A and ET-B receptor mRNA and protein levels were concomitantly up-regulated. It is suggested that increased release of ET-1 following MCAO by massive activated microglia can exert an immediate constriction of local blood vessels bearing ET-A receptor. ET-1 may also interact with activated microglia endowed with ET-B receptor via an autocrine manner that may be linked to chemokines/cytokines production. ET-1, ET-3 and ET-B receptor were also localized in reactive astrocytes along with some oligodendrocytes. We conclude that activated microglia together with other glial cells in the marginal zone after MCAO are the main cellular source of ETs that may be involved in regulation of vascular constriction and glial chemokines/cytokines production. However, dissecting the role of individual component of the endothelin system in the various glial cells, notably activated microglia, would be vital in designing of an effective therapeutic strategy for clinical treatment of stroke in which microglial cells have been implicated.

Topics: Animals; Brain Ischemia; Cell Proliferation; Cytokines; Disease Models, Animal; Encephalitis; Endothelin-1; Endothelin-3; Endothelins; Gliosis; Immunohistochemistry; Infarction, Middle Cerebral Artery; Lectins; Male; Microglia; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Staining and Labeling; Up-Regulation; Vasoconstriction

Brain edema is detrimental in ischemic stroke and its treatment options are limited. Kinins are proinflammatory peptides that are released during tissue injury. The effects of kinins are mediated by 2 different receptors (B1 and B2 receptor [B1R and B2R]) and comprise induction of edema formation and release of proinflammatory mediators.. Focal cerebral ischemia was induced in B1R knockout, B2R knockout, and wild-type mice by transient middle cerebral artery occlusion. Infarct volumes were measured by planimetry. Evan's blue tracer was applied to determine the extent of brain edema. Postischemic inflammation was assessed by real-time reverse-transcriptase polymerase chain reaction and immunohistochemistry. To analyze the effect of a pharmacological kinin receptor blockade, B1R and B2R inhibitors were injected.. B1R knockout mice developed significantly smaller brain infarctions and less neurological deficits compared to wild-type controls (16.8+/-4.7 mm(3) vs 50.1+/-9.1 mm(3), respectively; P<0.0001). This was accompanied by a dramatic reduction of brain edema and endothelin-1 expression, as well as less postischemic inflammation. Pharmacological blockade of B1R likewise salvaged ischemic tissue (15.0+/-9.5 mm(3) vs 50.1+/-9.1 mm(3), respectively; P<0.01) in a dose-dependent manner, even when B1R inhibitor was applied 1 hour after transient middle cerebral artery occlusion. In contrast, B2R deficiency did not confer neuroprotection and had no effect on the development of tissue edema.. These data demonstrate that blocking of B1R can diminish brain infarction and edema formation in mice and may open new avenues for acute stroke treatment in humans.

Topics: Animals; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Brain Edema; Cerebral Arteries; Cerebral Infarction; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Encephalitis; Endothelin-1; Gene Expression; Infarction, Middle Cerebral Artery; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Bradykinin B1; Receptor, Bradykinin B2; RNA, Messenger

Following acute and chronic neurodegenerative disorders, a cascade of pathological events including inflammatory response, excitotoxicity and oxidative stress induces secondary tissue loss in both gray and white matter. Axonal damage and demyelination are important components of the white matter demise during these diseases. In spite of this, a few studies have addressed the patterns of inflammatory response, axonal damage and demyelination following focal ischemic damage to the central nervous system (CNS). In the present study, we describe the patterns of inflammatory response, axonal damage and myelin impairment following microinjections of 10 pmol of endothelin-1 into the rat striatum. Animals were perfused at 1 day, 3 days and 7 days after injection. 20 mum sections were stained by hematoxylin and immunolabeled for neutrophils (anti-MBS-1), activated macrophages/microglia (anti-ED1), damaged axons (anti-betaAPP) and myelin (anti-MBP). The evolution of acute inflammation was quantitatively assessed by cell counts in different survival times. There was recruitment of both neutrophils and macrophages to the damaged striatal parenchyma with maximum recruitment at 1 day and 7 days, respectively. Progressive myelin impairment in the striatal white matter tracts has been observed mainly at later survival times. beta-APP+ endbulbs were not present in all evaluated time points. These results suggest that progress myelin impairment in the absence of damage to axonal cylinder is a feature of white matter pathology following endothelin-1-induced focal striatal ischemia.

Topics: Amyloid beta-Peptides; Animals; Axons; Biomarkers; Brain Ischemia; Cerebral Arteries; Chemotaxis, Leukocyte; Corpus Striatum; Demyelinating Diseases; Disease Progression; Encephalitis; Endothelin-1; Male; Microcirculation; Microglia; Microinjections; Myelin Basic Protein; Nerve Fibers, Myelinated; Neutrophils; Rats; Rats, Wistar

The role of endothelin (ET)B receptors in chemokine production in the brain of rats was examined. Intracerebroventricular administration of 500 pmol/day of Ala(1,3,11,15)-ET-1, a selective ETB agonist, for 3 or 7 days increased monocyte chemoattractant protein (MCP)-1 and cytokine-induced neutrophil chemoattractant (CINC)-1 mRNA in the caudate-putamen and cerebrum, whereas it had no effects on regulated on activation normal T-cell expressed and secreted (RANTES), fractalkine and stromal cell-derived factor (SDF)-1alpha mRNA expression. Immunoreactive MCP-1 and CINC-1 in the caudate-putamen and the cerebrum were increased by the ETB agonist. Immunohistochemical observations on the Ala(1,3,11,15)-ET-1-infused rats showed that glial fibrillary acidic protein-positive astrocytes had immunoreactivity for MCP-1 and CINC-1. These findings indicate that the activation of brain ETB receptors causes the production of MCP-1 and CINC-1, and suggest a pathophysiological role for brain ETB receptors in nervous system damage.

Topics: Animals; Astrocytes; Brain; Chemokine CCL2; Chemokine CXCL1; Chemokines, CXC; Encephalitis; Endothelin-1; Endothelins; Glial Fibrillary Acidic Protein; Gliosis; Immunohistochemistry; Injections, Intraventricular; Male; Neostriatum; Rats; Rats, Wistar; Receptor, Endothelin B; RNA, Messenger; Telencephalon; Up-Regulation

A beta peptides are the major protein constituents of Alzheimer's disease (AD) senile plaques and also form some deposits in the cerebrovasculature leading to cerebral amyloid angiopathy and hemorrhagic stroke. Functional vascular abnormalities are one of the earlier clinical manifestations in both sporadic and familial forms of AD. Most of the cardiovascular risk factors (for instance, diabetes, hypertension, high cholesterol levels, atherosclerosis and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of A beta on endothelin-1 induced vasoconstriction in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized A beta enhances endothelin-1 induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoactive effect of A beta in these large human cerebral arteries is inhibited by NS-398, a selective cyclooxygenase-2 inhibitor and by SB202190, a specific p38 Mitogen Activated Protein Kinase inhibitor suggesting the involvement of a pro-inflammatory pathway. Using a scanner laser Doppler imager, we observed that cerebral blood flow is decreased in the double transgenic APPsw Alzheimer mouse (PS1/APPsw) compared to PS1 littermates and can be improved by chronic treatment with either NS-398 or SB202190. Altogether, our data suggest a link between inflammation and the compromised cerebral hemodynamics in AD.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; Isoenzymes; Male; Membrane Proteins; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Prostaglandin-Endoperoxide Synthases; Vasoconstriction

The role of endothelin-1 (ET-1) in the development of experimental autoimmune encephalomyelitis (EAE) was studied by the blocking the action of ET-1 with a receptor antagonist, BQ-123. Intrathecal administration of BQ-123 significantly ameliorated EAE progression at the peak stage of EAE (p<0.05). By immunohistochemistry, ED-1-positive macrophages in EAE lesions were identified as major producers of ET-1, whereas the immunoreactivity of ET-1 on brain cells, such as astrocytes, was dramatically increased in accordance with the progression of EAE. This study points to a putative pro-1nflammatory role for ET-1 in the pathogenesis of EAE. One possible application for the ET-1 receptor antagonist might be helpful in the therapy of autoimmune neurological disorders.

Topics: Animals; Antihypertensive Agents; Astrocytes; Blood Vessels; Demyelinating Diseases; Disease Models, Animal; Encephalitis; Encephalomyelitis, Autoimmune, Experimental; Endothelin Receptor Antagonists; Endothelin-1; Female; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Spinal; Male; Nerve Degeneration; Peptides, Cyclic; Rats; Rats, Inbred Lew; Receptors, Endothelin; Spinal Cord; Treatment Outcome