Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Broad spectrum caspase inhibitors have been found to reduce neurodegeneration caused by cerebral ischemia. We studied whether blockade of group I caspases, mainly caspase-1, using the inhibitor Ac-YVAD.cmk reduced infarct volume and produced prolonged neuroprotection. Ac-YVAD.cmk (300 ng/rat) was injected intracerebroventricularly 10 min after permanent middle cerebral artery occlusion in the rat. Drug treatment induced a significant reduction of infarct volume not only 24 hr after ischemia (total damage, percentage of hemisphere volume: control, 41.1 +/- 2.3%; treated, 26.5 +/- 2.1%; p < 0.05) but also 6 d later (total damage: control, 30.6 +/- 2.2%; treated, 23.0 +/- 2.2%; p < 0.05). Ac-YVAD. cmk treatment resulted in a reduction not only of caspase-1 (control, 100 +/- 20.3%; treated, 3.4 +/- 10.4%; p < 0.01) but also of caspase-3 (control, 100 +/- 30.3%; treated, 13.2 +/- 9.5%; p < 0.05) activity at 24 hr and led to a parallel decrease of apoptosis as measured by nucleosome quantitation (control, 100 +/- 11.8%; treated, 47 +/- 5.9%; p < 0.05). Six days after treatment no differences in these parameters could be detected between control and treated animals. Likewise, brain levels of the proinflammatory cytokines IL-1beta and TNF-alpha were reduced at 24 hr (39.5 +/- 23.7 and 51.9 +/- 10.3% of control, respectively) but not at 6 d. Other cytokines, IL-10, MCP-1, MIP-2, and the gaseous mediator nitric oxide, were not modified by the treatment. These findings indicate that blockade of caspase-1-like activity induces a long-lasting neuroprotective effect that, in our experimental conditions, takes place in the early stages of damage progression. Finally, this effect is achieved by interfering with both apoptotic and inflammatory mechanisms.
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PMID:Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. 1084 8

Cytokines orchestrate T cell-mediated immune responses. In experimental autoimmune encephalomyelitis (EAE) the proinflammatory cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-12 and IL-18 are critically involved in the initiation and amplification of the local immune response in the CNS which is counter-balanced by upregulation of antiinflammatory cytokines such as IL-10. The predicted function of individual cytokines during EAE has recently been challenged by transgenic animal studies and neutralization experiments. Cytokine induction is not restricted to autoimmunity in the nervous system. Cytokines are involved in nerve regeneration and induced in focal cerebral ischemia both at the site of infarction and in remote nonischemic brain regions. In cerebral ischemia TNF-alpha and IL-1beta probably have dual functions: In concert with upregulation of inducible NO synthase (iNOS) they exert neurotoxicity while in the absence of iNOS, TNF-alpha and IL-1beta may contribute to neuroprotection and plasticity. The interplay between glial cells, infiltrating leukocytes and induced cytokines leading to CNS pathology is complex and incompletely understood. Further assessment of the functional contribution of cytokines critically depends on the elucidation of downstream secondary signaling mechanisms.
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PMID:Cytokines in CNS disorders: neurotoxicity versus neuroprotection. 1096 21

Brain ischemia is characterized by local inflammation reflected by accumulation of inflammatory cells and a multitude of mediators. Among them, cytokines and chemokines may influence the inflammatory cascade that follows cerebral ischemia. Here we report on brain hemispheric and systemic increase of pro-inflammatory IL-17 and IFN-gamma, the anti-inflammatory cytokines IL-4 and IL-10, and the chemokines IP-10, IL-8 and MIP-2, 1 h to 6 days after permanent middle cerebral artery occlusion (pMCAO). IL-17 and IFN-gamma mRNA levels were elevated in the ischemic hemispheres of pMCAO-operated rats compared with corresponding hemispheres of sham-operated rats. Levels were slightly elevated at 1 h, and peaked at 6 days after pMCAO. IL-8 and MIP-2 levels in the ischemic hemispheres peaked at 24 h, whereas IP-10 showed a biphasic profile with two peaks at 6 h and 6 days after pMCAO. IL-4 peaked in the ischemic hemispheres at 6 h, when IL-10 levels were lower than in sham-operated rats, and IL-10 levels peaked at 2 days after pMCAO. Systemically, the numbers of IL-17 and IFN-gamma mRNA expressing blood mononuclear cells were elevated already at 1 h after pMCAO, preceding the changes in the ischemic hemispheres. Altered levels of IL-17 and IFN-gamma after pMCAO may affect outcome of brain ischemia.
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PMID:IL-17 and IFN-gamma mRNA expression is increased in the brain and systemically after permanent middle cerebral artery occlusion in the rat. 1131 24

Previous studies demonstrated that C1-inhibitor (C1-INH), a complement and contact-kinin systems inhibitor, is neuroprotective in cerebral ischemia. To investigate the mechanism of this action, we evaluated the expression of neurodegeneration and inflammation-related factors in mice subjected to 2-h ischemia and 2 or 46 h reperfusion. C1-INH significantly dampened the mRNA expression of the adhesion molecules P-selectin and ICAM-1 induced by the ischemic insult. It significantly decreased the pro-inflammatory cytokine (TNF alpha, IL-18) and increased the protective cytokine (IL-6, IL-10) gene expression. C1-INH treatment prevented the decrease of NFH gene, a marker of cellular integrity and counteracted the increase of pro-caspase 3, an apoptosis index. Furthermore, C1-INH markedly inhibited the activation and/or recruitment of microglia/macrophage, as shown by immunohistochemistry. In conclusion, C1-INH exerts an anti-inflammatory and anti-apoptotic action on ischemia-reperfusion injury. Our present and past data support a major effect of C1-INH on cell recruitment from the vasculature to the ischemic site.
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PMID:C1-inhibitor protects against brain ischemia-reperfusion injury via inhibition of cell recruitment and inflammation. 1583 56

Ischaemia-reperfusion injury is associated with an inflammatory response as well as apoptosis in the affected area. Inflammatory responses are characterized, among others, by an increased production of several cytokines, while caspases are implicated in the control of apoptosis. The aim of the present work was to determine changes in the levels of inflammatory and apoptotic indices in the rat brain after cerebral ischaemia-reperfusion and to evaluate the effect of the non-steroidal anti-inflammatory compound N-(2-thiolethyl)-2-{2-[N'-[2,6-dichlorophenyl)aminolphenyl} acetamide on these indices. A cerebral ischaemia-reperfusion rodent model was used to investigate, via immunohistochemical and colorimetric techniques, the presence in the brain and spleen of inflammatory enzymes cycloxygenases COX-1 and COX-2, cytokines interleukin (IL)-1beta, IL-4, IL-6, IL-10, IL-18, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) as well as the activated form of caspase-3, in treated and untreated animals. Cerebral ischaemia-reperfusion caused elevated levels in the rat post ischaemia. Treatment with the antiinflammatory derivative reduced the elevation, caused by ischaemia, of IFN-gamma, TNF-alpha, IL-1beta IL-6, IL-18 and caspase-3 levels at 3 days post ischaemia, while it increased the levels of IL-10. It was shown that the increase in concentrations of a wide range of cytokines involved in the inflammatory reaction causing brain damage after ischaemia-reperfusion can be partially reversed by the anti-inflammatory derivative used in this study.
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PMID:Effects of the novel non-steroidal anti-inflammatory compound [N-(2-thiolethyl)-2- {2- [N'- (2,6- dichlorophenyl) amino] phenyl}acetamide on cytokines and apoptosis in ischaemic rat brain. 1722 64

This current review summarized animal models of heatstroke experimentation that promote our current knowledge of therapeutic effects on cerebrovascular dysfunction, coagulopathy, and/or systemic inflammation with human umbilical cord blood cells (HUCBCs) or estrogen in the setting of heatstroke. Accumulating evidences have demonstrated that HUCBCs provide a promising new therapeutic method against neurodegenerative diseases, such as stroke, traumatic brain injury, and spinal cord injury as well as blood disease. More recently, we have also demonstrated that post- or pretreatment by HUCBCs may resuscitate heatstroke rats with by reducing circulatory shock, and cerebral nitric oxide overload and ischemic injury. Moreover, CD34+ cells sorted from HUCBCs may improve survival by attenuating inflammatory, coagulopathy, and multiorgan dysfunction during experimental heatstroke. Many researchers indicated pro- (e.g. tumor necrosis factor-alpha [TNF-alpha]) and anti-inflammatory (e.g. interleukin-10 [IL-10]) cytokines in the peripheral blood stream correlate with severity of circulatory shock, cerebral ischemia and hypoxia, and neuronal damage occurring in heatstroke. It has been shown that intravenous administration of CD34+ cells can secrete therapeutic molecules, such as neurotrophic factors, and attenuate systemic inflammatory reactions by decreasing serum TNF-alpha but increasing IL-10 during heatstroke. Another line of evidence has suggested that estrogen influences the severity of injury associated with cerebrovascular shock. Recently, we also successfully demonstrated estrogen resuscitated heatstroke rats by ameliorating systemic inflammation. Conclusively, HUCBCs or estrogen may be employed as a beneficial therapeutic strategy in prevention and repair of cerebrovascular dysfunction, coagulopathy, and/or systemic inflammation during heatstroke.
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PMID:Human umbilical cord blood cells or estrogen may be beneficial in treating heatstroke. 1738 84

Multiorgan dysfunction ensuing from severe heatstroke includes hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. We attempted to assess whether human umbilical cord blood-derived CD34+ cell therapy improves survival during experimental heatstroke by attenuating multiorgan dysfunction. Anesthetized rats, immediately after the onset of heatstroke, were divided into 2 major groups and given CD34- or CD34+ cells (1 x 10(5)-5 x 10(5)/mL/kg body weight) i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Hypotension, hepatic and renal failure (evidenced by increased serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels in plasma), hypercoagulable state (evidenced by increased prothrombin time, activated partial thromboplastin time, and D-dimer, and decreased platelet count and protein C in plasma), activated inflammation (evidence by increased TNF-alpha levels in serum), and cerebral dysfunction (evidenced by intracranial hypertension, cerebral hypoperfusion and hypoxia, and cerebral ischemia and injury) were monitored. When the CD34- cell-treated or untreated rats underwent heat stress, their survival time values were found to be 19 to 23 min. Resuscitation with CD34+ cells significantly improved survival time (duration, 63-291 min). As compared with normothermic controls, all CD34- cell-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, CD34+ cell therapy significantly caused attenuation of all the above-mentioned heatstroke reactions. In addition, the levels of IL-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34+ cell therapy during heatstroke. Our data indicate that CD34+ cell therapy may resuscitate persons who had a heatstroke by reducing multiorgan dysfunction or failure.
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PMID:Human umbilical cord blood-derived CD34+ cells cause attenuation of multiorgan dysfunction during experimental heatstroke. 1750 7

Cerebral ischemia induces angiogenesis within and around infarcted tissue. The protection of existing and growth of new blood vessels may contribute to a more favorable outcome. The present study assessed whether angiogenesis can be used as a marker for neurodegeneration/neuroprotection in a model of hypoxia-ischemia (HI). Increased CD31 immunoreactivity 7 days post-HI indicated increased angiogenesis compared to controls (P<0.001). Treatment with the GABA(A) receptor modulator, clomethiazole (CMZ; 414 mg/kg/day), normalized the level of angiogenesis compared to HI + saline (P<0.001). Conversely, the non-selective nitric oxide synthase (NOS) inhibitor, L-NAME (5 mg/kg/day), markedly decreased angiogenesis compared to controls (P<0.001). Circulating plasma levels of IL-1alpha, IL-1beta and GM-CSF were significantly elevated post-HI. CMZ treatment attenuated these increases while also stimulating IL-10 levels. L-NAME treatment did not alter IL-1alpha or IL-1beta levels, but decreased endogenous IL-10 levels and exacerbated the ischemic lesion (P<0.001). CMZ treatment has been shown to increase NOS levels, while L-NAME halted the HI-induced increase in NOS activity (P<0.001). We conclude that angiogenesis can be used as a marker of neurodegeneration/neuroprotection for cerebral HI and is correlated to NOS activity and circulating inflammatory mediators.
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PMID:Angiogenesis as a predictive marker of neurological outcome following hypoxia-ischemia. 1776 Nov 53

Previous studies revealed that Guizhi-Fuling-Capsules (GZFLC), a traditional Chinese medical (Kampo) formulation composed of five kinds of medicinal plants, Cinnamomum cassia BLUME (Cinnamomi Cortex), Paeonia lactiflora PALL. (Peonies Radix), Paeonia suffruticosa ANDREWS (Moutan Cortex), Prunus persica BATSCH (Persicae Semen), and Poria cocos WOLF (Hoelen), exerts a protective effect against vascular injury and has a protective effect against glutamate- or nitro oxide-mediated neuronal damage. In the present study, the effect of GZFLC in a rat in vivo model of focal cerebral ischemia and reperfusion was investigated. Administration of GZFLC (0.3 and 0.9 g/kg, p.o.) after focal cerebral ischemia significantly decreased brain infarction and water contents in rats subjected to 2-h ischemia followed by 24-h reperfusion from 31.72 +/- 2.49%, 84.76 +/- 1.63% in the model group to 17.31 +/- 3.66%, 82.51 +/- 1.36% and 8.30 +/- 3.73%, 81.35 +/- 1.73%, respectively. Furthermore, analysis of inflammatory cytokines in ischemic brain showed that GZFLC treatment significantly down-regulated expressions of pro-inflammatory cytokines including interleukin (IL)-1beta and tissue necrosis factor-alpha and markedly up-regulated expressions of anti-inflammatory cytokines IL-10 and IL-10R both in mRNA and protein levels. The serum levels of these inflammatory cytokines were also regulated the same way. These results suggested that GZFLC may be beneficial for the treatment of brain ischemia-reperfusion injury partly due to its anti-inflammatory properties.
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PMID:Protective effects of Guizhi-Fuling-Capsules on rat brain ischemia/reperfusion injury. 1789 88

Pneumonia constitutes a serious medical complication and major cause of death in patients after cerebral stroke. In a mouse model of cerebral ischemia (MCAO), we have recently demonstrated that stroke animals spontaneously develop severe bacterial pneumonia which is preceded by a stress-mediated suppression of cellular immune responses in primary and secondary lymphoid organs. However, little is known about the mechanisms leading to impaired pulmonary antimicrobial immune response after cerebral ischemia. In this study, we demonstrate a rapid up-regulation of the immunomodulatory neuropeptide alpha-melanocyte-stimulating hormone (MSH) in the lung within 24 h after cerebral ischemia. Systemic administration of the naturally occurring alpha-MSH receptor-1 (MC-1R) antagonist agouti immediately after MCAO significantly reduced pulmonary bacterial burden at 72 h. In contrast, administration of recombinant alpha-MSH further increased bacterial load in lungs of MCAO animals. In addition, cerebral ischemia resulted in a strong modulation of local pulmonary immunity with increased production of IL-10 by lung macrophages, reduced pulmonary lymphocyte counts, as well as decreased lymphocytic IFN-gamma but increased IL-4 production. However, alpha-MSH blockade by administration of agouti did not prevent changes in lung immune cell numbers or cytokine production suggesting that suppression of cellular immune responses is not the primary mechanism of alpha-MSH mediated inhibition of pulmonary antibacterial defenses. This study indicates an important role of alpha-MSH for the increased infectious susceptibility after cerebral ischemia and may provide new therapeutic strategies to prevent post-stroke infectious complications.
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PMID:Alpha-MSH promotes spontaneous post-ischemic pneumonia in mice via melanocortin-receptor-1. 1830 33


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