Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide produced by the inducible nitric oxide synthase (iNOS) is believed to participate in the pathogenic events after cerebral ischemia. In this study, we examined the expression of iNOS in the brain after transient focal cerebral ischemia in mice. We detected differential expression of exons 2 and 3 of iNOS mRNA (16-fold upregulation at 24 to 72 h after middle cerebral artery occlusion, MCAO) compared with exons 6 to 8, 12 to 14, 21 to 22, and 26 to 27 (2- to 5-fold upregulation after 72 and 96 h), which would be compatible with alternative splicing. Expression levels of iNOS mRNA were too low for detection by the Northern blot analysis. Using specific antibodies, we did not detect any iNOS immunoreactivity in the mouse brain 1 to 5 days after MCAO, although we detected iNOS immunoreactivity in the lungs of mice with stroke-associated pneumonia, and in mouse and rat dura mater after lipopolysaccharide administration. In chimeric iNOS-deficient mice transplanted with wild-type bone marrow (BM) cells expressing the green fluorescent protein (GFP) or in wild-type mice transplanted with GFP(+) iNOS-deficient BM cells, no expression of iNOS was detected in GFP(+) leukocytes invading the ischemic brain or in resident brain cells. Moreover, both experimental groups did not show any differences in infarct size. Analysis of three different strains of iNOS-deficient mice and wild-type controls confirmed that infarct size was independent of iNOS deletion, but strongly confounded by the genetic background of mouse strains. In conclusion, our data suggest that iNOS is not a universal mediator of brain damage after cerebral ischemia.
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PMID:Inducible nitric oxide synthase does not mediate brain damage after transient focal cerebral ischemia in mice. 1785 54

Nitric oxide (NO), a free radical with signaling functions in the CNS, is implicated in some developmental processes, including neuronal survival, precursor proliferation, and differentiation. However, neuronal nitric oxide synthase (nNOS) -derived NO and inducible nitric oxide synthase (iNOS) -derived NO play opposite role in regulating neurogenesis in the dentate gyrus after cerebral ischemia. In this study, we show that focal cerebral ischemia reduced nNOS expression and enzymatic activity in the hippocampus. Ischemia-induced cell proliferation in the dentate gyrus was augmented in the null mutant mice lacking nNOS gene (nNOS-/-) and in the rats receiving 7-nitroindazole, a selective nNOS inhibitor, after stroke. Inhibition of nNOS ameliorated ischemic injury, up-regulated iNOS expression, and enzymatic activity in the ischemic hippocampus. Inhibition of nNOS increased and iNOS inhibitor decreased cAMP response element-binding protein phosphorylation in the ipsilateral hippocampus in the late stage of stroke. Moreover, the effects of 7-nitroindazole on neurogenesis after ischemia disappeared in the null mutant mice lacking iNOS gene (iNOS-/-). These results suggest that reduced nNOS is involved in ischemia-induced hippocampal neurogenesis by up-regulating iNOS expression and cAMP response element-binding protein phosphorylation.
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PMID:Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression. 1785 82

Dimemorfan, an antitussive and a sigma-1 (sigma(1)) receptor agonist, has been reported to display neuroprotective properties. We set up an animal model of ischemic stroke injury by inducing cerebral ischemia (for 1 h) followed by reperfusion (for 24 h) (CI/R) in rats to examine the protective effects and action mechanisms of dimemorfan against stroke-induced damage. Treatment with dimemorfan (1.0 microg/kg and 10 microg/kg, i.v.) either 15 min before ischemia or at the time of reperfusion, like the putative sigma(1) receptor agonist, PRE084 (10 microg/kg, i.v.), ameliorated the size of the infarct zone by 67-72% or 51-52%, respectively, which was reversed by pre-treatment with the selective sigma(1) receptor antagonist, BD1047 (20 microg/kg, i.v.). Major pathological mechanisms leading to CI/R injury including excitotoxicity, oxidative/nitrosative stress, inflammation, and apoptosis are all downstream events initiated by excessive accumulation of extracellular glutamate. Dimemorfan treatment (10 microg/kg, i.v., at the time of reperfusion) inhibited the expressions of monocyte chemoattractant protein-1 and interleukin-1beta, which occurred in parallel with decreases in neutrophil infiltration, activation of inflammation-related signals (p38 mitogen-activated protein kinase, nuclear factor-kappaB, and signal transducer and activator of transcription-1), expression of neuronal and inducible nitric oxide synthase, oxidative/nitrosative tissue damage (lipid peroxidation, protein nitrosylation, and 8-hydroxy-guanine formation), and apoptosis in the ipsilateral cortex after CI/R injury. Dimemorfan treatment at the time of reperfusion, although did not prevent an early rise of glutamate level, significantly prevented subsequent glutamate accumulation after reperfusion. This inhibitory effect was lasted for more than 4 h and was reversed by pre-treatment with BD1047. These results suggest that dimemorfan activates the sigma(1) receptor to reduce glutamate accumulation and then suppresses initiation of inflammation-related events and signals as well as induction of oxidative and nitrosative stresses, leading to reductions in tissue damage and cell death. In conclusion, our results demonstrate for the first time that dimemorfan exhibits protective effects against ischemic stroke in CI/R rats probably through modulation of sigma(1) receptor-dependent signals to prevent subsequent glutamate accumulation and its downstream pathologic events.
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PMID:Dimemorfan protects rats against ischemic stroke through activation of sigma-1 receptor-mediated mechanisms by decreasing glutamate accumulation. 1817 6

Estradiol-17beta exerts profound neuroprotective actions following cerebral ischemia through multiple molecular mechanisms. To examine the putative anti-inflammatory mechanisms employed by estradiol during stroke, we explored the interactions between estradiol and inducible nitric oxide synthase (iNOS) in both wildtype and iNOS knockout (iNOSKO) female mice following permanent middle cerebral artery occlusion (MCAO). Female mice were ovariectomized and treated with estradiol. One week later, they were subjected to MCAO, and then killed 24 h later. Analysis of total, cortical and striatal infarct volumes confirmed that estradiol is neuroprotective in wildtype mice. Infarct volumes were also significantly smaller in female iNOSKO female mice, but estradiol did not further decrease injury. We found that one mechanism by which estradiol may act is by decreasing nitric oxide synthase 2 gene expression in the cortex and in the striatum of wildtype mice. These results show that the pro-inflammatory actions of iNOS exacerbate stroke-induced injury within the cortex and striatum, and that iNOS deletion is neuroprotective in ovariectomized and estrogen-replaced female mice.
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PMID:Inducible nitric oxide synthase and estradiol exhibit complementary neuroprotective roles after ischemic brain injury. 1818 33

The association between nitric oxide synthase (eNOS and iNOS) status, oxidative stress, and cardiac function was evaluated in streptozotocin (STZ)-diabetic rats to understand the etiology of diabetic cardiomyopathy. Cardiac function was determined by echocardiography. eNOS and iNOS status and superoxide production were assessed by immunohistochemistry and chemiluminescence, respectively. In STZ-diabetic rats, stroke volume, cardiac output, and left ventricular ejection fraction were significantly lower than in controls (CT, P < .05), whereas left ventricular end-systolic volume was higher. Cardiac NOS activity increased from 161 +/- 18 cpm/mg tissue in CT rats to 286 +/- 20 cpm/mg tissue (P < .001) in STZ-diabetic rats. Furthermore, superoxide production and cardiac eNOS and iNOS levels were higher in STZ-diabetic rats than in CT rats (P < .05). An increased activation of cardiac eNOS and iNOS is observed concomitantly with decreased cardiac function. Thus, increased oxidative stress in the heart may be implicated in the development of dilated cardiomyopathy in STZ-diabetic rats.
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PMID:Cardiac oxidative stress is elevated at the onset of dilated cardiomyopathy in streptozotocin-diabetic rats. 1828 92

After an ischemic stroke, neurons in the core are rapidly committed to die, whereas neuron death in the slowly developing penumbra is more amenable to therapeutic intervention. Microglia activation contributes to delayed inflammation, but because neurotoxic mechanisms in the penumbra are not well understood, we developed an in vitro model of microglia activation and propagated neuron killing. To recapitulate inflammatory triggers in the core, microglia were exposed to oxygen glucose-deprived neurons and astrocytes. To model the developing penumbra, the microglia were washed and allowed to interact with healthy naive neurons and astrocytes. We found that oxygen-glucose deprivation (OGD)-stressed neurons released glutamate, which activated microglia through their group II metabotropic glutamate receptors (mGluRs). Microglia activation involved nuclear factor kappaB (NF-kappaB), a transcription factor that promotes their proinflammatory functions. The activated microglia became neurotoxic, killing naive neurons through an apoptotic mechanism that was mediated by tumor necrosis factor-alpha (TNF-alpha), and involved activation of both caspase-8 and caspase-3. In contrast to some earlier models (e.g., microglia activation by lipopolysaccharide), neurotoxicity was not decreased by an inducible nitric oxide synthase (iNOS) inhibitor (S-methylisothiourea) or a peroxynitrite scavenger [5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphinato iron (III) chloride], and did not require p38 mitogen-activated protein kinase (MAPK) activation. The same microglia neurotoxic behavior was evoked without exposure to OGD-stressed neurons, by directly activating microglial group II mGluRs with (2S,2'R,3'R)-2-(2'3'-dicarboxycyclopropyl) glycine or glutamate, which stimulated production of TNF-alpha (not nitric oxide) and mediated TNF-alpha-dependent neurotoxicity through activation of NF-kappaB (not p38 MAPK). Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNFalpha overproduction, and NF-kappaB activation to reduce neuron death in the ischemic penumbra.
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PMID:Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. 1857 26

Nitric oxide (NO) is important for the homeostasis of organ functions. We studied the structural and functional changes in the cardiovascular (CV) and renal systems following early NO deprivation by various nonspecific and specific NO synthase (NOS) inhibitors: N-nitro-L-arginine methyl ester (L-NAME), N-nitro-L-arginine (L-NA), S-methyl-isothiourea (SMT), and L-N6-(1-iminoethyl)-lysine (L-Nil). The aim is to elucidate the involvement of NO through endothelial or inducible NOS (eNOS and iNOS). Drugs were given to spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY) from a young age (5-wk-old). Physiological, biochemical, and pathological examinations were performed. L-NAME and L-NA treatment caused a rapid increase in tail cuff pressure (TCP). The TCP of SHR reached a malignant level within 30 days with signs of stroke, proteinuria [corrected] severe glomerular sclerosis, and moderate ventricular hypertrophy (VH). The plasma nitrite/nitrate was reduced, while creatinine, urea nitrogen and uric acid were elevated. The renal tissue cyclic guanosine monophosphate (cGMP) was decreased with an elevated collagen content. The numbers of sclerotic glomeruli, arteriolar and glomerular injury scores were markedly increased, accompanied by reduction in renal blood flow, filtration rate, and fraction. Plasma endothelin-1 was increased following L,-NAME or L-NA treatment for 10 days. The expression of eNOS and iNOS mRNA was depressed by L-NAME and L-NA. The relevant iNOS inhibitors, SMT and L-Nil depressed the iNOS expression, but did not produce significant changes in CV and renal systems. The continuous release of NO via the eNOS system provides a compensatory mechanism to prevent the genetically hypertensive rats from rapid progression to malignant phase. Removal of this compensation results in VH, stroke, glomerular damage, renal function impairment, and sudden death.
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PMID:Malignant alterations following early blockade of nitric oxide synthase in hypertensive rats. 1844 11

Activation and injury of microglial cells are involved in a broad range of brain diseases including stroke, brain infection and neurodegenerative diseases. However, there is very little information regarding how to reduce microglial reaction and preserve these cells to provide neuroprotection. Here, we showed that the incubation of C8-B4 mouse microglial cells with lipopolysaccharide (LPS) plus interferon-gamma (IFNgamma) for 24 h decreased the viability of these cells. Pretreatment of these cells with 1%, 2% or 3% isoflurane, a commonly used volatile anesthetic, for 1 h at 30 min before the exposure to LPS plus IFNgamma attenuated the reduction of cell viability (preconditioning effect). LPS plus IFNgamma also activated these microglial cells to express inducible nitric oxide synthase (iNOS) and to induce accumulation of nitrite, a stable oxidation product of nitric oxide, in the incubation medium. Isoflurane preconditioning attenuated these LPS plus IFNgamma effects on the iNOS expression and nitrite accumulation. Aminoguanidine, an iNOS inhibitor, attenuated the LPS plus IFNgamma-induced glutamate release and decrease of microglial viability. Isoflurane preconditioning also reduced LPS plus IFNgamma-induced glutamate release. Exogenous glutamate decreased microglial viability. Finally, the isoflurane preconditioning-induced protection was abolished by chelerythrine, a protein kinase C inhibitor. These results suggest that LPS plus IFNgamma activates the iNOS-nitric oxide-glutamate pathway to induce microglial injury and that this activation is attenuated by isoflurane preconditioning. Protein kinase C may be involved in the isoflurane preconditioning effects.
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PMID:Isoflurane preconditioning reduces mouse microglial activation and injury induced by lipopolysaccharide and interferon-gamma. 1849 58

Nitric oxide (NO), synthesized from l-arginine by NO synthases, is a small endogenous free radical with multiple functions. The c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in mediating apoptosis in cerebral ischemia and reperfusion. In this study, we found that the NO donor sodium nitroprusside (SNP) can decrease the damage of hippocampal neurons induced by cerebral ischemia and reperfusion. Our current study demonstrates that SNP can suppress the phosphorylation of JNK3 by suppressing the increased S-nitrosylation of JNK3 induced by cerebral ischemia and reperfusion. In contrast, dithiothreitol reversed the effect of SNP on S-nitrosylation of JNK3. Furthermore, the inhibitor of nNOS (7-NI) and the inhibitor of iNOS (AMT) can decrease JNK3 phosphorylation through decreasing S-nitrosylation of JNK3. Our data suggest that endogenous NO synthesized by NO synthases can increase JNK3 phosphorylation by means of S-nitrosylation during global ischemia/reperfusion in rat hippocampus. However, the exogenous NO (SNP) can reverse the effect of endogenous NO by inhibiting S-nitrosylation of JNK3. Together, these results suggest that the exogenous NO may provide a new clue for stroke therapy.
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PMID:Exogenous nitric oxide negatively regulates c-Jun N-terminal kinase activation via inhibiting endogenous NO-induced S-nitrosylation during cerebral ischemia and reperfusion in rat hippocampus. 1856 7

Curcumin (diferuloylmethane), an active ingredient of turmeric, obtained from the powdered rhizomes of Curcuma longa Linn., has been traditionally recognized for treatment of several diseases. To evaluate the potential clinical use of curcumin, we determined the dose dependence of its effects in the therapeutic window and of the neuroprotective efficacy in a cerebral thromboembolic model of the rat. Rats were subjected to occlusion of the middle cerebral artery (MCAo) by a thrombus and treated with different doses of curcumin or the vehicle at 4h after ischemia. The animals were assessed after 24h for motor performance and neurological deficit. The rats were sacrificed immediately afterwards for evaluation of infarct, edema volume, estimation of nitrate and nitrite levels, neutrophil infiltration and levels of GSH and glutathione peroxidase (GSH-Px) in brain tissue. Curcumin reduced in a dose-dependent manner the ischemia-induced cerebral infarct and edema volume and attenuated neurological deficits observed after 24h. Curcumin reduced post-ischemic brain neutrophil infiltration, nitrate and nitrite levels and ameliorated the loss of GSH-Px and tends to increase the GSH levels but not significantly in the brain tissue. Neuronal levels of reactive oxygen species, peroxynitrite, and nitric oxide were lowered and in brain cryosections inducible nitric oxide synthase expression were significantly inhibited after treatment with curcumin. The present study is the first evidence of effectiveness of curcumin when given 4h post-ischemia in the rat thromboembolic stroke models, as it reduces infarct volume, ameliorates the sensory motor function and significantly attenuated the nitrosative stress.
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PMID:Dose dependence and therapeutic window for the neuroprotective effects of curcumin in thromboembolic model of rat. 1861 16


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