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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal cell death as a result of apoptosis is associated with cerebrovascular stroke and various neurodegenerative disorders. Pharmacological agents that maintain normal intracellular Ca2+ levels and inhibit cellular oxidative stress may be effective in blocking abnormal neuronal apoptosis. In this study, a spontaneous (also referred to as age-induced) model of apoptosis consisting of rat cerebellar granule cells was used to evaluate the antiapoptotic activities of voltage-sensitive Ca2+ channel blockers and various antioxidants. The results of these experiments demonstrated that the charged, dihydropyridine Ca2+ channel blocker amlodipine had very potent neuroprotective activity in this system, compared with antioxidants and neutral Ca2+ channel blockers (nifedipine and nimodipine). Within its effective pharmacological range (10-100 nM), amlodipine attenuated intracellular neuronal Ca2+ increases elicited by KCl depolarization but did not affect Ca2+ changes triggered by N-methyl-D-aspartate receptor activation. Amlodipine also inhibited free radical-induced damage to lipid constituents of the membrane in a dose-dependent manner, independent of Ca2+ channel modulation. In parallel experiments, spontaneous neuronal apoptosis was inhibited in dose- and time-dependent manners by antioxidants (U-78439G, alpha-tocopherol, and melatonin), nitric oxide synthase inhibitors (N-nitro-L-arginine and N-nitro-D-arginine), and a nitric oxide chelator (hemoglobin) in the micromolar range. These results suggest that spontaneous neuronal apoptosis is associated with excessive Ca2+ influx, leading to further intracellular Ca2+ increases and the generation of reactive oxygen species. Agents such as amlodipine that block voltage-sensitive Ca2+ channels and inhibit cellular oxidative stress may be effective in the treatment of cerebrovascular stroke and neurodegenerative diseases associated with excessive apoptosis.
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PMID:Inhibition of excessive neuronal apoptosis by the calcium antagonist amlodipine and antioxidants in cerebellar granule cells. 1009 48

A residual blood supply to the ischaemic brain is a crucial determinant for tissue survival. Early changes in the vascular network and subsequent angiogenesis may be mediated by short-lived molecules like nitric oxide (NO) or growth factors such as transforming growth factor-beta1 (TGF-beta1). Although TGF-beta1 can inhibit NO production, this interaction has not been studied after ischaemia in humans. Serum samples were taken from patients at 24 h and 6 months and cerebrospinal fluid (CSF) samples at 24 h and 1 week later for possible correlation between the two factors. Tissue expression of TGF-beta1 and of the inducible isoform of NO synthase (NOS2) was assessed by immunohistochemistry. CSF levels of NO2-/NO3- as well as total (active + latent) TGF-beta1 were higher in stroke patients as compared to controls 24 h after the stroke. Both NO2-/NO3- and TGF-beta1 were lower 6 months after the stroke compared to 24 h. Levels of NO2-/NO3- correlated with levels of TGF-beta1 within the time points (P = 0.041, Kendall correlation coefficient). There was a strong staining for NOS2 in brain tissue sections in neurones, reactive astrocytes, infiltrating white blood cells, and endothelial cells of larger microvessels. TGF-beta1 expression was mainly limited to neurones and reactive astrocytes. These findings suggest that the interaction between TGF-beta1 and NOS2 might be important for angiogenesis after cerebral ischaemia and may indicate that TGF-beta1 is upregulated as a negative feedback response to elevated levels of NO.
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PMID:Inducible nitric oxide production and expression of transforming growth factor-beta1 in serum and CSF after cerebral ischaemic stroke in man. 1034 87

The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O2-) was examined. O2- generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O2- generation was increased in male and female SHRSP (4.11+/-0.24 and 3. 84+/-0.28 nmol O2-. min-1. mg-1 respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22+/-0.08 in males and 0.8+/-0.08 nmol O2-. min-1. mg-1 respectively) (SHRSP versus WKY P<0.0001, 95% CI -3.39, -2.51; male versus female WKY P=0.0029, 95% CI -0.67, -0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O2- generation in SHRSP but not WKY. In males, removal of the endothelium reduced O2- generation from 3.86+/-0.12 to 1.35+/-0. 08 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13+/-0.17 to 1.32+/-0.16 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females. L-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O2- generation in SHRSP from 4.04+/-0.11 to 2.36+/-0.40 nmol. min-1. mg-1 (P=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O2- generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O2- appear to be the endothelium and eNOS, respectively. The increase in O2- generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.
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PMID:Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. 1037 15

Endothelial-derived nitric oxide (NO) is an important mediator of vascular function. Clinical studies indicate that HMG-CoA reductase inhibitors (statins) improve endothelial function and reduce the incidence of stroke and myocardial infarction. Treatment of human endothelial cells with statins increased the expression of endothelial NO synthase (eNOS) protein and mRNA expression. Statins increased eNOS mRNA half-life but did not change eNOS gene transcription. Inhibition of mevalonate synthesis by statins not only blocks the formation of cholesterol but also of isoprenoids. The upregulation of eNOS expression by statins was independent of cholesterol but mediated via the inhibition of the isoprenoid geranylgeraniol, whereas farnesiol had no effect on eNOS. Immunoblot analyses, (35S)-GTP gamma S-binding assays and transfection studies revealed that statins upregulate eNOS expression by blocking the geranylgeranylation of the GTPase Rho which is necessary for its membrane-associated activity. Studies with mice showed, that statin treatment upregulates eNOS expression and function independent of serum cholesterol levels. Prophylactic treatment with statins augmented cerebral blood flow and reduced cerebral infarcts in normocholesterolemic mice. These effects of statins were completely absent in eNOS-deficient mice indicating that enhanced eNOS activity by statins is the predominant mechanism by which these agents protect against cerebral injury. Our results suggest that statins provide a novel prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia. Upregulation of eNOS by inhibiting Rho may provide a new pharmacologic target for the treatment of arteriosclerosis, pulmonary hypertension, and heart failure.
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PMID:[Regulation of endothelial NO production by Rho GTPase]. 1037 57

1. The aim of this study was to investigate the effect of N-(3-(aminomethyl)benzyl)acetamidine (1400W), a selective inhibitor of inducible calcium-independent nitric oxide synthase (iNOS), on the functional and histopathological outcomes of experimental transient focal cerebral ischaemia in rats. 2. Transient ischaemia was produced by the occlusion for 2 h of both the left middle cerebral artery and common carotid artery. Treatments with 1400W (20 mg kg(-1)) or vehicle were started 18 h after occlusion of the arteries and consisted in seven subcutaneous injections at 8 h interval. Ischaemic outcomes and NOS activities (constitutive and calcium-independent NOS) were evaluated 3 days after ischaemia. 3. 1400W significantly reduced ischaemic lesion volume by 31%, and attenuated weight loss and neurological dysfunction. 4. 1400W attenuated the calcium-independent NOS activity in the infarct by 36% without affecting the constitutive NOS activity. 5. These findings suggest that iNOS activation contributes to tissue damage and that selective inhibitors of this isoform may be of interest for the treatment of stroke.
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PMID:Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury. 1038 57

Therapeutic interventions for acute ischemic stroke have not yet been established in clinical practice. The recognition of an area of reduced blood flow in which neuronal death may be prevented has focused attention on treatments aiming at minimizing ischemic brain damage, if they are initiated within short time after occlusion. The combination of restoring blood flow and providing neuroprotection may be the most productive approach in human acute ischemic stroke, but this combined therapy requires testing through clinical trials. To gain insight into the molecular mechanisms of cerebral ischemia, this review examines the excito-toxic cascade, synthesis and role of nitric oxide and oxidants, gene regulation and possible neuroprotective therapeutic targets. As neuroprotectants, glutamate-antagonists, calcium-antagonists and free radical scavengers have been investigated. The role of nitric oxide is very complex, as it can be cytotoxic or cytoprotective in relation to sources, time of synthesis, and medium redox state. Animal gene studies suggest that nitric oxide produced by endothelial nitric oxide synthase may be advantageous, while nitric oxide produced by neuronal and inducible nitric oxide synthase disadvantageous. A treatment strategy could involve the use of selective inhibitors of different types of nitric oxide synthase. Cell death after cerebral ischemia occurs through the dual pathway of ischemic necrosis and apoptosis. Novel therapies may be directed at genes mediating either recovery or apoptosis. There are, as yet, no conclusive data concerning the safety and efficacy of neuroprotectants in humans. Differences between animal models and clinical conditions may justify the discrepancy between experimental data and clinical practice.
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PMID:[The molecular mechanisms of cerebral ischemia: the possible therapeutic interventions]. 1039 71

Nitric oxide (NO) is a new intercellular messenger that occurs naturally in the brain without causing overt toxicity. Yet, NO has been implicated as a mediator of cell death in cell death. One explanation is that ischemia causes overproduction of NO, allowing it to react with superoxide to form the potent oxidant peroxynitrite. To address this question, we used immunohistochemistry for citrulline, a marker for NO synthase activity, and 3-nitrotyrosine, a marker for peroxynitrite formation, in mice subjected to reversible middle cerebral artery occlusion. We show that ischemia triggers a marked augmentation in citrulline immunoreactivity but more so in the peri-infarct than the infarcted tissue. This increase is attributable to the activation of a large population (approximately 80%) of the neuronal isoform of NO synthase (nNOS) that is catalytically inactive during basal conditions, indicating a tight regulation of physiological NO production in the brain. In contrast, 3-nitrotyrosine immunoreactivity is restricted to the infarcted tissue and is not present in the peri-infarct tissue. In nNOS(Delta/Delta) mice, known to be protected against ischemia, no 3-nitrotyrosine immunoreactivity is detected. Our findings provide a cellular localization for nNOS activation in association with ischemic stroke and establish that NO is not likely a direct neurotoxin, whereas its conversion to peroxynitrite is associated with cell death.
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PMID:Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage. 1040 30

Regional distribution and age-related change of Mn-, Cu/Zn-superoxide dismutase (SOD) and constitutive type of nitric oxide synthase (NOS) activities in the brain were determined using stroke-prone spontaneously hypertensive rats (SHRSP). In the hippocampus (HIP), Mn- and Cu/Zn-SOD activities in SHRSP of 31-week-old were significantly lower than those of 15-week-old or normotensive rats (WKY). From Mn-SOD immunohistochemical staining of several subfields of the HIP, our results suggested that SHRSP hippocampal CA1 was more vulnerable to oxidative stress compared with WKY and other subfields. In the 31-week-old SHRSP cerebral cortex (CC), the activities of Mn-, Cu/Zn-SOD and NOS were significantly lower than those in WKY. At this age, most of the SHRSP developed cerebral injuries. These observations indicated that hypertensive vascular disease observed in the SHRSP CC resulted from the decreased antioxidant capacity that is closely associated with the development of stroke and, in turn, shortened life span.
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PMID:Age-related change of antioxidant capacities in the cerebral cortex and hippocampus of stroke-prone spontaneously hypertensive rats. 1050 47

In Inactin-anesthetized Wistar rats with an intact renal innervation, intratubular nitro-L-arginine methyl ester (L-NAME, 10(-4) M) increased proximal fluid uptake (J(va), at 2.47 +/- 0.61 x 10(-4) mm(3). mm(-2). s(-1)) by 17% (P < 0.05), whereas coadministration with sodium nitroprusside (SNP, 10(-4) M) decreased J(va) by 18% (P < 0.01). Similar manipulation of NO generation was without effect in groups of Wistar rats subjected to acute renal denervation. Intratubular aminoguanidine (10(-4) M), a selective inducible nitric oxide synthase (NOS) blocker, had no effect on J(va) in intact kidneys of Wistar rats, but the neuronal NOS (nNOS) blocker, 7-nitroindazole (10(-4) M and 10(-6) M) increased J(va) by 19-23% (both P < 0.001). In stroke-prone spontaneously hypertensive rats (SHRSP), J(va) values in the innervated kidneys were lower (P < 0.05) than in the corresponding Wistar groups and were unchanged by intratubular L-NAME or L-NAME plus SNP. The tonic attenuation of proximal epithelial transport by NO was dependent on the renal sympathetic nerves and appeared to be generated by the nNOS isoform of the enzyme. This role of NO was not evident in the SHRSP.
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PMID:Nitric oxide and renal nerve-mediated proximal tubular reabsorption in normotensive and hypertensive rats. 1051 80

Roles proposed for nitric oxide (NO) in CNS pathophysiology are increasingly diverse and range from intercellular signaling, through necrotic killing of cells and invading pathogens, to the involvement of NO in apoptosis and tissue remodeling. In vitro evidence and observations from experimental animal models of a variety of human neuropathologies, including stroke, indicate that glial cells can produce NO. Regulation of at least one of the NO synthase genes (NOS-2) in glia has been well described; however, apart from hints emerging out of co-culture studies and extrapolation based upon the reactivity of NO, we are a long way from identifying functions for glial-derived NO in the CNS. Although the assumption is that NO is very often cytotoxic, it is evident that NO production does not always equate with tissue damage, and that both the cellular source of NO and the timing of NO production are important factors in terms of its effects. With the development of strategies to transfer or manipulate expression of the NOS genes in specific cells in situ, the ability to deliver NO into the CNS via long-lived chemical donors, and the emergence of more selective NOS inhibitors, an appreciation of the significance of glial-derived NO will change.
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PMID:Production of nitric oxide by glial cells: regulation and potential roles in the CNS. 1059 18


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