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)

Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor that acts as an essential nutrient, antioxidant, and redox modulator. PQQ has been demonstrated to oxidize the redox modulatory site of N-methyl-d-aspartic acid (NMDA) receptors. Such agents are known to be neuroprotective in experimental stroke models. Therefore, we examined the possible ameliorating effect of PQQ on spinal cord injury (SCI) in adult rats. Intraperitoneal administration of PQQ effectively promoted the functional recovery of SCI rats after hemi-transection, which was preceded by the attenuation of the expression of inducible nitric oxide (NO) synthase (iNOS) mRNA in the injury site. NO is involved in the secondary detrimental mechanisms and has been implicated in NMDA receptor-mediated neurotoxicity. In fact, administration of PQQ induced significantly decreased lesion size and increased axon density adjoining the lesion area. These observations suggest that PQQ protects against the secondary damage by reducing iNOS expression following primary physical injury to the spinal cord.
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PMID:Pyrroloquinoline quinone attenuates iNOS gene expression in the injured spinal cord. 1902 89

Ischemic brain infarction is high among th causes of death in Japan, and the medical and social burden by severe sequela is also extremely serious. In this symposium, we show that treatment with anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) remarkably ameliorated brain infarction induced by 2-hour occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Whereas HMGB1 is usually localized in nucleus, after stimulation it is secreted into extracellular space by an unknown non-classical pathway, and exhibits an inflammatory cytokine-like activity. Treatment with mAb reduced infarct size, and the accompanying neurological deficits in locomotor function were significantly improved. In addition, some biochemical markers such as permeability of the blood-brain barrier, the expression of tumor necrosis factor-alfa, inducible nitric oxide synthase and matrix metalloproteinase-9 were altered by mAb injection. These findings indicate the usefulness of HMGB1 as a novel therapeutic to target ischemic stroke.
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PMID:[Therapeutic effect of anti-nucleokine monoclonal antibody on ischemic brain infarction]. 1912 33

Stress is known to be one of the risk factors of stroke, but only a few experimental studies have examined the possible mechanisms by which prior stress may affect stroke outcome. In stroke patients, infections impede neurological recovery and increase morbidity as well as mortality. We previously reported that stress induces a bacterial translocation and that prior immobilization stress worsens experimental stroke outcome through mechanisms that involve inflammatory mediators such as release of proinflammatory cytokines and enzyme activation. We now investigate whether bacterial translocation from the intestinal flora of rats with stress before experimental ischemia is involved in stroke outcome. We used an experimental paradigm consisting of exposure of Fischer rats to repeated immobilization sessions before permanent middle cerebral artery occlusion (MCAO). The presence of bacteria and the levels and expression of different mediators involved in the bacterial translocation were analyzed. Our results indicate that stress before stroke is related to the presence of bacteria in different organs (mesenteric nodes, spleen, liver, and lung) after MCAO and increases inflammatory colonic parameters (such as cyclooxygenase-2, inducible nitric oxide synthase, and myeloperoxidase), but decreases colonic immunoglobulin A, and these results are correlated with colonic inflammation and bacterial translocation. Understanding the implication of bacterial translocation during stress-induced stroke worsening is of great potential clinical relevance, given the high incidence of infections after severe stroke and their main role in mortality and morbidity in stroke patients.
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PMID:Colonic bacterial translocation as a possible factor in stress-worsening experimental stroke outcome. 1919 44

It has been demonstrated that a short ischemic event (ischemic preconditioning, IPC) results in a subsequent resistance to severe ischemia (ischemic tolerance, IT). We have recently demonstrated the role of innate immunity and in particular of toll-like receptor (TLR) 4 in brain ischemia. Several evidences suggest that TLR4 might also be involved in IT. Therefore, we have now used an in vivo model of IPC to investigate whether TLR4 is involved in IT. A 6-min temporary bilateral common carotid arteries occlusion was used for focal IPC and it was performed on TLR4-deficient mice (C57BL/10ScNJ) and animals that express TLR4 normally (C57BL/10ScSn). To assess the ability of IPC to induce IT, permanent middle cerebral artery occlusion was performed 48 h after IPC. Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. IPC caused neuroprotection as shown by a reduction in infarct volume and better outcome in mice expressing TLR4 normally. TLR4-deficient mice showed less IPC-induced neuroprotection than wild-type animals. Western blot analysis of tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) showed an up-regulation in the expression of these proteins in both substrains of mice measured 18, 24 and 48 h after IPC, being higher in mice with TLR4. Similarly, nuclear factor-kappa B (NF-kappaB) activation was observed 18, 24 and 48 h after IPC, being more intense in TLR4-expressing mice. These data demonstrate that TLR4 signalling is involved in brain tolerance as shown by the difference in the percentage of neuroprotection produced by IPC between ScSn and ScNJ (60% vs. 18%). The higher expression of TNF-alpha, iNOS and cyclooxygenase-2 and NF-kappaB activation in mice expressing TLR4 is likely to participate in this endogenous neuroprotective effect.
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PMID:Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning. 1920 Mar 41

The roots of Panax notoginseng (PN) are commonly used as a therapeutic agent to stop hemorrhage and as a tonic to promote health in traditional Korean medicine. Stroke triggers an inflammatory response that not only plays a central role in the pathogenesis of cerebral ischemia, but also induces secondary damage. This study was designed to investigate the neuroprotective effects of the methanol extract of PN on the infarct volume induced by middle cerebral artery occlusion (MCAO) (90-min occlusion and 24-h reperfusion) in rat brains. The PN extract (50 mg/kg, i.p.) was administered 2 h after the onset of MCAO. The PN-treated groups had a reduction in infarct volume by 23.82 +/- 8.9%. In the PN extract-treated groups, the microglial density was significantly decreased in the peri-infarct region; the underlying mechanism was inhibition of inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, via blocking of the NF-kappaB pathway. Furthermore, in vitro studies showed that the PN extract significantly reduced the production of iNOS-derived NO and COX-2-derived prostaglandin E(2) through the regulation of gene transcription levels in primary microglia and BV-2 cells. These results suggest that anti-inflammatory and microglial activation inhibitory effects of the PN extract may contribute to its neuroprotective effects in brain ischemia.
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PMID:Panax notoginseng Attenuates the Infarct Volume in Rat Ischemic Brain and the Inflammatory Response of Microglia. 1930 21

Tissue-type plasminogen activator (tPA) is the only drug approved for the treatment of thromboembolic stroke, but it might lead to some neurotoxic side effects. tPA is a highly specific serine proteinase, one of the two principal plasminogen activators and one of the three trypsin-like serine proteinases of the tissue kallikrein family. We have observed that tPA injection in the SN leads to the degeneration of the dopaminergic neurons in a dose-dependent manner, without affecting the GABAergic neurons. We also found that tPA injected in the substantia nigra of rats produced the disruption of the blood-brain barrier (BBB) integrity, the induction of microglial activation, the loss of astroglia and the expression of aquaporin 4 (AQP4), as well as an increase in the expression of NMDA receptors and the brain derived neurothrophic factor (BDNF). All these effects, along with the changes produced in the phosphorylated forms of several MAP kinases and the transcription factor CREB, and the increase in the expression of nNOS and iNOS observed under our experimental conditions, could be involved in the loss of dopaminergic neurons.
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PMID:The intranigral injection of tissue plasminogen activator induced blood-brain barrier disruption, inflammatory process and degeneration of the dopaminergic system of the rat. 1944 25

Cytoprotective or neuroprotective interventions would be of value if they could block the processes leading to delayed neuronal death or if they could delay the period between the onset of ischemia and irreversible necrotic injury, thereby lengthening the period for effective reperfusion therapy. Experimental studies in cell culture systems and laboratory animals show that statins have several potential cytoprotective actions, including promotion of angiogenesis, reduction of clot formation and facilitation of clot lysis, upregulation of endothelial nitric oxide synthase, downregulation of inducible nitric oxide synthase, reduction of excitotoxicity, and modulation of the inflammatory response. Clinically, statins appear to protect against vasospasm-related ischemic injury after subarachnoid hemorrhage. There have been no prospective randomized trials aimed at determining whether statins reduce acute stroke severity, and observational studies have had inconsistent results. Although a prospective, randomized trial assessing the effect of pre- or poststroke statin treatment on initial stroke severity would be the most appropriate study design to test for this type of effect, it is unlikely that such a trial will be conducted given the benefits of these drugs in reducing the risk of cardiovascular events and stroke in high-risk populations.
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PMID:Statins and ischemic stroke severity: cytoprotection. 1950 Apr 93

This study examined the effect of Natrii sulfas, a treatment for stroke patients suffering constipation in Oriental medicine, on the physiological indices and brain edema of rats. Brain edema was induced by a middle cerebral artery occlusion (MCAO), Natrii sulfas was administered after the MCAO. At 3, 6, 15, 24, and 48 hours after reperfusion, the physiological indices such as the fecal weight, urine volume and water content in the stools were assessed. The edema index was measured 48 hours after reperfusion. At 48 hours, the expressions of iNOS, MMP9, VEGF, GFAP, Bax, Bcl-2, c-Fos, and HSP72 positive astrocytes were observed on the brain tissues by immunohistochemistry. Natrii sulfas significantly improved the decrease in fecal weight, urine volume and water content in the stool caused by the ischemic insult (p < 0.05) and attenuated the brain edema caused by the ischemia insult (p < 0.05). Natrii sulfas significantly down-regulated iNOS and MMP9 expressions and attenuated the astrocyte swelling due to brain edema in the penumbra of the cerebral cortex of MCAO rats. Natrii sulfas reduced the excess Bax and HSP72 expressions in ischemic brain, which was statistically significant in the penumbra of the cerebral cortex but not in the caudate putamen. These results suggest Natrii sulfas has a protective effect on ischemia-induced brain edema and improves the physiological symptoms.
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PMID:Protective effects of natrii sulfas on cerebral focal ischemia induced by MCAO in rats. 1950 72

There is considerable evidence that activated microglia play a central role in the pathogenesis of many prominent neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. The elevated NADPH oxidase activity of these microglia contributes importantly to their pathogenic impact, collaborating with increased iNOS activity to generate the cytotoxic oxidant peroxynitrite. Phycocyanobilin (PCB), a chromophore derived from biliverdin that constitutes up to 1% of the dry weight of spirulina, has recently been shown to be a potent inhibitor of NADPH oxidase. The possibility that orally administered PCB could reach the brain parenchyma in sufficient concentrations to influence microglial function is consistent with the findings of two rodent studies: orally administered C-phycocyanin (the spirulina holoprotein that includes PCB) suppresses the neurotoxic impact of the excitotoxin kainite in rats, and a diet high in spirulina ameliorates the loss of dopaminergic neurons in the MPTP-induced Parkinsonian syndrome in mice. Hence, supplemental PCB may have considerable potential for preventing or slowing the progression of a range of neurodegenerative disorders. Some of the central physiological effects of PCB may also reflect inhibition of neuronal NADPH oxidase, which is now known to have a modulatory impact on neuron function, and can mediate neurotoxicity in certain circumstances. Neuronal NADPH oxidase activation is an obligate mediator of the central pressor effect of angiotensin II, and there is suggestive evidence that it may also play a role in inflammatory hyperalgesia; these findings point to possible antihypertensive and analgesic applications for PCB. The likely favorable effects of PCB on vascular health may also protect the brain by decreasing stroke risk, and inhibition of NADPH oxidase in rodents has been shown to lessen the neurotoxic impact of temporary cerebral ischemia. PCB may thus have versatile potential for preserving the healthful function of the central nervous system into advanced old age--albeit optimal neuroprotection may require more complex regimens that incorporate PCB along with other well tolerated nutraceuticals and drugs, in conjunction with prudent lifestyle modifications.
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PMID:Oral phycocyanobilin may diminish the pathogenicity of activated brain microglia in neurodegenerative disorders. 1957 98

There is still much that is unknown about how nitric oxide (NO) biosynthesis by NO synthase (NOS) isoform is tightly regulated at the molecular level. This is remarkable because deviated NO production in vivo has been implicated in an increasing number of diseases that currently lack effective treatments, including stroke and cancer. Given the significant public health burden of these diseases, the NOS enzyme family is a key target for development of new pharmaceuticals. Three NOS isoforms, inducible, endothelial and neuronal NOS (iNOS, eNOS and nNOS, respectively), achieve their key biological functions via stringent regulations of interdomain electron transfer (IET) processes. Unlike iNOS, eNOS and nNOS isoforms are controlled by calmodulin (CaM) binding through facilitating catalytically significant IET processes. The CaM-modulated NOS output state is an IET-competent complex between the flavin mononucleotide (FMN) domain and the catalytic heme domain. The output state facilitates the catalytically essential FMN-heme IET, and thereby enables NO production by NOS. Due to lack of reliable techniques for specifically determining the inter-domain FMN-heme interactions and their direct effects on the catalytic heme center, the molecular mechanism that underlies the output state formation remains elusive. The recent developments in our understanding of mechanisms of the NOS output state formation that are driven by a combination of molecular biology, laser flash photolysis, and spectroscopic techniques are the subject of this perspective.
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PMID:Regulation of interdomain electron transfer in the NOS output state for NO production. 1969 Jun 75


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