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

Recent evidence suggests that stress-activated protein kinases expressed in glial cells have very important roles during cerebral ischemia. The neuroprotective agent chlomethiazole, which is known to enhance the conductance at the GABA(A) receptor complex, is presently in clinical trials for the treatment of severe stroke. Here the authors suggested that chlormethiazole has anti-inflammatory properties because it potently and selectively inhibited p38 mitogen-activated protein (MAP) kinase in primary cortical glial cultures. The inhibition of p38 MAP kinase resulted in the attenuation of the induction of c-fos and c-jun mRNA and AP-1 DNA binding by lipopolysaccharide (LPS). In addition, chlomethiazole inhibited the activation of an AP-1-dependent luciferase reporter plasmid in SK-N-MC human neuroblastoma cells in response to glutamate. Chlomethiazole inhibited the p38 MAP kinase activity as revealed by the decrease in the LPS-induced phosphorylation of the substrates ATF-2 and hsp27, whereas the phosphorylation status of the p38 MAP kinase itself was unaffected. Interestingly, chlomethiazole exhibited an IC(50) of approximately 2 micromol/L for inhibition of c-fos mRNA expression, indicating 25 to 75 times higher potency than reported EC(50) values for enhancing GABA(A) chloride currents. The results indicated a novel mechanism of action of chlomethiazole, and provided support for a distinctive role of p38 MAP kinase in cerebral ischemia.
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PMID:Neuroprotective agent chlomethiazole attenuates c-fos, c-jun, and AP-1 activation through inhibition of p38 MAP kinase. 1090 41

Insulin has been demonstrated to be neuroprotective in brain and spinal cord ischemia. The mechanism of neuroprotection may involve alterations in metabolism, protein synthesis or uptake of GABA by astrocytes. Conversely, hyperglycemia increases the extent of neurologic damage observed during ischemia/reperfusion. Diabetic patients are 2-4 times more likely to suffer a stroke as normoglycemic patients and they also have worsened neurologic outcome. Determining if insulin, which many diabetics already use as therapy, can be neuroprotective, would be a possible means of alleviating the detrimental outcome from diabetic stroke. This study looked at the relationship between topically administered insulin (1 mIU insulin/ml and 100 mIU insulin/ml) during a four vessel occlusion model of global ischemia and the release of amino acids, especially glutamate, from the cortex in streptozotocin (STZ)-treated rats. The rats were utilized either 5-7 days (ASTZ) or 4-6 weeks (CSTZ) after a single STZ injection. In the ASTZ animals both doses of insulin increased the amount of the excitotoxic amino acids, aspartate and glutamate, released during reperfusion and the higher dose also increased the levels of taurine and GABA during reperfusion. In the CSTZ animals, both doses of insulin increased the amount of excitotoxic amino acids during reperfusion and the lower dose increased GABA levels released during reperfusion. The differences between the ACTZ and CSTZ animals may be due to metabolic differences in the utilization of glucose. Insulin may act as a neuroprotectant by increasing extracellular GABA resulting in neuroinhibition.
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PMID:The effect of topical insulin on the release of excitotoxic and other amino acids from the rat cerebral cortex during streptozotocin-induced hyperglycemic ischemia. 1092 72

The aim of the present study was to determine whether or not descending control of spinal dorsal horn neuronal responsiveness following neuronal activation at pressor sites in the rostral ventrolateral medulla is selective for nociceptive information. Extracellular single-unit activity was recorded from 49 dorsal horn neurons in the lower lumbar spinal cord of anaesthetized rats. The 30 Class 2 neurons selected for investigation responded to noxious (pinch and radiant heat) and non-noxious (prod, stroke and/or brush) stimulation within their cutaneous receptive fields on the ipsilateral hindpaw. The excitatory amino acid, DL-homocysteic acid, was microinjected into either the rostral or the caudal rostral ventrolateral medulla at sites that evoked increases in arterial blood pressure. Effects of neuronal activation at these sites were then tested on the responses of Class 2 neurons to noxious and non-noxious stimulation within their excitatory receptive fields. The noxious pinch and radiant heat responses of Class 2 neurons were depressed, respectively to 13+/-3.8% (n=23) and to 16+/-3.7% (n=18) of control, following stimulation at sites in the rostral rostral ventrolateral medulla. In contrast, the low-threshold (prod) responses of eight Class 2 neurons tested were not depressed following neuronal activation at the same sites. When tested, control injections of the inhibitory amino acid, GABA, at the same sites in the rostral rostral ventrolateral medulla had no significant effects on neuronal activity. Neither intravenous administration of noradrenaline (to mimic the pressor responses evoked by DL-homocysteic acid microinjections in the rostral ventrolateral medulla) nor activation at pressor sites in the caudal rostral ventrolateral medulla had any significant effect on neuronal responsiveness. With regard to sensory processing in the spinal cord, these data suggest that descending inhibitory control that originates from neurons in pressor regions of the rostral rostral ventrolateral medulla is highly selective for nociceptive inputs to Class 2 neurons. These data are discussed in relation to the role of the rostral ventrolateral medulla in executing the changes in autonomic and sensory functions that are co-ordinated by higher centres in the CNS.
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PMID:Inhibitory effects evoked from the rostral ventrolateral medulla are selective for the nociceptive responses of spinal dorsal horn neurons. 1102 45

Amyotrophic lateral sclerosis (ALS) has become an increasingly attractive area for the pharmaceutical industry, the most experimentally tractable of the neurodegenerative diseases. Mechanisms underlying cell death in ALS are likely to be important in more common but more complex disorders. Riluzole, the only drug launched for treatment ALS is currently undergoing industrial trials for Alzheimer's, Parkinson's, Huntington disease, stroke and head injury. Other compounds in Phase III testing for ALS (mecamserin, xaliproden, gabapentin) are also in trials for other neurodegenerative disorders. Mechanisms of action of these advanced compounds are limited to glutamate antagonism, direct or indirect growth factor activity, as well as GABA agonism and interaction with calcium channels. A broader range of mechanisms is represented by compounds in Phase I trials: glutamate antagonism (dextramethorphan/p450 inhibitor; talampanel), growth factors (leukemia inhibiting factor; IL-1 receptor; encapsulated cells secreting CNTF) and antioxidants (TR500, a glutathione-repleting agent; recombinant superoxide dismutase; procysteine.) An even broader range of mechanisms is being explored in preclinical discovery programs. Recognition of the difficulties associated with delivery of protein therapeutics to the CNS has led to development of small molecules interacting either with neurotrophin receptors or with downstream intracellular signalling pathways. Other novel drug targets include caspaces, protein kinases and other molecules influencing apoptosis. High-throughput screens of large libraries of small molecules yield lead compounds that are subsequently optimized by chemists, screened for toxicity, and validated before a candidate is selected for clinical trials. The net is cast wide in early discovery efforts, only about 1% of which result in useful drugs at the end of a decade-long process. Successful discovery and development of novel drugs will increasingly depend on collaborative efforts between the academy and industry.
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PMID:Novel drug development for amyotrophic lateral sclerosis. 1109 Aug 60

The effects of aniracetam on extracellular levels of dopamine (DA), serotonin (5-HT) and their metabolites were examined in five brain regions in freely moving stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal DA release in SHRSP was uniformly lower in all regions tested than that in age-matched control Wistar Kyoto rats. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were altered in the basolateral amygdala, dorsal hippocampus and prefrontal cortex of SHRSP. While basal 5-HT release decreased in the striatum and increased in the basolateral amygdala, there was no associated change in 5-hydroxyindoleacetic acid levels. Systemic administration of aniracetam to SHRSP enhanced both DA and 5-HT release with partly associated change in their metabolite levels in the prefrontal cortex, basolateral amygdala and dorsal hippocampus, but not in the striatum and nucleus accumbens shell, in a dose-dependent manner (30 and/or 100 mg/kg p.o.). Microinjection (1 and 10 ng) of aniracetam or its metabolites (N-anisoyl-GABA and 2-pyrrolidinone) into the nucleus accumbens shell produced no turning behavior. These findings indicate that SHRSP have a dopaminergic hypofunction throughout the brain and that aniracetam elicits a site-specific activation in mesocorticolimbic dopaminergic and serotonergic pathways in SHRSP, possibly via nicotinic acetylcholine receptors in the ventral tegmental area and raphe nuclei. The physiological roles in the aniracetam-sensitive brain regions may closely link with their clinical efficacy towards emotional disturbances appearing after cerebral infarction.
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PMID:Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats. 1128 61

Estrogen has demonstrated great potential as a therapeutic agent in focal ischemic brain injury, as exogenous beta-estradiol has proven beneficial in a variety of focal stroke models. In contrast, the relatively few studies of estrogen's efficacy in transient forebrain ischemia have produced inconsistent results. The present study was therefore designed to clarify estrogen's neuroprotective potential in selective hippocampal neuronal injury resulting from four-vessel occlusion in the rat. Female Wistar rats (normal, ovariectomized, or ovariectomized and estradiol-treated) received 5 or 10 min of ischemia. No differences in hippocampal cell loss were found amongst the groups with 10 min of ischemia. Amongst the groups with 5 min of ischemia, the mildest injury was found in the ovariectomized animals, which lost only 32% of their CA1 pyramidal cells. In comparison, mean cell losses were 54% and 49%, respectively, in intact females and in ovariectomized animals with estradiol replacement. Linear regression analysis demonstrated a highly significant relationship between cell loss and plasma estradiol levels. The mechanism by which exogenous and endogenous estrogen exacerbated the injury is unclear, as estrogen has many neuroprotective effects. On the other hand, many other reported effects of estrogen in hippocampal area CA1 might confer increased sensitivity to ischemia, either by modulating the excitatory effects of glutamate or by modifying the inhibitory effects of GABA. Determining how to modulate the various competing effects of estrogen is of both theoretical and practical importance, as it is now clear that one cannot assume that estrogen administration will always improve outcome in cerebral ischemia.
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PMID:Deleterious effect of beta-estradiol in a rat model of transient forebrain ischemia. 1132 56

Reversal of the Na(+)/Ca(2+) exchanger (NCX) occurs during ischemia-reperfusion injury as a result of changes in intracellular pH and sodium concentration. Inhibition of NCXs has been shown to be neuroprotective in vitro. In this study, we evaluated the effects of KB-R7943 (50 microM), a specific inhibitor of the reverse mode of NCX, applied topically onto rat cerebral cortex prior to and during ischemia. Amino acid and free fatty acid levels in cortical superfusates, withdrawn at 10-min intervals from bilateral cortical windows, were analyzed by high-performance liquid chromatography. During a 20-min period of ischemia in control animals, there were significant increases in all amino acids and in all FFAs. Following reperfusion, all FFAs remained significantly elevated. Application of KB-R7943 (50 microM) significantly inhibited effluxes of phosphoethanolamine, but had no effect on glutamate, aspartate, taurine or GABA levels. KB-R7943 also resulted in significant reductions in levels of myristic, docosahexaenoic and arachidonic acid during ischemia and in reperfusion levels of arachidonic and docosahexaenoic acids. These data indicate that inhibition of Na(+)/Ca(2+) exchange likely prevented the activation of phospholipases that usually occurs following an ischemic insult as evidenced by its attenuation of phosphoethanolamine and free fatty acid efflux. The inhibition of phospholipases may be an essential component of the neuroprotective benefits of Na(+)/Ca(2+) exchange inhibitors in ischemia-reperfusion injury and may provide a basis for their possible use in therapeutic strategies for stroke.
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PMID:Inhibition of Na(+)/Ca(2+) exchange by KB-R7943, a novel selective antagonist, attenuates phosphoethanolamine and free fatty acid efflux in rat cerebral cortex during ischemia-reperfusion injury. 1159 6

Aniracetam, a cognition enhancer, has been recently found to preferentially increase extracellular levels of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex (PFC), basolateral amygdala and dorsal hippocampus of the mesocorticolimbic system in stroke-prone spontaneously hypertensive rats. In the present study, we aimed to identify actually active substances among aniracetam and its major metabolites and to clarify the mode of action in DA and 5-HT release in the PFC. Local perfusion of mecamylamine, a nicotinic acetylcholine (nACh) and N-methyl-D-aspartate (NMDA) receptor antagonist, into the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) completely blocked DA and 5-HT release, respectively, in the PFC elicited by orally administered aniracetam. The effects of aniracetam were mimicked by local perfusion of N-anisoyl-gamma-aminobutyric acid [corrected] (N-anisoyl-GABA), one of the major metabolites of aniracetam, into the VTA and DRN. The cortical DA release induced by N-anisoyl-GABA applied to the VTA was also completely abolished by co-perfusion of mecamylamine. Additionally, when p-anisic acid, another metabolite of aniracetam, and N-anisoyl-GABA were locally perfused into the PFC, they induced DA and 5-HT release in the same region, respectively. These results indicate that aniracetam enhances DA and 5-HT release by mainly mediating the action of N-anisoyl-GABA that targets not only somatodendritic nACh and NMDA receptors but also presynaptic nACh receptors.
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PMID:Aniracetam enhances cortical dopamine and serotonin release via cholinergic and glutamatergic mechanisms in SHRSP. 1159 8

We have previously demonstrated that the overexpression of endothelial NO synthase (eNOS) in the rostral ventrolateral medulla (RVLM) decreases blood pressure, heart rate, and sympathetic nerve activity via an increase in gamma-amino butyric acid release in normotensive Wistar-Kyoto rats (WKY). Stroke-prone spontaneously hypertensive rats (SHRSP) appear to have reductions of NO production and GABA release in the RVLM. The aim of this study was to determine whether the effects of the increase in NO production in the RVLM in SHRSP are different from those in WKY. We transfected adenovirus vectors encoding either eNOS (AdeNOS) or beta-galactosidase (Adbetagal) into the RVLM of both strains. In the AdeNOS-treated group, mean arterial blood pressure and heart rate in the conscious state were significantly decreased at day 7 after the gene transfer in both strains. The decreases in mean arterial blood pressure and heart rate were significantly greater in SHRSP than in WKY. Urinary norepinephrine excretion was also decreased to a greater degree in SHRSP than in WKY after the gene transfer. The pressor response evoked by bicuculline into the RVLM of WKY was greater than that of SHRSP in the nontransfected group. However, in the AdeNOS-treated group, the pressor response did not differ between SHRSP and WKY after the gene transfer. These results indicate that the increase in NO production evoked by the overexpression of eNOS in the RVLM causes greater depressor and sympathoinhibitory responses in SHRSP than in WKY by improving an inhibitory action of GABA on the RVLM neurons.
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PMID:Cardiovascular effects of overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla in stroke-prone spontaneously hypertensive rats. 1184 95

This paper describes some of the problems that were encountered during implementation of the Early GABA-ergic Activation Study In Stroke (EGASIS), a large international multicenter clinical trial evaluating the neuroprotective effect of diazepam in acute stroke. The focus is on obtaining funding for such a large international nonprofit trial, getting approval from all national and local ethics committees, shipping trial medication, and trial insurance. For each topic the specific problems and ways in which they were solved are described. Several recommendations for facilitating the running of a large international multicenter clinical trial such as EGASIS are made.
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PMID:Implementing the EGASIS trial, an international multicenter acute intervention trial in stroke. 1185 68


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