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

Basic neuroscience research findings during the past five years have established a clear relationship between the excitatory amino acid (EAA) neurotransmitters (glutamic and aspartic acid) and various pathological states. A major mechanism of neural tissue degeneration following cerebral ischemia, and perhaps other neurodegenerative diseases, seems to involve overactivity of the EAA system in brain. This process is called delayed excitotoxicity and it has become a focal point for the design of new drugs that inhibit its course (EAA receptor blockers). Very recently it has been shown that it is possible to block delayed excitotoxicity using adenosine A1 receptor agonists which inhibit EAA release pre-synaptically. This approach is very effective in reducing post-stroke neurological damage in a number of animal models and has certain advantages when compared to the EAA receptor blocker strategy. Adenosine agonists not only inhibit excitotoxicity but they also block granulocyte activation and the capillary no-reflow phenomenon which results. An additional adenosinergic approach involves brain permeable adenosine uptake blockers which would serve to increase adenosine levels somewhat selectively at ischemic foci thereby inhibiting EAA release. The adenosinergic approach to stroke therapeutics may be a potentially effective strategy for new drug development in neurology, and may have general applicability to other neurodegenerative disease states where excitotoxicity is being implicated.
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PMID:Adenosinergic approaches to stroke therapeutics. 197 12

The levels of the neurotransmitter amino acids glutamate, aspartate, and GABA were determined in different brain regions during ischemia and post-ischemic recirculation periods using the unilateral carotid artery occlusion model of stroke in gerbils. The levels of glutamate, aspartate and GABA in ischemic hemisphere were increased significantly by 10 min of ischemia and later declined with time. Reperfusion for 30 min following 10 min. of ischemia further enhanced the levels of glutamate and aspartate. Increase in GABA levels were found during early periods of reperfusion. Regional variations in the changes of amino acids' levels were noticed following ischemia. Hippocampus showed the highest increase in glutamate levels followed by striatum and cerebral cortex. Aspartate levels in striatum and hippocampus increased during 10 min ischemia (46% and 30%) and recirculation (70% and 79%), whereas in cerebral cortex the levels were doubled only during recirculation. Ischemia induced elevations of GABA levels were observed in cerebral cortex (68%) and in hippocampus (30%), and the levels were normalized during recirculation. No changes in GABA levels were found in striatum. It is suggested that the large increase in the levels of excitatory neurotransmitter amino acids in brain regions specially in hippocampus during ischemia and recirculation may be one of the causal factors for ischemic brain damage.
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PMID:Changes in regional levels of putative neurotransmitter amino acids in brain under unilateral forebrain ischemia. 257 Oct 93

Effects of oral administration of NC-1100 on the metabolism of neuroactive amino acids in rat brain were studied using stroke-prone spontaneously hypertensive (SHR-SP) and Wistar Kyoto rats. The repeated administration of NC-1100 induced a significant increase of gamma-aminobutyric acid (GABA) content in the cerebellum and medulla oblongata of SHR-SP. The decrease of aspartic acid contents in the cerebellum and medulla oblongata of SHR-SP was also noted following NC-1100 administration. Although the activity of L-glutamic acid decarboxylase did not change in these cerebral areas, the activity of GABA-transaminase:succinic semialdehyde dehydrogenase was found to be significantly reduced in the cerebellum of SHR-SP following the repeated administration of NC-1100. The turnover rate of GABA was also significantly reduced in the cerebellum and medulla oblongata of SHR-SP. It was also found that the spontaneous release of preloaded [3H]GABA from cerebral cortical slices was significantly retarded by the continuous oral administration of NC-1100. These results suggest that NC-1100 may be a drug inducing the increase of GABA in the cerebellum and medulla oblongata following continuous administration, especially in animals having hypertension associated cerebrovascular disorders such as SHR-SP.
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PMID:Effect of NC-1100 [1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl) ethanol dihydrochloride] on gamma-aminobutyric acid (GABA) metabolism in rat brain: analysis using stroke-prone spontaneously hypertensive rat. 277 51

To determine the hemodynamic effects of a hypotensive dose of atrial natriuretic factor (ANF), a synthetic peptide containing 26 amino acids of endogenous rat ANF (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH) was studied in two groups of barbiturate anesthetized rats. In the first experiment, a 20-minute infusion of a hypotensive dose, 95 pmole/min i.v., of the synthetic ANF decreased mean arterial pressure (MAP) by 40 +/- 3 mm Hg from a baseline of 128 +/- 5 mm Hg, and cardiac output (CO) (microsphere method) by 7.8 +/- 1.8 ml/min/100 gm from a baseline of 23.5 +/- 1.3 ml/min/100 gm. Synthetic ANF did not significantly affect the total peripheral resistance (TPR) measured at the end of the 20-minute infusion. Sodium nitroprusside (SNP), infused at an equihypotensive dose of 20 micrograms/kg/min i.v., produced the same hemodynamic profile in seven other animals; in contrast, 0.3 mg/kg i.v. of hydralazine (n = 7) lowered MAP by 56 +/- 6 mm Hg and reduced TPR index by 3.0 +/- 0.6 mm Hg/ml/min/100 gm, but did not change CO. Other than an increase in coronary blood during SNF infusion, there were no significant changes in the distribution of cardiac output. Infusion of the saline vehicle had no significant effects on any of these parameters. The results of the second experiment in anesthetized rats confirmed that hypotensive doses of 40 and 100 pmole/kg/min i.v. lowered CO (dye dilution method) from a baseline of 33 +/- 6 to a minimum of 24 +/- 2 ml/min/100 gm (p less than 0.05) without affecting TPR. In addition, synthetic ANF did not significantly affect heart rate (HR) but it slightly reduced cardiac contractility (dp/dt50). These results suggest that the hypotensive dose of synthetic ANF reduced cardiac output, partially by diminishing stroke volume, and perhaps contractility.
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PMID:Cardiac and hemodynamic responses to synthetic atrial natriuretic factor in rats. 294 28

This study tests the hypothesis that aspartate enrichment of glutamate-blood cardioplegia improves metabolic and functional recovery after ischemic and reperfusion damage. Ischemic and reperfusion damage were produced in 15 dogs by 45 minutes of aortic clamping at 37 degrees C and 5 minutes of blood reperfusion, before 2 more hours of aortic clamping (simulated operation). Six received multidose blood cardioplegia at 4 degrees C. In nine others, the cardioplegic solution was infused at 37 degrees C for the first 5 minutes, followed by multidose infusions at 4 degrees C. Four received 26 mmol glutamate-enriched cardioplegic solution. In five, the glutamate (13 mmol) cardioplegic solution was enriched with aspartate (13 mmol). Oxygen uptake and ventricular function (stroke work index, left atrial pressure) were measured. These data suggest aspartate enrichment produced the highest oxygen uptake (32 +/- 4 versus 17 +/- 2 ml/100 gm for glutamate and 7 +/- 1 ml/100 gm for 4 degrees C blood cardioplegia). Complete functional recovery occurred in aspartate/glutamate-treated hearts (stroke work index 90% +/- 4%, left atrial pressure 12 +/- 2 mm Hg), whereas recovery was incomplete with both glutamate alone (stroke work index 66% +/- 14%, left atrial pressure 20 +/- 3 mm Hg) and 4 degrees C blood cardioplegia at low cardiac outputs. Eight of 10 hearts not receiving aspartate failed at high cardiac outputs. Aspartate enrichment of glutamate-blood cardioplegia improves recovery after severe ischemic/reperfusion damage by improving oxidative metabolism during cardioplegic infusion and during postischemic work.
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PMID:Safety of prolonged aortic clamping with blood cardioplegia. III. Aspartate enrichment of glutamate-blood cardioplegia in energy-depleted hearts after ischemic and reperfusion injury. 395 Dec 46

The concentrations of amino acids (AA), stroke index and infarct area were determined in 26 gerbils which were divided into 3 groups: RSM-treated (n = 8), Saline-treated (n = 10) and sham-operated (n = 8). The levels of AA were measured with microdialysis technique in cerebral cortex. The concentrations of neurotransmitter AA, as Glu and GABA and Asp, were significantly increased during the first 60 min after CCA ligation, while the concentrations of non-neurotransmitter AA, as Thr and Ser, had no significant changes. In RSM-treated gerbils, the level of Glu was significantly lower than that of the saline-treated, but the GABA in RSM-treated was significantly higher than that of the saline-treated. The ratio of Glu/GABA was significantly decreased after ischemia. The RSM could improve the reduction of ratio of Glu/GABA during 0-30 min and 91-120 min after cerebral ischemia. There were statistically significant decrease in terms of stroke index in RSM-treated group when compared with saline-treated group at 24 h and 16 h after CCA ligation respectively. The RSM has a tendency to decrease the size of infarct area, but no statistical difference. The results suggest that the neurotransmitter AA involve in the pathophysiological procedures of cerebral ischemia and the RSM can attenuate dysfunctions of EAA and IAA. Furthermore, the results also imply that there may be an alternate way to treat cerebral ischemia by inhibiting the presynaptic releasing of Glu and stimulating the releasing of GABA.
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PMID:Effect of radix salviae miltiorrhizae on EAA and IAA during cerebral ischemia in gerbils: a microdialysis study. 819 18

We describe a novel transthyretin mutation at codon 18 where Asp is replaced by Gly (D18G) in a Hungarian kindred. This mutation is associated with meningocerebrovascular amyloidosis, producing dementia, ataxia, and spasticity. Fifty different transthyretin mutations are related to amyloid deposition, typically producing a peripheral neuropathy or cardiac dysfunction. These symptoms are absent in this family. Up to now, amyloid-beta (A beta), cystatin C, and prion proteins have been known to be deposited as amyloid in the brain, leading to stroke or dementia. With this report we establish that transthyretin amyloid deposition can also produce central nervous system dysfunction as the major clinical symptom.
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PMID:Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD 18G) 857 96

The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.
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PMID:Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. 905 Aug 95

Methionine synthase and 5,10-methylenetetrahydrofolate reductase (MTHFR) sequentially catalyze the remethylation of homocysteine to methionine. A point mutation in the encoding region of the methionine synthase gene, which results in substitution of an aspartic acid for a glycine residue (D919G), has been identified in patients of the cblG genetic complementation group; these patients exhibit significantly decreased methionine synthase activity. Nevertheless, the D919G mutation has also been reported to be common in the general population. In this study, we analyzed the distribution of methionine synthase D/G polymorphism in the Japanese population and examined the extent to which it is associated with altered homocysteine metabolism and late-onset vascular diseases. We studied 215 patients with coronary artery disease, 251 patients with histories of ischemic stroke, and 257 control subjects. The methionine synthase genotype was analyzed by polymerase chain reaction followed by HaeIII digestion; allele frequencies for the D919G variant of the enzyme proved to be similar in all 3 subject groups (control subjects, 0.17; coronary artery disease patients, 0. 17; and ischemic stroke patients, 0.19). Furthermore, in patients with ischemic stroke, plasma levels of homocyst(e)ine and folate were similar, irrespective of methionine synthase genotype. Thus, the methionine synthase D919G mutation was found to be common in the Japanese general population, and it appears unlikely that this polymorphism has a major effect on homocysteine metabolism and/or the onset of vascular diseases.
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PMID:Polymorphism of the methionine synthase gene : association with homocysteine metabolism and late-onset vascular diseases in the Japanese population. 997 10

In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.
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PMID:Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. 1020 88


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