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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuroprotective effects of enhancing neuronal inhibition with a gamma-aminobutyric acid (GABA) uptake inhibitor were studied in gerbil hippocampus following transient ischemia. We used in vivo microdialysis to determine a suitable dosing regimen for tiagabine (NNC328) to elevate extracellular levels of GABA within the hippocampus. In anesthetized (normothermic) gerbils, tiagabine (45 mg/kg, i.p.) selectively elevated extracellular GABA levels 450% in area CA1 of the hippocampus. In gerbils subjected to cerebral ischemia via 5-min bilateral carotid occlusion, extracellular GABA levels increased 13-fold in area CA 1 returning to baseline within 30-45 min. When tiagabine was injected 10 min following onset of reperfusion, GABA levels remained elevated (200-470%) for 90 min. In addition, tiagabine significantly reduced the ischemic-induced elevation of glutamate levels in area CA1 during the postischemic period when GABA levels were elevated. There was no effect of postischemic tiagabine on aspartate or six other amino acids. Using the same dosing regimen, we evaluated the degree of neuroprotection in the hippocampus of gerbils 4 and 21 days after ischemia. Tiagabine decreased body temperature a maximum of 2.7 degrees C beginning 30 min into reperfusion and lasting 90 min. In untreated gerbils sacrificed 4 and 21 days after ischemia, there was severe necrosis (99%) of the pyramidal cell layer in area CA1. Whereas tiagabine significantly protected the CA1 pyramidal cell layer in ischemic gerbils at 4 days (overt necrosis confined to about 17% of area CA1), the protection diminished significantly 21 days postischemia. When normothermia was maintained both during and after ischemia in a separate group of tiagabine-treated animals, approximately 77% of the CA1 pyramidal cell layer was necrotic at 4 days. Based on these findings, we suggest that 1) tiagabine slows the development of hippocampal degeneration following ischemia, and 2) that mild, postischemic hypothermia is responsible, in large part, for the neuroprotective actions of this drug. We conclude that the histological outcome after administration of cerebral neuroprotectants should be assessed following long-term survival.
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PMID:Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus. 877 58

Under aerobic conditions the addition of (C2N5)2N(N[O]NO)-.Na+(DEA/NO), S-nitroso-N-acetyl penicillamine and nitric oxide (NO)-saturated buffer, but not S-nitroso-L-glutathione, to dopamine solutions resulted in dopamine o-semiquinone formation that was dependent on the formation of a NO/oxygen intermediate. High pressure liquid chromatography (HPLC) electrochemical analysis of dopamine demonstrated that the DEA/NO-induced oxidation of dopamine was abrogated in the presence of the antioxidants, ascorbate and glutathione. NO spontaneously released from DEA/NO decreased [3H]dopamine accumulation in primary cultures of mesencephalic neurons in a dose-dependent fashion. In contrast, [3H] gamma-aminobutyric acid uptake by mesencephalic neurons tested under the same conditions was unchanged. When DEA/NO was added to incubation buffer that contained [3H]dopamine and the antioxidant, ascorbate or glutathione, [3H]dopamine uptake was also inhibited. These data excluded that oxidation of extracellular [3H]dopamine by the intermediates of the NO/O2 reaction could have caused this decrease. Instead, NO may have acted directly on a not yet identified target operative in the regulation of dopamine storage and release. Analysis of the rate constants for the NO reaction with ascorbate, glutathione and dopamine revealed that dopamine quinone formation was delayed by the presence of antioxidants. Since the formation of NO as well as neurotransmitter release are activated during ischemia reperfusion injury, it is possible that prolonged NO exposure could deplete antioxidants and facilitate the oxidation of dopamine and thereby cause neurotoxicity.
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PMID:Role of antioxidants in the nitric oxide-elicited inhibition of dopamine uptake in cultured mesencephalic neurons. Insights into potential mechanisms of nitric oxide-mediated neurotoxicity. 879 43

The time courses of changes in extracellular levels of the transmitter amino acids, glutamate, aspartate and gamma-aminobutyric acid (GABA), and of the purines, adenosine and inosine, during 20 or 40 min periods of four vessel occlusion rat cerebral ischemia, followed by reperfusion, were investigated using a cerebral cortical cup technique. During a 20 min period of ischemia, superfusate amino acids increased by 10-30-fold and adenosine levels increased five-fold. Reperfusion was followed by the return of amino acids and purines towards pre-ischemic levels. Significantly greater increases in glutamate and aspartate levels were observed during a 40 min ischemia and, in contrast to the 20 min ischemia, the efflux of all compounds remained elevated throughout the 40 min reperfusion period. These results suggest that longer periods of ischemia are associated with increasing degrees of plasma membrane disruption allowing for a greater leakage of intracellular contents. The failure of extracellular levels of amino acids and purines to return towards pre-ischemic levels indicates that cells may be unable to effectively reconstitute their membranes after longer periods of ischemia.
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PMID:Changes in extracellular amino acid neurotransmitters and purines during and following ischemias of different durations in the rat cerebral cortex. 883 39

The protective effects of carnosine and related compounds on isolated rat heart were studied under experimental ischemia. The ability of carnosine to suppress significantly the development of ischemic reperfusion contracture and to support the restoration of the contractile force during reperfusion were shown. At the same time, a decrease of myoglobin and nucleoside release from myocytes was observed, this indicating a membrane-protecting effect of carnosine. Methylation of carnosine at the N1 or N3 atom of the imidazole ring significantly decreased the protective effect; the substitution of beta-alanine with gamma-aminobutyric acid (resulting in formation of homocarnosine) actually augmented ischemic damage to the heart. Acetylation of carnosine at the beta-amino group amplified the membrane-protecting properties of the molecule, the acetylated derivative of carnosine also showing the ability to induce contractile activity of the ischemic heart. Histidine alone or in combination with beta-alanine and sodium acetate had no effect, while acetylhistidine showed a significant protective effect during reperfusion. The comparison of the effects of natural histidine-containing dipeptides versus synthetic antioxidants indicates that the anti-ischemic effect of carnosine and acetylcarnosine involves antiradical and membrane-protecting mechanisms; nevertheless, the effect cannot be reduced to these mechanisms alone. The observed phenomena of heart muscle protection by acetylated derivatives of carnosine and anserine under ischemia correlates with the preferential localization of these compounds in high quantities in the myocardium.
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PMID:Effect of histidine-containing dipeptides on isolated heart under ischemia/reperfusion. 911 34

Nitric oxide release during cerebral ischemia is the result of both neuronal and endothelial subclasses of nitric oxide synthase (NOS). In this study, we examined the role of specific neuronal NOS inhibition (nNOSI) on excitatory neurotransmitter and gamma-aminobutyric acid (GABA) release during global cerebral ischemia. Microdialysis probes were placed into the striatum of 24 rats. After probe stabilization, rats were randomized to receive 7-nitroindazole (7-NI), a selective nNOSI, in doses of 0, 5, 10, or 20 mg/kg. Temporary global forebrain ischemia was induced for 15 min, followed by 60 min of reperfusion. nNOSI administration did not produce detectable changes in neurotransmitter recovery prior to ischemia. There were significant increases in aspartate (ASP), glutamate (GLU), glycine (GLY), and GABA recovery during ischemia in the absence of nNOSI. 7-NI resulted in an attenuation in GLU, GLY, and GABA recovery during ischemia and reperfusion. No differences in ASP recovery were detected with nNOSI. Differences between the present study and other studies that examine the role of nonspecific constitutive NOSI during cerebral ischemia demonstrate the contribution of neuronal NOS on the modulation of ischemic excitatory neurotransmitter and GABA release.
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PMID:Modulation of ischemic excitatory neurotransmitter and gamma-aminobutyric acid release during global temporary cerebral ischemia by selective neuronal nitric oxide synthase inhibition. 949 47

Systemic nitric oxide synthase inhibition (NOSI) decreases cerebral blood flow, which may worsen ischemic insults. To examine the local effects of NOSI without this confounding effect, we examined the role of a locally administered NOSI, NG-nitro-L-arginine-methyl-ester (L-NAME), on neurotransmitter recovery during cerebral ischemia. Rats were assigned to one of three groups: locally administered L-NAME via a striatal microdialysis probe (n = 11), systemic L-NAME (n = 5), or control (n = 11). Temporary global forebrain ischemia was induced for 15 min, followed by 60 min of reperfusion. L-NAME resulted in decreases of basal aspartate (ASP; 74% of basal) and glutamate (GLU; 60% of basal) recovery. While systemic L-NAME caused significant increases in ischemic ASP and GLU recovery (by 224% and 110%, respectively, compared with ischemic controls), local NOSI administration resulted in a significant attenuation of peak ASP, GLU, glycine, and gamma-aminobutyric acid recovery (43%, 38%, 53%, and 72%, respectively, compared with ischemic controls). We conclude that local NOSI attenuated ischemic neurotransmitter recovery during ischemia/reperfusion. Our results emphasize the importance of the systemic effects of NOSI and suggest both deleterious and beneficial effects of NOSI during ischemia/reperfusion.
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PMID:Modulation of ischemic excitatory neurotransmitter and gamma-aminobutyric acid release during global temporary cerebral ischemia by local nitric oxide synthase inhibition. 914 22

Changes in inhibitory neuronal functioning may contribute to morbidity following traumatic brain injury (TBI). Evoked responses to orthodromic paired-pulse stimulation were examined in the hippocampus and dentate gyrus at 2 and 15 days following lateral fluid percussion TBI in adult rats. The relative strength of inhibition was estimated by measuring evoked paired pulses in three afferent systems: the CA3 commissural input to the CA1 region of the hippocampus; the entorhinal cortical input to the ipsilateral CA1 area (temporoammonic system); and the entorhinal input to the ipsilateral dentate gyrus (perforant path). In addition to quantitative electrophysiological estimates of inhibitory efficacy, levels of gamma-aminobutyric acid (GABA) were qualitatively examined with immunohistochemical techniques. Effects of TBI on paired-pulse responses were pathway-specific, and dependent on time postinjury. At 2 days following TBI, inhibition of population spikes was significantly reduced in the CA3 commissural input to CA1, which contrasted with injury-induced increases in inhibition in the dentate gyrus seen at both 2 and 15 days postinjury. Low-level stimulation, subthreshold for population spikes, also revealed changes in paired-pulse facilitation of field extracellular postsynaptic potentials (fEPSPs), which depended on fiber pathway and time postinjury. Significant injury-induced electrophysiological changes were almost entirely confined to the hemisphere ipsilateral to injury. Intensity of GABA immunobinding exhibited a regional association with electrophysiological indices of inhibition, with the most pronounced increases in GABA levels and inhibition found in the dentate gyrus. TBI-induced effects showed a regional pattern within the hippocampus which corresponds closely to inhibitory changes reported to follow ischemia and kindling. This degree of similarity in outcome following dissimilar injuries may indicate common mechanisms in the nervous system response to injury.
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PMID:The effects of traumatic brain injury on inhibition in the hippocampus and dentate gyrus. 920 May 6

The effect of dl-3-butylphthalide (NBP) on the contents of amino acids and dopamine in the rat striatum during globe cerebral ischemia has been studied. By using the technique of microperfusion in the striatum of rats subjected to 4-vessel occlusion cerebral ischemia, the extracellular contents of glutamate, taurine, gamma-aminobutyric acid and dopamine were found to be significantly increased in the striatum during the 20 min of cerebral ischemia. NBP (40 mg.kg-1; i.p. 30 min before ischemia) was shown to reduce the contents of dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the striatal extracellular fluid of the rat during ischemia. The content of glycine before and after ischemia was also reduced. However, no significant effect on the contents of glutamate and some other amino acids was observed. The results suggest that NBP may improve the striatal ischemic injury.
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PMID:[Effect of dl-3-butylphthalide on the striatum extracellular amino acid and dopamine contents in the rat during cerebral ischemia]. 920 46

We examined the functionality of hippocampal CA1 neurons at early times after transient global ischemia, by electrophysiologic recordings in brain slices. Transient ischemia was conducted on rats using the method of 15-minute four-vessel occlusion, and brain slices were obtained from these animals at different times after ischemia. Within 24 hours after insult, CA1 neurons showed no substantial damage as identified by morphologic means, but exhibited dramatic decreases in synaptic activities by 12 hours after insult, which became further decreased at more extended times after recovery. Blocking gamma-aminobutyric acid A (GABAA) receptors with bicuculline produced a reversible augmentation of the diminished synaptic responses in slices prepared from 12-hour postinsult animals, but failed to do so in slices obtained from rats 24 hours after insult. Recorded in whole-cell mode, the minimum depolarizing current required to elicit an action potential was about twofold larger in the ischemic CA1 neurons than in sham controls, suggesting that an elevated spiking threshold exists in these neurons. We suggest that decreases in electrophysiologic activities precede the morphologic deterioration in postischemic CA1 neurons. The early decrease in CA1 synaptic activities may be associated with an imbalance between glutamate-mediated synaptic excitation and GABAA-mediated synaptic inhibition, whereas substantial impairments in synaptic transmission likely take place after prolonged post-ischemic recovery.
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PMID:Transient ischemia induces an early decrease of synaptic transmission in CA1 neurons of rat hippocampus: electrophysiologic study in brain slices. 930 9

Following transient cerebral ischemia, pyramidal cells within area CA1 of the hippocampus exhibit delayed neuronal death. While interneurons within this sector continue to survive long-term, there is evidence that some interneurons in area CA1 are vulnerable to damage. To determine the nature of vulnerability in a neurochemically heterogeneous population of interneurons throughout area CA1, we examined the labeling of gamma-aminobutyric acid (GABA)ergic interneurons with an antibody to the GABAA receptor alpha 1-subunit 1-35 days following cerebral ischemia in the Mongolian gerbil. Unlike some other GABA interneuron markers, this antibody labels both the dendrites and soma of interneurons, allowing dendritic structure to be examined. Three to four days following ischemia, the pyramidal cells in area CA1 had degenerated, and the alpha 1-subunit-positive interneurons in all layers of area CA1 had developed severely beaded dendrites. At longer survival times (21-35 days), the alpha 1-subunit-immunolabeled dendrites of these interneurons had a fragmented appearance. In contrast, interneurons bordering str. oriens and alveus typically exhibited normal dendritic morphology. Despite the pathologic changes, there was no evidence of interneuron loss in area CA1 up to 35 days post-ischemia. Normal interneuron morphology was also observed in area CA3 and dentate gyrus, regions where neither pyramidal neurons nor granule cells, respectively, die following 5 min of cerebral ischemia. To determine if the ischemia-induced changes in interneuron morphology could be prevented, diazepam was administered 30 and 90 min following ischemia. Diazepam produces long-term neuroprotection of area CA1 pyramidal neurons. In gerbils sacrificed 35 days after ischemia, diazepam markedly attenuated the dendritic beading of the area CA1 interneurons. In addition, the dendrites did not display the fragmented labeling by the alpha 1-subunit antibody. Thus, despite their long-term survival, CA1 hippocampal interneurons in the gerbil can express severe structural abnormalities after transient cerebral ischemia coincident with pyramidal cell degeneration, and the injury to the dendrites can be prevented by the neuroprotectant diazepam.
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PMID:Effect of transient cerebral ischemia on gamma-aminobutyric acidA receptor alpha 1-subunit-immunoreactive interneurons in the gerbil CA1 hippocampus. 934 48


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