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

This study addresses the possible involvement of an agonist-induced postischemic hyperactivity in the delayed neuronal death of the CA1 hippocampus in the rat. In two sets of experiments, dialytrodes were implanted into the CA1 either acutely or chronically (24 h of recovery). During 20 min of cerebral ischemia (four-vessel occlusion model) and 8 h of reflow, we followed extracellular amino acids and multiple-unit activity. Multiple-unit activity ceased within 20 sec of ischemia and remained zero during the ischemic insult and for the following 1 h of reflow. During ischemia, extracellular aspartate, glutamate, taurine, and gamma-aminobutyric acid increased in both acute and chronic experiments (seven- to 26-fold). Multiple-unit activity recovered to preischemic levels following 4-6 h of reflow. In the group with dialytrodes implanted acutely, the continuous increase in multiple-unit activity reached 110% of basal at 8 h of reflow. In the group with dialytrodes implanted chronically, multiple-unit activity recovered faster and reached 140% of control at 8 h, paralleled by an increase in extracellular aspartate (5.5-fold) and glutamate (twofold). In conclusion, the postischemic increase of excitatory amino acids and the recovery of the neuronal activity may stress the CA1 pyramidal cells, which could be detrimental in combination with, e.g., postsynaptic impairments.
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PMID:Changes in extracellular amino acids and spontaneous neuronal activity during ischemia and extended reflow in the CA1 of the rat hippocampus. 205 Nov 65

We evaluated whether regional differences in the magnitude of glutamate, gamma-aminobutyric acid (GABA), and glycine release could explain why some regions are vulnerable to ischemia whereas others are spared. By means of the microdialysis technique, the temporal profile of ischemia-induced changes in extracellular levels of glutamate, GABA, and glycine was compared in regions that demonstrate differing susceptibilities to a 10- and 20-min ischemic insult (dorsal hippocampus, anterior thalamus, somatosensory cortex, and dorsolateral striatum). The degree of ischemia (as established by local cerebral blood flow reduction) and the magnitude of histopathological neuronal damage were also evaluated in these regions. The blood flow reduction was severe and uniform in all regions; however, the histopathological outcome illustrated a different pattern. Whereas the CA1 sector of the hippocampus was severely damaged, the thalamus and cortex were relatively spared from both 10 and 20 min of ischemia. Striatal neurons were resistant to a 10-min insult but severely damaged after 20 min of ischemia. Ischemia-induced increase in glutamate and GABA content were of a similar magnitude and temporal profile in all four brain regions. A uniform increase in extracellular glycine levels was also observed in all four brain structures. The postischemic response, however, was different. Glycine levels remained twofold higher than baseline in the hippocampus but fell to baseline in the cortex and thalamus after both 10- and 20-min insults. In the striatum, glycine levels returned to baseline after 10 min of ischemia but remained relatively high after a 20-min insult.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative effect of transient global ischemia on extracellular levels of glutamate, glycine, and gamma-aminobutyric acid in vulnerable and nonvulnerable brain regions in the rat. 207 98

The activation of 5-hydroxytryptamine receptors exerts an inhibitory influence on neuronal activity in a way similar to the activation gamma-amino-n-butyric acid and adenosine A1 receptors. Therefore, we hypothesized that 5-HT1A-receptor agonists might exert a neuroprotective effect. We tested the full agonists Bay R 1531 and 8-OH-DPAT and the partial agonists ipsapirone and gepirone in the model of transient global ischemia in the Mongolian gerbil. Ipsapirone protected 53% of pyramidal neurons (p less than 0.05) in the CA1 area of the hippocampus from ischemic damage at a dose of 3 mg/kg. Bay R 1531 showed a powerful neuroprotective effect with 100% preservation of neurons at a dose of 3 mg/kg (p less than 0.001) while gepirone and 8-OH-DPAT were ineffective. These findings suggest that 5-HT1A-receptor agonists might be effective tools for the therapy of cerebral ischemia. However, the varying results indicate that transient forebrain ischemia in the gerbil may not be the optimal model system to demonstrate clearly the neuroprotective activity of these compounds.
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PMID:Effects of 5-hydroxytryptamine1A-receptor agonists on hippocampal damage after transient forebrain ischemia in the Mongolian gerbil. 214 36

The effects of short-duration forebrain ischemia on cerebral metabolism in the rat have been studied using several nuclear magnetic resonance (NMR) techniques. In vivo phosphorus-31 (31P) NMR spectroscopy showed that the model produces rapid cerebral energy failure and acidosis. Reperfusion was accompanied by recovery of high-energy metabolites in about 30 minutes, with a slower recovery of pH. Proton (1H) NMR spectra of perchloric acid extracts of selected brain regions showed that levels of alanine and gamma-aminobutyric acid (GABA) were elevated and the level of glutamate was depressed immediately after the ischemic insult, returning to normal by 24 hours. The lactate level remained elevated for up to 7 days after ischemia, suggesting ongoing abnormal mitochondrial function. Postischemic cerebral glucose metabolism was monitored using carbon-13 (13C)-labelled glucose as an NMR probe. Glycolysis was impaired immediately after the ischemic insult, resulting in accumulation of glucose in the tissue and reduced formation of amino acids and tricarboxylic acid cycle intermediates. Glycolysis recovered by 1 hour, but underwent a secondary decrease at 24 hours, the time at which neuronal injury became manifest histologically and physiologically. Nuclear magnetic resonance imaging was used to follow the regional development of tissue injury in selectively vulnerable brain regions. Striatal changes were evident by 24 hours after reperfusion, increasing in intensity and accompanied by hippocampal changes by 48 hours, then becoming less pronounced by 72 hours. Histologic analysis of regional neuronal injury correlated well with the imaging results, establishing NMR imaging as a noninvasive method of visualizing the regional development of ischemic tissue injury.
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PMID:Experimental cerebral ischemia studied using nuclear magnetic resonance imaging and spectroscopy. 215 86

Epilepsy complicates severe head trauma. Development of persistent seizures appears to correlate with the extent of trauma. Although early reports suggested that prophylactic administration of antiepileptic drugs would prevent epileptogenesis, controlled studies have failed to corroborate this assumption. Head trauma initiates a sequence of responses that includes altered blood flow and vasoregulation, disruption of the blood-brain barrier, increases in intracranial pressure, focal or diffuse ischemia, hemorrhage, inflammation, necrosis, and disruption of fiber tracts. The presence of an intracranial hematoma has a robust association with the development of post-traumatic epilepsy. Extravasation of blood is followed by hemolysis and deposition of heme-containing compounds into the neuropil, initiating a sequence of univalent redox reactions and generating various free radical species, including superoxides, hydroxyl radicals, peroxides, and perferryl ions. Free radicals initiate peroxidation reactions by hydrogen abstraction from methylene groups adjacent to double bonds of fatty acids and lipids within cellular membranes. Intrinsic enzymatic mechanisms for control of free radical reactions include activation of catalase, peroxidase, and superoxide dismutase. Steroids, proteins, and tocopherol also terminate peroxidative reactions. Tocopherol and selenium are effective in preventing tissue injury initiated by ferrous chloride and heme compounds. Treatment strategies for prevention or prophylaxis of post-traumatic epilepsy must await absolute knowledge of mechanisms. Antioxidants and chelators may be useful, given the speculation that peroxidative reactions may be an important component of brain injury responses. However, potential treatment strategies involving gamma-aminobutyric acid (GABA) agonists, NMDA receptor antagonists, and barbiturates need further scientific assessment.
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PMID:Post-traumatic epilepsy: cellular mechanisms and implications for treatment. 222 73

Baclofen, the most effective drug for treating spasticity, is a specific agonist of gamma-aminobutyric acid-B receptors, and is very abundant in the superficial layers of the spinal cord. Given orally, baclofen does not easily penetrate the blood-brain barrier, and is distributed equally to the brain and spinal cord. Direct intrathecal administration was given in order to change the distribution of the drug by preferentially perfusing the spinal cord. Eighteen patients presenting a severe spastic syndrome were treated with chronic intrathecal infusion of baclofen in the lumbar cerebrospinal fluid. After clinical preselection, 38 patients were implanted with a lumbar access port allowing long-term trials in order to determine the efficacy of baclofen therapy and the effective 12-hour dose. The 18 patients selected for chronic administration were implanted with a programmable pump. The pathology in these cases was: multiple sclerosis (6 cases), posttrauma spastic syndrome (eight cases), and (one case each) cerebral palsy, ischemic cerebral lesion, spinal ischemia, and transverse myelitis. The mean follow-up period was 18 months (range 4 to 43 months). The clinical results were evaluated according to muscular hypertony on Ashworth's scale (changed for occurrence of painful spasms) and functional improvement. Results were better for spastic syndrome secondary to traumatic medullary lesion than for demyelinating disease. Hypertonia was improved in all cases as confirmed by the registration of the Hoffman (H) reflex. Painful muscular spasms disappeared in 14 of the 16 affected patients. Significant functional improvement was noted in nine patients and was considerable in three. The risk of side effects secondary to overdose (such as excessive hypotonia or central depression) and the absence of a specific baclofen antagonist stresses the necessity for accurate determination of the efficient dose. After an initial titration period and adjustment of the therapeutic dose, the individual doses were from 21 to 500 micrograms/24 hrs (mean 160 micrograms/24 hrs). This new conservative method is very effective, perfectly reversible, and safe when administered in conditions favorable to its use.
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PMID:Chronic intrathecal baclofen administration for control of severe spasticity. 230 74

Sulfonylurea-sensitive adenosine triphosphate (ATP)-regulated potassium (KATP) channels are present in brain cells and play a role in neurosecretion at nerve terminals. KATP channels in substantia nigra, a brain region that shows high sulfonylurea binding, are inactivated by high glucose concentrations and by antidiabetic sulfonylureas and are activated by ATP depletion and anoxia. KATP channel inhibition leads to activation of gamma-aminobutyric acid (GABA) release, whereas KATP channel activation leads to inhibition of GABA release. These channels may be involved in the response of the brain to hyper- and hypoglycemia (in diabetes) and ischemia or anoxia.
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PMID:Glucose, sulfonylureas, and neurotransmitter release: role of ATP-sensitive K+ channels. 230 57

The aim of this study was to measure extracellular chemical changes in the cerebral cortex in response to compression contusion trauma in rats. Energy-related metabolites (i.e., lactate, pyruvate, adenosine, inosine, and hypoxanthine) and amino acids were harvested from the extracellular fluid (ECF) using microdialysis and analyzed by high-performance liquid chromatography. The measurements were performed in cortical tissue, where neuronal injury occurs in this model. The severity of the trauma was varied by using different depths of impact: mild trauma, 1.5 mm; severe trauma, 2.5 mm. The trauma induced a dramatic increase in the ECF levels of energy-related metabolites that was conditioned by the severity of the insult. The ECF level of taurine, glutamate, aspartate, and gamma-aminobutyric acid (GABA) also rose markedly, while other amino acids did not change significantly. The results suggest that the trauma induced a transient, profound focal disturbance of energy metabolism in the cortical tissue, probably as a result of mechanically induced disruption of ion homeostasis and reduced blood flow in combination. The data support the potential role of glutamate and aspartate as mediators of traumatic brain injury. However, the concomitantly released adenosine, GABA, and taurine may be protective and ameliorate excitotoxicity. In analogy with the reported cumulative damaging effects of repeated ischemic insults, the observed ECF changes may help explain the vulnerability of traumatized brain tissue to secondary ischemia.
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PMID:Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. 238 36

Correlations were made among ATP synthesis, transmembrane K+ gradients, and leakage of three amino acid neurotransmitters, gamma-aminobutyric acid (GABA), aspartate, and glutamate, in rat brain synaptosomes incubated under normoxic and respiration-limited conditions. Even under normoxic conditions, a substantial proportion of total ATP synthesis (8%) was provided by glycolysis. Limitation of respiration by approximately 30% through addition of amobarbital (Amytal) caused a twofold decrease in the creatine phosphate/creatine ([CrP]/[Cr]) ratio, and consequently the [ATP]/[ADP] ratio, and a threefold increase in lactate production. There was a detectable decrease in intracellular [K+] and small rises in external GABA, aspartate, and glutamate concentrations. More severe limitations in ATP synthesis caused larger declines in the [CrP]/[Cr] ratio and progressive leakage of K+ and neurotransmitter amino acids. A comparison of delta GATP and delta GNa, K showed the former to be larger by 6 kcal, which indicates that the plasma membrane Na+/K+ pump operates at far from equilibrium. Under respiration-limited conditions, even when total ATP synthesis decreased by approximately 80% and [ATP] declined to less than 0.4 mM, delta GATP was still larger than delta GNa,K. It is suggested that during hypoxia and ischemia, the activity of the plasma membrane Na+/K+ pump in brain becomes limited by [ATP], which falls below the Km value for the low-affinity regulatory site on the enzyme. This failure of the pump and consequent collapse of the ion gradients may contribute to the leakage of neurotransmitter amino acids that occurs in these pathological states.
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PMID:Relationships among ATP synthesis, K+ gradients, and neurotransmitter amino acid levels in isolated rat brain synaptosomes. 244 8

Transient global ischemia was produced in rats by cisternal fluid infusion, producing a negative cerebral perfusion pressure by elevating the intracranial pressure (ICP) 25-50 mm Hg above mean arterial pressure (MAP). Animals were allowed to survive for 2-7 days following a transient ischemic episode of 5-30 min. The brains were examined for signs of ischemic degeneration in Nissl-stained sections and adjacent sections reacted with antisera against glial fibrillary acidic protein (GFAP) or aspartate aminotransferase (AAT). Neurons in the thalamic reticular nucleus (RT), a pure population of gamma-aminobutyric acid (GABA)ergic neurons which project their axons to thalamic relay nuclei, were found to have the lowest threshold for degeneration in this model, consistently undergoing degeneration under conditions which completely spared the hippocampal CA1 from degeneration. Whereas it took up to 30 min of complete ischemia to produce degeneration of CA1 neurons when ICP was raised using room temperature infusion fluids, 15 min of ischemia under these conditions was sufficient to produce extensive degeneration of neurons in the entire ventral 3/4 of the RT. Prolonged (greater than 25 min) episodes of partial ischemia (ICP less than or equal to MAP) were also sufficient to produce massive degeneration of RT neurons. The lesion in the RT was most clearly evident in sections reacted with antisera to GFAP, labeling intensely reactive protoplasmic astrocytes within the regions of the RT where neuronal degeneration had occurred. Neuronal loss and accompanying proliferation of microglial cells were evident in Nissl-stained sections but the extent of the neuronal loss was most clearly obvious in sections reacted with an antisera to AAT, an enzyme present in detectable quantities in GABAergic neurons. Pretreatment with the non-competitive NMDA antagonist MK-801 at doses sufficient to completely prevent massive degeneration of the hippocampal CA1 failed to prevent the degeneration of RT neurons, suggesting that if RT degeneration involves an excitotoxic process it acts through non-NMDA receptors.
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PMID:Degeneration of neurons in the thalamic reticular nucleus following transient ischemia due to raised intracranial pressure: excitotoxic degeneration mediated via non-NMDA receptors? 255 11


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