Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of mRNA encoding the 70 kDa stress/heat shock protein, hsp70, was evaluated in post-ischemic gerbil brain by in situ hybridization using an oligonucleotide probe selective for stress-inducible members of this gene family. Expression of hsp70 sequences was most pronounced in hippocampal CA1 neurons that fail to accumulate immunoreactive hsp70 protein, and that are selectively lost following ischemia. Hybridizable RNA continued to be expressed in CA1 through at least 48 h, essentially until the onset of cell death in this model. In contrast, dentate granule cells and CA2 neurons destined to survive the insult showed transient induction of hsp70 mRNA during the first 24 h of recirculation that disappeared prior to the detection of maximal hsp70 immunoreactivity in these cell populations. Pretreatment with a single injection of MK-801 (10 mg/kg) considerably attenuated the induction of hsp70 mRNA in hippocampus at 6 h of recirculation, an effect apparently mediated by persistent drug-induced hypothermia. The drug did not prevent the later, selective appearance of hsp70 hybridization in CA1 neurons at 24 h, nor did it protect against the subsequent loss of these cells. These results demonstrate a prolonged postischemic stress response at the transcriptional level in vulnerable hippocampal neurons, and suggest its utility as a marker for neuronal pathophysiology associated with mechanisms mediating delayed neuronal death.
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PMID:Localization of 70 kDa stress protein mRNA induction in gerbil brain after ischemia. 201 50

A combined autoradiographic and immunohistochemical method was used to correlate the extent of focal cerebral ischemia and morphologic ischemic damage following unilateral carotid occlusion in 16 gerbils for 5-30 minutes. Immunohistochemical lesions detectable by the reaction for microtubule-associated proteins 1 and 2 were visible in the subiculum-CA1 and CA2 regions of the hippocampus and layer III/IV of the cerebral cortex after 5 minutes of ischemia (n = 4). Local blood flow was promptly reduced but still heterogeneous after 10 minutes of ischemia (n = 4); local blood flow in immunohistochemical lesions was less than 5 ml/100 g/min except in highly vulnerable regions, where flow values of 5-15 ml/100 g/min were observed. After 15 minutes of ischemia (n = 4) local blood flow in less vulnerable regions including the thalamus and caudoputamen also declined to less than 5 ml/100 g/min, and immunohistochemical lesions became visible in those regions after 30 minutes of ischemia (n = 4). On the other hand, many brain regions tolerated local blood flow of less than 5 ml/100 g/min without ischemic damage. The present study demonstrates that selective tissue vulnerability during progressive cerebral ischemia depends on the degree of hypoperfusion and on factors inherent to neurons in various brain regions.
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PMID:Cerebral blood flow and neuronal damage during progressive cerebral ischemia in gerbils. 212 Aug 2

We used brief bilateral carotid artery occlusion in gerbils to examine the effects of temperature on ischemia-induced inhibition of calcium/calmodulin-dependent protein kinase II activity and neuronal death. In normothermic (36 degrees C) gerbils, ischemia induced a severe loss of hippocampal CA1 pyramidal neurons measured 7 days after ischemia (28.4 neurons/mm, n = 10; control density in 10 naive gerbils 262.1 neurons/mm) and a significant decrease in forebrain calcium/calmodulin-dependent protein kinase II autophosphorylation measured 2 hours after ischemia (12.9 fmol/min, n = 6; control phosphorylation in six naive gerbils 23.5 fmol/min). The effect of temperature on these indicators of ischemic damage was examined by adjusting intracerebral temperature before and during the ischemic insult. Hyperthermic (39 degrees C) gerbils showed almost complete loss of neurons in the CA1 region (3.0 neurons/mm, n = 11) and extension of neuronal death into the CA2, CA3, and CA4 regions. In addition, hyperthermia exacerbated ischemia-induced inhibition of calcium/calmodulin-dependent protein kinase II activity (4.2 fmol/min, n = 6). Hypothermia (32 degrees C) protected against ischemia-induced CA1 pyramidal cell damage (257.0 neurons/mm, n = 20) and inhibition of calcium/calmodulin-dependent protein kinase II activity (26.0 fmol/min, n = 6). Our results are consistent with the hypothesis that loss of calcium/calmodulin-dependent protein kinase II activity may be a critical event in the development of ischemia-induced cell death.
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PMID:Temperature modulation of ischemic neuronal death and inhibition of calcium/calmodulin-dependent protein kinase II in gerbils. 226 78

In the hippocampi of individuals with temporal lobe epilepsy, cells in CA1, CA3, and the dentate hilus are often gone, but dentate granule cells and CA2 are relatively spared. Several animal models have been developed which mimic portions of this damage. In the present work, combined intraventricular kainate and forebrain ischemia produced a lesion most like that observed clinically; the dentate granule cells and a resistant cluster of pyramidal cells, which received mossy fiber input, were the only principle neurons remaining. This preparation may be valuable both in determining the nature of cells that survive and in understanding the consequences of such damage.
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PMID:Combined kainate and ischemia produces 'mesial temporal sclerosis'. 227 64

The influence on hippocampal glucose utilization was determined in male Wistar rats 7 days after a 10-min forebrain ischemia. Ischemia was induced by clamping of the carotid arteries and lowering blood pressure to 40 mm Hg. Despite severe neuronal damage as assessed by histological techniques, local cerebral glucose utilization (LCGU) was significantly increased in the pyramidal and radiatum layer of the CA1 sector, while in layers of the CA2, CA3 and CA4 sector and dentate gyrus. LCGU was reduced compared to non-ischemic controls. The increases in LCGU are suggested to reflect long-lasting hyperexcitation in the selectively vulnerable CA1 sector, implicating a correlation between cellular hypermetabolism and neuronal damage.
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PMID:Postischemic glucose utilization in rat hippocampal layers. 232 49

Evolution, progression and recovery of neural damage during and following cerebral ischemia were investigated in the gerbil after occlusion of a posterior communicating artery and by using the immunohistochemical reaction for tubulin and creatine kinase BB-isoenzyme which are enriched in the neuronal structure and the reaction for astroprotein which is specific for astrocytes. The transcardiac perfusion study with India ink revealed marked hypoperfusion diffusely in the hippocampus and moderately in the thalamus on the occluded side. The earliest immunohistochemical lesion, manifested as loss of the reaction for tubulin and creatine kinase BB-isoenzyme in dendrites and nerve cell bodies, was found in the CA1 and CA2 region of the hippocampus after ischemia for 4 min, while it took 10 min before the earliest lesion became visible in the ventral nucleus of the thalamus and it took over 1 h before scattered lesions evolved in granular cells of the dentate gyrus. The staining with hematoxylin-eosin was much less sensitive in detection of early ischemic lesions. After re-establishment of blood flow to the posterior communicating artery, the ischemic lesions which were visualized with the reaction for tubulin or creatine kinase BB-isoenzyme disappeared or reduced the size, if the ischemic period was brief. Beyond a certain ischemic period, the lesion expanded further during the early postischemic period. The reaction for astroprotein visualized reactive astrocytes even in the area without any abnormalities with other reactions, an evidence of subtle ischemic insults.
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PMID:Immunohistochemical investigation of regional cerebral ischemia in the gerbil: occlusion of the posterior communicating artery. 242 52

An important feature of ischemic brain damage is the exceptional vulnerability of specific neuronal populations and the relative resistance of others. Silver impregnation was used to delineate the extent and time-course of neuronal degeneration produced by 5 min of complete forebrain ischemia in the Mongolian gerbil. Lesions were confined to four brain regions: (1) hippocampal areas CA1, CA2-CA3a and CA4; (2) the dorsomedial portion of the lateral septal nucleus; (3) the dorsolateral portion of the striatum; and (4) the somatosensory neocortex. The ischemic lesion evolved with time in all four regions, but at different rates. Somatic argyrophilia developed rapidly in the striatum and hippocampal area CA4 (maximal in 24 h or less), at intermediate rates in the somatosensory neocortex, hippocampal areas CA1a and CA2-CA3a and the lateral septal nucleus (maximal in 2 days), and slowly in hippocampal area CA1b (maximal in 3 days). These results emphasize that the extent and rate of neuronal degeneration can vary even within a presumably homogeneous neuronal population, as evidenced by the different results in areas CA1a and CA1b. Similar results were obtained from analysis of brain sections stained with Cresyl Violet, hematoxylin-eosin or hematoxylin-eosin/Luxol Fast Blue. Terminal-like silver granules were observed in the projection fields of degenerated neurons. They also appeared, however, in the perforant path terminal zone of the hippocampal dentate molecular layer 1-2 days after transient ischemia and in stratum oriens and stratum radiatum of area CA1b prior to somatic degeneration. These granular deposits could not be clearly related to the degeneration of neuronal somata. Novel findings of this study include the degeneration of some dentate basket cells and lateral septal neurons and the appearance of terminal-like argyrophilia in the hippocampal formation without any obvious relation to somatic degeneration. Some of our results lend support to the hypothesis that ischemic neuronal cell death constitutes an excitotoxic process. Other results, however, suggest that the selective vulnerability of neurons to transient ischemia must involve factors beyond excitotoxicity.
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PMID:Selective neuronal death after transient forebrain ischemia in the Mongolian gerbil: a silver impregnation study. 246 45

The hippocampus is a brain structure specifically vulnerable to short periods of transient cerebral ischemia, and which displays delayed neuronal necrosis. Protein ubiquitination is a posttranslational modification of proteins and an important factor in heat shock response and a regulator of ATP-dependent protein degradation. Using affinity purified antibodies against ubiquitin and ubiquitin-protein conjugates we have found that the ubiquitin immunoreactivity (UIR), normally present in all neurons of the hippocampus, disappears in the early recirculation period following cerebral ischemia from all hippocampal cells except the interneurons. Later UIR reappears in the different hippocampal regions over a 72 h period in the following order: granule cells-CA3 pyramidal cells-CA2 pyramidal cells. This is the inverse order of sensitivity of these cells to ischemia. The UIR never recovers in the CA1 pyramidal neurons where a 95% neuronal necrosis is seen following three days of recovery. We propose that the loss of UIR in the pyramidal neurons in the CA1 region signifies a persistent impairment of protein ubiquitination, and thus a change in the turnover of structural and regulatory proteins, which could be an essential part of the mechanism of slow neuronal death following cerebral ischemia.
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PMID:Impairment of protein ubiquitination may cause delayed neuronal death. 254 80

Experimental cerebral ischemia was produced in gerbils by occlusion of the right common carotid artery in the neck. The evolution of the ischemic lesions was followed from five minutes to six hours by using the immunohistochemical techniques for tubulin and creatine kinase BB-isoenzyme. The earliest lesion was found in the subiculum-CA1 and CA2 regions of the hippocampus in five minutes. There was loss of staining in the apical dendrites and perikarya of the pyramidal cells. The earliest lesion in the cerebral cortex, visible in ten minutes, was a laminar loss of staining for tubulin. Evolution of the ischemic lesions in the thalamus and caudoputamen was delayed. However, in two hours widespread ischemic lesions were seen there. Evolution of the ischemic lesions was slightly slower with the reaction for creatine kinase BB-isoenzyme as compared to the reaction for tubulin, but was far more sensitive than hematoxylin-eosin staining. The distribution of ischemic lesions detected by the immunohistochemical method compared to ischemic areas detected by an India ink perfusion study suggested that both the extent of regional ischemia and regional difference in tissue vulnerability were contributing factors for the emergence of early ischemic lesions. The mechanism for prompt disappearance of the immunohistochemical reaction for tubulin is not clear, but the present investigation demonstrates the usefulness of the immunohistochemical technique for detecting early ischemic lesions and provides a possible biochemical mechanism for cellular damage after ischemic insults.
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PMID:Immunohistochemical investigation of cerebral ischemia in gerbils. 257 10

This study was designed to determine if dizocilipine maleate (MK-801), administered following 11 min of complete ischemia in dogs, could favorably alter neurologic outcome and hippocampal damage. Eighteen dogs were anesthetized and subjected to complete cerebral ischemia by temporary occlusion of the ascending aorta and the venae cavae via a thoracotomy. Five min postischemia, 9 dogs were given dizocilipine 150 micrograms/kg, followed by an infusion of 1.25 microgram/kg/min for 8 h. Control dogs were given equal volumes of placebo. Dogs were evaluated neurologically at 24, 48, and 72 h; thereafter, the brains were perfused, fixed and harvested. There was no significant difference in outcome between dizocilipine- and placebo-treated dogs: 5 of 9 given dizocilipine were normal, 1 was mildly injured and 3 were severely injured or dead. In the control animals given placebo, 3 of 9 were normal, 2 were mildly injured and 4 were moderately to severely injured. Histopathologic examination was limited to the hippocampus. CA1 and CA2,3,4 pyramidal neurons were graded according to degree of injury on a 5-point scale. There were no differences in histopathologic grades between the two groups. However, in both groups combined there was a significant correlation between neurologic outcome grade and histopathologic grade. The only notable systemic effect of dizocilipine appeared to be prolonged sedation which extended beyond 24 h postischemia but was not evident at 48 h postischemia. The authors conclude that more outcome studies in more sensitive models are needed.
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PMID:Evaluation of the glutamate antagonist dizocilipine maleate (MK-801) on neurologic outcome in a canine model of complete cerebral ischemia: correlation with hippocampal histopathology. 265 24


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