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 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the effects of treatment with the inner ester derivative of the monosialoganglioside GM1 on cortical electroencephalographic activity and hippocampal CA1 morphology after transitory, near-complete cerebral ischemia in rats. Ischemia was induced by the four-vessel occlusion method, and we studied only the 58 rats that showed flattening of the cortical electroencephalogram for the entire 30 minutes of occlusion. The ganglioside (n = 30) or saline (n = 28) was administered intravenously immediately after release of the carotid clips and then intramuscularly for 21 days of observation. Cortical electroencephalographic activity was monitored throughout the experiment. After 21 days of recirculation we assessed hippocampal CA1 damage by light microscopy. The results indicate that treatment with the ganglioside reduces postischemic secondary damage to the cortical circuitry (as indicated by significantly higher cortical electroencephalographic activity late after reperfusion) and limits neuronal loss in the CA1 region. Our results lend support to the possible therapeutic use of ganglioside in human pathologic conditions associated with cerebrovascular insufficiencies.
Stroke 1990 Nov
PMID:Protective effects of a monosialoganglioside derivative following transitory forebrain ischemia in rats. 223 55

If oxygen is withdrawn from rat hippocampal slices, a spreading depression-like response occurs earlier and is of larger amplitude in the CA1 area than in the dentate gyrus. After reoxygenation, recovery of synaptic transmission correlates inversely with the time spent in spreading depression. Recovery occurs more frequently in dentate gyrus than in CA1. Chlorpromazine and the gangliosides GM1 and AGF2 promote recovery from hypoxic depression of synaptic transmission in CA1. Prevention of irreversible loss of function correlates closely with a shortening of the time spent in spreading depression. If Ca2+ is withdrawn before hypoxia, then synaptic function recovers upon restoration of oxygen and [Ca2+]o, despite prolonged spreading depression. When spreading depression lasting more than 6-9 minutes is induced in fully oxygenated slices by superfusion with high-K+ solution, then transient recovery is followed by long-lasting loss of synaptic function. In intact brain of anesthetized rats, synaptic transmission in CA1 recovers after spreading depression-like depolarization lasting more than 30 minutes, but is lost irreversibly after 60 minutes. We conclude that entry of Ca2+ into neurons caused by spreading depression-like depolarization is important in the selective vulnerability of neurons; the duration of depolarization is critical to cell survival; and in the presence of a normal blood supply, neurons resist protracted spreading depression-like depolarization.
Stroke 1990 Nov
PMID:Spreading depression-like depolarization and selective vulnerability of neurons. A brief review. 223 79

We correlated the efficacy of several clinically relevant pharmacotherapies with their ability to prevent calcium influx into neurons and subsequent binding to calmodulin. We studied the administration of CGS 19755, nimodipine, nicardipine, and combinations of these drugs before or immediately after ischemia in globally ischemic rats. Calcium-calmodulin binding was graded by an immunohistochemical assay after 2 and 24 hours of reperfusion (n = 5-6 at each time period), and histologic damage was graded by light microscopy after 72 hours of reperfusion (n = 6). Calcium-calmodulin binding correlated with the severity of delayed histologic damage in various brain regions. In untreated ischemic control rats, marked calcium-calmodulin binding was seen in CA1 and CA3 after 24 hours of reperfusion (p less than or equal to 0.01). Administered before ischemia, CGS 19755 prevented calcium-calmodulin binding across all brain regions after 2 and 24 hours of reperfusion compared with controls (p less than or equal to 0.05). This effect was most prominent in CA3 and CA1, where the drug also reduced delayed neuronal damage (p less than or equal to 0.05). Lower doses or postischemic administration of CGS 19755, nimodipine, nicardipine, and a combination of postischemic CGS 19755 and nicardipine had a more limited effect on calcium-calmodulin binding and did not protect against delayed neuronal damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Stroke 1990 Nov
PMID:Neuronal protection correlates with prevention of calcium-calmodulin binding in rats. 223 82

Excessive release of glutamate is thought to play a major role in the susceptibility of neurons to ischemia. In the present study, we evaluated whether differences in the magnitude of glutamate release resulted in some regions being vulnerable to ischemia, but others being spared from irreversible histopathologic damage. Specifically, we compared the temporal profile of ischemia-induced changes in extracellular levels of glutamate in a region selectively vulnerable to 10 minutes of transient ischemia (CA1 sector of the hippocampus) to the changes occurring in regions that, although rendered ischemic, are usually unaffected by a 10-minute insult (i.e., thalamus, cortex, and dorsolateral striatum). In an attempt to correlate the regional changes in glutamate release to the magnitude of the ischemic insult, the degree of ischemia (e.g., ATP depletion, lactate accumulation, and local cerebral blood flow reduction) and the final histopathologic outcome were also evaluated in these regions. Blood flow reduction and energy depletion were severe and uniform in all regions. However, the histopathologic outcome illustrated a different pattern. Although the CA1 sector of the hippocampus was severely damaged, all other brain regions were unaffected by the 10-minute insult. Extracellular glutamate levels, measured by microdialysis, were significantly elevated during ischemia in all four regions. These levels continued to increase during the early recirculation period and gradually returned to baseline by 30 minutes of reperfusion, with a similar temporal changes in all four brain structures. These results, taken with our previous findings, demonstrate that elevated intraischemic glutamate levels are insufficient to independently engender ischemic damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Stroke 1990 Nov
PMID:Ischemia induces release of glutamate in regions spared from histopathologic damage in the rat. 223 84

U78517F is a novel inhibitor of iron-catalyzed lipid peroxidation that combines the tetramethylchroman antioxidant ring portion of alpha-tocopherol with the amine of the previously described 21-aminosteroids (e.g., U74006F). U78517F inhibited 200 microM FeCl2-initiated lipid peroxidation in rat brain homogenates by 50% at a concentration of 0.6 microM compared with 8 microM for U74006F, 28 microM for alpha-tocopherol, and 43 microM for the ring portion of alpha-tocopherol (i.e., trolox). U78517F is devoid of hypothermic or antiexcitotoxic actions or interactions with known neurotransmitter receptors. When administered intraperitoneally to male gerbils at 10 minutes before and again at the end of a 3-hour period of unilateral carotid artery occlusion, U78517F decreased 24-hour postischemic cortical neuronal necrosis. Neuronal density in the medial portion of the cortex was increased from 34.2% of normal in vehicle-treated animals to 86.3% in the U78517F-treated animals. In the lateral cortical area, the vehicle group showed only 3.3% neuronal survival versus 48.2% in the drug-treated group. In a separate series of experiments with the same focal ischemia model, identical dosing with U78517F enhanced the postischemic recovery of cortical extracellular calcium without any effect on ischemic or postischemic cortical blood flow. The effect on calcium recovery was observed at intraperitoneal doses as low as 0.1 mg/kg. The compound also was effective in partially attenuating 1-week postischemic hippocampal CA1 neuronal loss in a gerbil global ischemia model involving brief (15-minute) bilateral carotid occlusion, but sustained dosing was required. These results document the anti-ischemic efficacy of a novel and potent inhibitor of iron-catalyzed lipid peroxidation and further support a key role of oxygen radicals in postischemic brain damage.
Stroke 1990 Nov
PMID:Nonsteroidal lazaroid U78517F in models of focal and global ischemia. 223 90

In the present study, we investigated the protective effect of nimodipine against postischemic neuronal damage in the rat and considered the question of whether this histologic finding coincides with an improvement of cerebral circulation. Male Wistar rats were subjected to 10 minutes of forebrain ischemia by clamping both common carotid arteries and lowering blood pressure to 40 mm Hg. Histologic evaluation was performed 7 days after ischemia. Local cerebral blood flow was determined with the 14C-iodoantipyrine technique in anatomically defined areas of the brain, including hippocampus. Preischemic application of nimodipine (3.0 mg/kg p.o.) significantly reduced the percentage of damaged neurons in hippocampal CA1 subfield from 78 +/- 4% in controls to 59 +/- 6% in treated rats (mean +/- SEM; p less than 0.05, Mann-Whitney U test). After 10, 60, and 180 minutes of recirculation no differences in local cerebral blood flow between control and drug-treated animals were observed. Our results demonstrate that nimodipine reduces ischemia-induced neuronal damage in rat hippocampus. We did not consider increased cerebral blood flow in the hypoperfusion state in the applied experimental design since improvement of cerebral blood flow seems to bear little relation to the neuroprotective activity of nimodipine.
Stroke 1990 Dec
PMID:Neuroprotective effect of nimodipine is not mediated by increased cerebral blood flow after transient forebrain ischemia in rats. 226 Jan 31

Delayed death of pyramidal neurons of Ammon's horn CA1 sector after short-term forebrain ischemia in Mongolian gerbils represents a type of ischemic neuronal injury in which calcium influx plays an important role. We evaluated the influence of the calcium channel blocker nimodipine in animals subjected to 7.5 minutes of bilateral carotid artery ligation that were given 1 mg/kg i.p. nimodipine at various periods in relation to the ischemic incident. The control animals were subjected to cerebral ischemia with no medication. Five days after ischemia, the state of CA1 sector neurons was morphometrically evaluated and compared with that in animals not subjected to an experimental procedure. Nimodipine exerted a full protective effect on CA1 pyramidal neurons only after repeated application extending over 24 hours after the ischemia. A less conspicuous effect was obtained with a single dose applied at a late postischemic period, and a double dose given in the peri-ischemic stage remained ineffective. The time-dependent effectiveness of nimodipine is discussed in relation to the characteristics of this model of cerebral ischemia.
Stroke 1990 Dec
PMID:Nimodipine prevents delayed neuronal death of sector CA1 pyramidal cells in short-term forebrain ischemia in Mongolian gerbils. 226 Jan 35

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.
Stroke 1990 Dec
PMID:Temperature modulation of ischemic neuronal death and inhibition of calcium/calmodulin-dependent protein kinase II in gerbils. 226 78

(S)-Emopamil is a novel calcium channel blocker of the phenylalkylamine class, with potent serotonin S2 antagonist activity. We investigated the effect of (S)-emopamil on the histopathologic consequences of global brain ischemia in anesthetized rats. Pretreated rats (n = 15) received 20 mg/kg i.p. (S)-emopamil 30 minutes before and 2 hours following 10 minutes of bilateral common carotid artery occlusion plus arterial hypotension (50 mm Hg). Quantitative cell counts following 3 days' survival revealed a marked loss of pyramidal neurons in all subsectors of the hippocampal CA1 area of untreated ischemic rats (n = 15). In contrast, in (S)-emopamil pretreated rats numbers of normal neurons were significantly higher, by 2.4-, 1.9-, and 1.8-fold, respectively, in the medial, middle, and lateral subsectors of the CA1 area. For example, normal neuron counts in the medial CA1 subsector were 34 +/- 9 (mean +/- SEM) in untreated ischemic rats compared with 82 +/- 13 in (S)-emopamil pretreated rats (control nonischemic value [n = 5] 157 +/- 2). By semiquantitative grading, (S)-emopamil also decreased ischemic changes in the cerebral cortex. No significant effect of (S)-emopamil on ischemic injury was detected in rats treated beginning 30 minutes after the ischemic insult (n = 10). Thus, pretreatment with (S)-emopamil is beneficial in decreasing the severity of neuronal injury in global brain ischemia.
Stroke 1990 Dec
PMID:(S)-emopamil protects against global ischemic brain injury in rats. 226 81

Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.
Stroke 1990 Jun
PMID:Calcium-calmodulin binding in ischemic rat neurons after calcium channel blocker therapy. 234 99


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