Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoradiographic localizations of major second messengers and a selective cyclic adenosine monophosphate (cyclic-AMP) phosphodiesterase in the brain were visualized in the gerbil and the rat using receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]inositol 1,4,5-trisphosphate (IP3), [3H]forskolin, [3H]cyclic-AMP, and [3H]rolipram were used to label protein kinase C, IP3 receptor, adenylate cyclase, cyclic-AMP-dependent protein kinase (cyclic-AMP-DPK), and Ca2+/calmodulin-independent cyclic-AMP phosphodiesterase (PDE), respectively. Most second messengers and rolipram binding activities were especially found in the limbic system, basal ganglia, and cerebellum. Marked differences were noted in the hippocampus, where cyclic-AMP and rolipram binding activities were very low in gerbils but high in rats. In contrast, regional localization in the binding sites of PDBu, IP3, and forskolin in gerbil brain was relatively similar to that in rat brain. Further, alteration of the cyclic-AMP and rolipram binding sites was studied in the gerbil hippocampus 7 days after 10-min cerebral ischemia. The results suggest that the gerbil differs from the rat with respect to the characteristic neurons or interneurons, especially in the hippocampal formation. This finding may help further elucidate the relationship or difference between gerbils and rats for brain function and behavioral pharmacology. Furthermore, our results suggest that cyclic-AMP and rolipram binding sites are predominantly distributed on the pyramidal cell layer of the hippocampal CA1 sector and that transient cerebral ischemia can cause marked reduction in these binding sites in the hippocampus.
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PMID:Mapping of second messenger and rolipram receptors in mammalian brain. 132 28

The brain cyclic AMP generation was studied in rats subjected to 15 min of cardiac arrest. We have used a particulate, synaptoneurosomal fraction to demonstrate the effect of ischemia in vivo on the responsiveness of adenylate cyclase (AC) system. It has been shown that, although there is a slight decrease in AC activity after ischemia, the in vitro fractions produce more cAMP in response to a variety of stimuli, suggesting an indirect, nonadenylate cyclase activation mechanism. For elucidation of this mechanism we have probed phorbol-12,13-dibutyrate (PDBu) as a direct PKC activator, forskolin to activate the catalytic subunit of AC, and cholera toxin (CT) for stabilizing the active, GTP-bound form of stimulatory guanine nucleotide binding protein (Gs). All these postreceptor AC modulators as well as the receptor activators such as adenosine and alpha 1-adrenergic agonists markedly enhanced cAMP production in the rat brain particulate fraction, although the postischemic hyperactive response to these stimuli was still present. However, when AC was stimulated by the combination of CT and PDBu, cAMP responses were identical in both control and postischemic fractions. The data, taken together, support the hypothesis that ischemia increases cAMP accumulation by facilitating the postreceptor AC activation through a PKC-involving pathway and by promoting the stronger coupling of membrane AC receptors with G-protein. Protein kinase C (PKC) activity during cerebral ischemia was also investigated. In contradistinction to our expectation PKC decreased significantly in the ischemic brain to 85% of the control activity in the cytosol and 72% in the membranes. However, in the incubated post-ischemic brain particulate fraction a relative increase in the membrane-bound form of the enzyme, from 30% for control to 53% for ischemia, was observed. This may suggest that ischemia-induced membrane changes could promote the enzyme translocation/activation during recovery, resulting in the sensitization of cAMP producing system.
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PMID:Postreceptor modulation of cAMP accumulation in rat brain particulate fraction after ischemia--involvement of protein kinase C. 135 40

Idebenone, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone, at a dose of 100 mg/kg (i.p.) markedly increased the level of 5-hydroxyindole-3-acetic acid (5-HIAA) in several brain regions without affecting monoamine contents in normal rats. In rats with cerebral ischemia, idebenone (10 mg/kg, i.p.) normalized the decreased levels of 5-HIAA in the cerebral cortex, hippocampus, diencephalon and brain stem. A 5-hydroxytryptamine (serotonin, 5-HT) biosynthesis inhibitor, DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) decreased the levels of 5-HT to one-third of the control level 24 h after administration. Idebenone (10, 30, or 100 mg/kg, i.p.), administered 24 h after the treatment with PCPA, accelerated the PCPA-induced 5-HT decreased in the hippocampus, diencephalon and brain stem in a dose-dependent manner. Idebenone (100 mg/kg, i.p.) stimulated the release of 5-HT in the dorsal hippocampus as determined by in vivo differential pulse voltammetry. Idebenone, like p-chloroamphetamine (PCA), stimulated 5-HT release from slices of hippocampus and diencephalon, and the formation of cyclic AMP in a concentration-dependent manner in rat diencephalon slice. This stimulation was almost completely blocked by methysergide, a 5-HT receptor blocker. Idebenone slightly and PCA markedly inhibited 5-HT uptake into hippocampus slices. The mechanism of the 5-HT releasing actions of idebenone in the hippocampal slices may be mediated through endogenous calcium. These results suggest that idebenone has an enhancing effect on the turnover of 5-HT in the hippocampus, diencephalon, and brain stem of rats.
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PMID:Effects of idebenone on metabolism of monoamines and cyclic AMP formation in rats. 247 75

We investigated the ameliorating effects of DN-1417 (a TRH analog) on the changes of behavior, EEG, neurochemical parameters and regional cerebral blood flow (rCBF) in rats with global cerebral ischemia. Global cerebral ischemia was produced by 10-min occlusion of both common carotid arteries 24 hr after the permanent electrocauterization of bilateral vertebral arteries. DN-1417 was administered intraperitoneally as soon as possible, following recirculation of carotid blood flow. DN-1417 shortened significantly the recovery times of righting reflex (RR) and spontaneous movement (SM) at 2.5 mg/kg and higher doses, and it recovered effectively the EEG activity at 10 mg/kg during recirculation after 10-min cerebral ischemia. In addition, DN-1417 (10 mg/kg) recovered the various changes such as decrease of 5-hydroxytryptamine (5-HT) levels, increase of cyclic AMP (cAMP) levels, inhibition of [3H]-choline uptake, depression of choline acetyltransferase (CAT) and acetylcholine esterase (AChE) activities, and shortened the durations of hyperperfusion and hypoperfusion of rCBF. As a result, it is identified that DN-1417 ameliorates the disturbance of consciousness supposedly caused by behavioral and EEG abnormalities during recirculation following the temporary cerebral ischemia, and the effect of DN-1417 seems to be mediated by normalizing of alterations in the brain monoaminergic and cholinergic systems, as well as rCBF, and the effectiveness for disturbance of consciousness in clinical situations would be expected.
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PMID:[Pharmacological study of the temporary cerebral ischemic rats produced by bilateral vertebral and carotid artery occlusion. Effects of DN-1417]. 286 Nov 49

The present study was an extension of earlier work regarding the role of cyclic nucleotides and related enzymes during cerebral ischemia in the gerbil. Following unilateral carotid occlusion, levels of cyclic AMP and cyclic GMP were measured in four rapidly inactivated brain regions at 3, 6, and 24 hr after permanent occlusion and at 2 hr of occlusion plus 1 hr of reflow. An analysis of variance indicated significant minor fluctuations in the steady-state levels of the two cyclic nucleotides within the frontal cortex, the hippocampus, the striatum, and especially the olfactory tubercle with respect to occlusion time (3 and 24 hr) but not when comparing control vs ischemic hemispheres (except at 3 hr). Changes occurred only in animals developing neurological symptoms of ischemia. At 24 hr postocclusion the specific activity of the low-Km form of cyclic AMP phosphodiesterase was elevated especially on the ischemic side when determined in homogenates of the four brain regions. Alternatively, the high-Km form of the enzyme in the presence or absence of Ca2+-calmodulin was unchanged. Guanylate cyclase activity in tissue homogenates was not influenced by the conditions of ischemia until 24 hr had elapsed, an event likewise unique to symptomatic gerbils. The sensitivity of the enzyme to hematin-catalase was decreased in the ischemic hemispheres of the hippocampus, striatum, and olfactory tubercle. In addition, further activation of the hematin-catalase response by NaN3 was depressed in the ischemic side of the hippocampus and striatum. Taken together these and previous studies indicate that fluctuations in the steady-state levels of cyclic nucleotides that occur rather prominently during acute and to a lesser degree during prolonged ischemia are not correlated with associated changes in enzymes responsible for their synthesis and/or degradation.
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PMID:Regional profiles of steady-state levels of cyclic nucleotides, cyclic AMP phosphodiesterase, and guanylate cyclase activities during late stages of unilateral ischemia in gerbil forebrain. 290 8

The concentrations of cyclic AMP, noradrenaline, glycogen, glucose, lactate, pyruvate, labile phosphate compounds, and free fatty acids were investigated in the rat neocortex and hippocampus during and following cerebral ischemia. An incomplete ischemia of 5 and 15 min duration was induced by bilateral carotid clamping combined with hypotension. The postischemic events were studied after 5, 15, and 60 min of recirculation. Five minutes of ischemia did not significantly alter the neocortical or hippocampal concentrations of cyclic AMP. After 15 min of ischemia the neocortical levels decreased significantly below control values. In the recirculation period following ischemia a significant elevation of the cyclic AMP concentrations was observed. Following 5 min of recirculation after 5 min of ischemia the levels increased from 2.53 +/- 0.21 nmol X g-1 to 5.18 +/- 0.09 nmol X g-1 in the neocortex and from 2.14 +/- 0.16 nmol X g-1 to 3.52 +/- 0.35 nmol X g-1 in the hippocampus. Five minutes of recirculation following 15 min of ischemia led to a significant increase in the levels of cyclic AMP, to 12.86 +/- 1.43 nmol X g-1 in the neocortex to 5.58 +/- 0.57 nmol X g-1 in the hippocampus. With longer recirculation periods the cyclic AMP levels progressively decreased and were similar to control values after 60 min. Depletion of cortical noradrenaline by at least 95% was performed by injections of 6-hydroxydopamine into the ascending axon bundles from the locus ceruleus. The lesion did not significantly change the ischemic or post-ischemic neocortical and hippocampal levels of cyclic AMP, glycogen, or free fatty acids including arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic AMP concentrations in rat neocortex and hippocampus during and following incomplete ischemia: effects of central noradrenergic neurons, prostaglandins, and adenosine. 298 51

Effects of S-adenosyl-L-methionine (SAMe) on experimental cerebral ischemia were investigated using two different ischemic models. Cerebral energy metabolites (ATP, lactate, c-AMP) and brain water content were measured. It is reported that SAMe accelerates synthesis of phosphatidyl choline and increases erythrocyte membrane fluidity. Complete ischemia was produced by heart excision using wistar kyoto rats. SAMe (100 mg/kg, I.P.) was administered twice at one hour and immediately before inducing ischemia. The brain of rats were irradiated by microwave to stop the enzyme activity exactly 60 seconds after inducing ischemia and brain energy metabolites were measured. Recirculation model was produced by one hour recirculation following two hours ischemia induced by clipping of bilateral common carotid arteries using stroke-prone spontaneously hypertensive rats. SAMe (100 mg/kg, I.V.) was administered twice one hour after clipping and ten minutes after recirculation. The brain metabolites and water content were measured one hour after recirculation. In the complete ischemia, ATP and c-AMP levels were statistically high in the SAMe treated group compared to the untreated group (vehicle). But there was no statistical difference in lactate between the treated group and the untreated group. In the recirculation model, lactate elevation was suppressed in the SAMe treated group compared to the vehicle group with statistical difference, but there was no difference in ATP and c-AMP. Also, there was no difference in water content between the treated and the untreated group. SAMe protected energy failure in ischemia and accelerated recovery from ischemia. It is indicated that this agent is beneficial for treatment of cerebral ischemia in the acute stage.
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PMID:[Effects of S-adenosyl-L-methionine on experimental cerebral ischemia]. 299 May 9

The effect of nimodipine on cerebral metabolism during ischemia and reflow was studied in female mongolian gerbils. Animals were divided into three experimental groups. Group 1 received 1 mg/kg nimodipine i.p. 1 h prior to ischemia. Group 2 received an injection of the vehicle, 5% polyethylene glycol 400. Group 3 received an equal volume of normal saline. Cerebral ischemia was induced by bilateral common carotid artery occlusion for 1, 2, or 5 min. Recirculation was established for 0, 1, or 5 min. Sham-operated animals served as nonischemic controls. Gerbils were killed by microwave irradiation. Regional levels of ATP, phosphocreatine, glucose, glycogen, cyclic AMP, and cyclic GMP were measured in brain extracts using standard assay techniques. Levels of metabolites in sham-operated animals did not differ among Groups 1, 2, and 3. At 1 min of ischemia, cortical and striatal ATP levels were highest in Group 1 (p less than 0.05 and p less than 0.01, respectively). After 5 min of recirculation, cortical and striatal glucose levels were highest in Group 1 (p less than 0.005). Regional levels of the metabolites measured at other times did not differ significantly among the three groups. Pretreatment with nimodipine thus retards the fall in ATP and facilitates the recovery of glucose in mongolian gerbils subjected to common carotid artery occlusion. A regional variability of this effect was observed.
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PMID:Effect of nimodipine on cerebral metabolism during ischemia and recirculation in the mongolian gerbil. 299 44

The susceptibility to cerebral ischemia was studied in stroke-resistant spontaneously hypertensive rats (SHRSR) treated by a long-term antihypertensive treatment, and compared with untreated SHRSR and Wistar rats (WR). Male SHRSR, aged 8 weeks, were divided into two groups and a long-term antihypertensive treatment for 4-6 weeks was started on one group (treated SHRSR: T-SHR) while the other group was left untreated as control (untreated SHRSR: U-SHR). The changes of blood pressure were checked on these rats. The prior treatment of hypertension was achieved by administration of hydroflumethiazide (120 mg/kg/day) and captopril (15-30 mg/kg/day) orally for 4-6 weeks by mixing in drinking water. All the experiments were performed at the age of 12-16 weeks and WR of similar age served as normotensive untreated control. Cerebral ischemia was induced by bilateral common carotid artery ligation (BLCL) and blood pressure was always checked before BLCL. The survival ratio was observed from 1 hour to 24 hours after BLCL. The regional cerebral blood flow (rCBF) were measured before and 4 hours after BLCL periodically. The brain energy metabolites were measured 4 hours after BLCL. rCBF were measured at the thalamus by the hydrogen clearance method. ATP concentrations were determined by luciferine-luciferase method, c-AMP was measured by RIA and lactate by enzymatic method. The brain water content was measured by freeze-dry method.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effect of long-term prior antihypertensive treatment on cerebral ischemia induced by bilateral common carotid artery ligation in SHRSR]. 300 93

Nimodipine is known to improve postischemic cerebral blood flow (CBF) and neurologic outcome in experimental animals. Whether or not the two observations are related is unknown. This study searched for a possible improved rate of brain metabolic recovery in animals treated with nimodipine postischemia. Complete cerebral ischemia was produced for 11 min in 16 dogs, followed by reperfusion for 70 min. Prior to ischemia, glucose was administered (0.75 g X kg-1) in 12 dogs. Half of the glucose-treated dogs were given i.v. nimodipine, beginning 5 min postischemia (10 micrograms X kg-1 bolus followed by 1 microgram X kg-1 X min-1). The other half were given only saline postischemia. The remaining four dogs were given no glucose and received saline only postischemia. In all dogs, serial brain biopsies were taken at 2, 20, 40, and 70 min postischemia. In 5 dogs, the integrity of the blood-brain barrier (BBB) was tested by injection of Evans blue dye and postmortem examination of the brains. Brain biopsies were assayed for concentrations of phosphocreatine, ATP, ADP, AMP, glucose, lactate, and pyruvate. In all dogs, there was rapid restoration of a normal brain energy state following reperfusion. Brain lactate had returned to near normal in all dogs by 70 min postischemia, and the rate of lactate depletion was not different between groups. The integrity of the BBB was only minimally affected. A portion of the brain lactate was converted to pyruvate rather than crossing the BBB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nimodipine does not affect cerebral lactate levels following complete ischemia in dogs. 365 2


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