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)

1. We studied the postischemic time-course of dopamine D1 receptors in selectively vulnerable areas in the gerbil using receptor autoradiography. 2. [3H]SCH 23390 was used to label dopamine D1 receptors and transient cerebral ischemia was induced for 10 min. 3. [3H]SCH 23390 binding showed no significant alteration in selectively vulnerable areas at an early stage (1-24 hr) of recirculation. Thereafter, [3H]SCH 23390 binding showed a significant reduction in most selectively vulnerable areas 48 hr or 7 days of recirculation. The ventromedial striatum and dentate gyrus which were resistant to ischemia also exhibited a significant reduction in [3H]SCH 23390 binding. 4. Especially, marked reduction was noted in the dorsolateral striatum. However, this reduction in the dorsolateral striatum was not seen early in the recirculation prior to morphological neuronal damage. 5. The result suggests that transient cerebral ischemia can cause a severe reduction in dopamine D1 receptors in most selectively vulnerable areas. Furthermore, they suggest that dopamine D1 transmission is not always responsible for the evolution of ischemic brain damage. 6. These findings are discussed in relation to the mechanism of ischemic brain damage.
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PMID:Autoradiographic analysis of dopamine D1 receptors in the gerbil brain following transient cerebral ischemia. 148 17

We investigated the postischemic alterations in dopamine D1 receptor and Ca2+/calmodulin independent cyclic adenosine monophosphate (cyclic AMP) selective phosphodiesterase in gerbils and examined the effect of pentobarbital on these alterations. [3H]SCH 23390 and [3H]rolipram, respectively, were used to label dopamine D1 receptor and Ca2+/calmodulin independent cyclic-AMP selective phosphodiesterase. Transient cerebral ischemia was induced for 10 min, and pentobarbital (40 mg/kg) was administered intraperitoneally 30 min prior to ischemia. 5 h after ischemia, [3H]rolipram binding decreased significantly in the striatum and hippocampus, whereas no significant change was found in [3H]SCH 23390 binding. 7 days after ischemia, however, there was a marked reduction in both [3H]SCH 23390 and [3H]rolipram binding in the striatum and hippocampus, where histological neuronal damage was found. Pentobarbital significantly ameliorated postischemic decreases in [3H]rolipram binding both 5 h and 7 days after recirculation in most areas studied. Furthermore, this drug significantly prevented postischemic reduction in [3H]SCH 23390 binding (only) 7 days after ischemia. These results suggest that alteration of cyclic AMP selective phosphodiesterase is more sensitive at an earlier stage after ischemic insult than that of dopamine D1 receptors. Our results also demonstrate that pentobarbital reduces the alteration in [3H]SCH 23390 and [3H]rolipram binding after cerebral ischemia.
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PMID:Effect of pentobarbital on postischemic SCH 23390 and rolipram binding in gerbil brain. 822 65

We investigated the long-term changes that occur in the gerbil brain following transient cerebral ischemia using histology and receptor autoradiography. Transient ischemia was induced for 3 and 10 min, and animals were allowed to survive for 8 months. A histological study showed that 3-min ischemia caused neuronal damage and mild atrophy only in the hippocampal CA1 sector, and that 10-min ischemia produced severe neuronal damage and marked shrinkage in the hippocampal CA1 and CA3 sectors. Furthermore, severe neuronal damage was seen in the striatum after 10-min ischemia. Autoradiography study revealed that 3-min ischemia caused a significant reduction in [3H] naloxone binding in the frontal cortex, striatum, dentate gyrus, and thalamus, whereas [3H]SCH 23390 and [3H] forskolin binding was not significantly altered in all regions. In contrast, 10-min ischemia produced marked alteration in these binding sites in the striatum, hippocampus, thalamus, and substantia nigra. The alteration was especially notable in the hippocampal region and substantia nigra. These results indicate that hippocampal damage after transient ischemia, compared with that in other regions, is not static, but particularly progressive. Furthermore, they demonstrate a reduction in adenylate cyclase system in the striatum and substantia nigra after transient ischemia. Moreover, our results suggest that long-term survival after ischemia may induce synaptic modification of neurotransmitter and adenylate cyclase system in the hippocampus.
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PMID:Long-term observations in gerbil brain following transient cerebral ischemia: autoradiographic and histological study. 827 28

1. We investigated alterations in dopamine D1 receptors in the striatum and hippocampus after transient cerebral ischemia in gerbils using [3H]SCH 23390 autoradiography. 2. We also examined the effect of vinconate against the alterations in dopamine D1 receptors after transient ischemia. 3. Transient ischemia was induced for 10 min, and vinconate (100 and 300 mg/kg) was given intraperitoneally 10 min before ischemia. 4. [3H]SCH 23390 binding showed no significant alterations in the striatum and hippocampus 5 hr after ischemia, whereas severe reduction in these areas was found after 7 days of recirculation. 5. Vinconate showed no significant alterations in [3H]SCH 23390 binding in the striatum and hippocampus except for a decrease in the hippocampal CA3 sector and dentate gyrus 5 hr after ischemia. By contrast, vinconate prevented a significant reduction in [3H]SCH 23390 binding in the striatum, hippocampal CA3 sector, hilus, and dentate gyrus 7 days after ischemia. 6. Vinconate inhibited lipid peroxidation in rat brain homogenates in a concentration-related manner. 7. These results indicate that free radicals generated from abnormal dopamine metabolism may play a key role in the development of ischemic brain damage. Furthermore, they suggest that vinconate prevents ischemic brain damage by inhibiting lipid peroxidation.
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PMID:Neuroprotective effect of vinconate against postischemic alterations in binding of [3H]SCH 23390 in the gerbil brain. 848 99

To characterise the role played by dopamine receptors in ischaemic brain damage, we have evaluated the effects of pergolide, bromocriptine and lisuride (dopamine D2 receptor agonists), haloperidol (a dopamine D2 receptor antagonist), 2,3,4,5-tetrahydro-7,8,dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393; a dopamine D1 receptor agonist) and (R)-(+)-8-chloro 2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390; a dopamine D1 receptor antagonist) in the gerbil model of global cerebral ischaemia. Ischaemia was induced by 5 min of bilateral carotid artery occlusion under halothane anaesthesia. Sham operated animals were used as controls. Pergolide (0.5 or 1.0 mg/kg i.p), bromocriptine (0.5 or 1.0 mg/kg i.p.), lisuride (0.5 or 1.0 mg/kg i.p.), SCH 23390 (0.1 or 1.0 mg/kg i.p.), haloperidol (0.5, 1.0 or 2 mg/kg i.p.) and SKF 38393 (1.0 or 2 mg/kg i.p.) were administered 1 h before occlusion. Five-minute-occluded animals had extensive damage in the CA1 region of the hippocampus 5 days after surgery. Pergolide 0.5 and 1.0 mg/kg i.p. provided significant (P < 0.05 and P < 0.01, respectively) neuroprotection against the ischaemia-induced hippocampal damage. Bromocriptine and lisuride also provided significant (P < 0.05) neuroprotection, but only at the higher 1.0 mg/kg dose. In contrast, the dopamine D2 receptor antagonist (haloperidol), the dopamine D1 receptor agonist (SKF 38393) and the dopamine D1 receptor antagonist (SCH 23390) failed to provide any neuroprotection in the model. These results support studies indicating that dopamine is important in ischaemic situations. The results also indicate that dopamine D2 receptor agonists are neuroprotective against ischaemia-induced brain injury and may play a role in neurodegenerative disorders.
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PMID:Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia. 971 65

Blockade of adenosine receptors can reduce cerebral infarct size in the model of global ischaemia. Using the potent and selective A2A adenosine receptor antagonist, SCH 58261, we assessed whether A2A receptors are involved in the neuronal damage following focal cerebral ischaemia as induced by occluding the left middle cerebral artery. SCH 58261 (0.01 mg/kg either i.p. or i.v.) administered to normotensive rats 10 min after ischaemia markedly reduced cortical infarct volume as measured 24 h later (30% vs controls, p < 0.05). Similar effects were observed when SCH 58261 (0.01 mg/kg, i.p.) was administered to hypertensive rats (28% infarct volume reduction vs controls, p < 0.05). Neuroprotective properties of SCH 58261 administered after ischaemia indicate that blockade of A2A adenosine receptors is a potentially useful biological target for the reduction of brain injury.
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PMID:Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. 987 35

1. The aim of this work was to evaluate the role of leukotrienes in brain damage in vivo in a model of focal cerebral ischaemia in the rat, obtained by permanent occlusion of middle cerebral artery. 2. A significant (P < 0.01) elevation of LTC(4), LTD(4) and LTE(4) (cysteinyl-leukotrienes) levels occurred 4 h after ischaemia induction in the ipsilateral cortices of ischaemic compared to sham-operated animals (3998 +/- 475 and 897 +/- 170 fmol g(-1) tissue, respectively, P < 0.01). 3. The NMDA receptor antagonist MK-801 and the adenosine A(2A) receptor antagonist SCH 58261 were administered in vivo at doses known to reduce infarct size and compared with the leukotriene biosynthesis inhibitor MK-886. 4. MK-886 (0.3 and 2 mg kg(-1) i.v.) and MK-801 (3 mg kg(-1) i.p.) decreased cysteinyl-leukotriene levels (-78%, P < 0.05; -100%, P < 0.01; -92%, P < 0.01, respectively) 4 h after permanent occlusion of the middle cerebral artery, whereas SCH 58261 (0.01 mg kg(-1) i.v.) had no significant effects. 5. MK-886 (2 mg kg(-1) i.v.) was also able to significantly reduce the cortical infarct size by 30% (P < 0.05). 6. We conclude that cysteinyl-leukotriene formation is associated with NMDA receptor activation, and that it represents a neurotoxic event, the inhibition of which is able to reduce brain infarct area in a focal ischaemic event.
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PMID:Production of leukotrienes in a model of focal cerebral ischaemia in the rat. 1149 18

Adenosine released during cerebral ischemia is considered to act as a neuroprotectant, possibly through the inhibition of glutamate release. The involvement of A(1) and A(2A) receptors in the control of the rise of extracellular glutamate during ischemia was investigated by monitoring the effects of selective A(1) and A(2A) receptor antagonists on ischemia-evoked glutamate release in rat cerebrocortical slices.Slices were superfused with oxygen- and glucose-deprived medium and [(3)H]D-aspartate or endogenous glutamate was measured in the superfusate fractions. Withdrawal of Ca(2+) ions or addition of tetrodotoxin more than halved the ischemia-evoked efflux of [(3)H]D-aspartate or glutamate, compatible with a vesicular-like release. The glutamate transporter inhibitor DL-TBOA prevented the ischemia-evoked efflux of [(3)H]D-aspartate by about 40%, indicating a carrier-mediated efflux. The ischemia-evoked efflux of [(3)H]D-aspartate or glutamate was increased by the A(1) receptor antagonist DPCPX. The A(2A) antagonist SCH 58261 decreased [(3)H]D-aspartate or endogenous glutamate efflux (50 and 55% maximal inhibitions; EC(50): 14.9 and 7.6 nM, respectively); the drug was effective also if added during ischemia. No effect of either the A(1) or the A(2A) receptor antagonist was found on the ischemia-evoked efflux of [(3)H]D-aspartate in Ca(2+)-free medium. Our data suggest that adenosine released during cerebral ischemia can activate inhibitory A(1) and stimulatory A(2A) receptors that down- or up-regulate the vesicular-like component of glutamate release.
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PMID:Sensitivity to selective adenosine A1 and A2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices. 1284 26

The most effective treatment of Parkinson's disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A(2A) receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A(2A) antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Fos-like-immunoreactivity in neurons of the lesioned striatum. Likewise, other A(2A) receptor antagonists such as (3,7-dimethyl-1-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] (KF 17837) and [E-1,3-diethyl-8(3,4-dimethoxystyryl-7-methyl-3,7-dihydro-1H-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in non-human primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTP-treated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A(2A) receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A(2A) antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the MPTP model of PD. Adenosine A(2A) receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.
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PMID:Adenosine A(2a) receptor antagonists: potential therapeutic and neuroprotective effects in Parkinson's disease. 1511 Dec 44

We investigated the protective effect of subchronic treatment of the A2A receptor antagonist, SCH 58261 (0.01 mg/kg, i.p.), administered 5 min, 6 h and 15 h after permanent right middle cerebral artery occlusion (MCAo). Twenty-four hours after ischemia, an extensive pallid area, evaluated by cresyl violet staining, is evident in the vascular territories supplied by the MCA, the striatum and the sensory motor cortex. The pallid area reflects the extent of necrotic neurons. Soon after waking, rats showed a definite contralateral turning behavior which was significantly reduced by SCH 58261 treatment. Twenty-four hours after MCAo, SCH 58261 significantly improved the neurological deficit and reduced ischemic damage in the striatum and cortex. Phospho-p38 mitogen-activated protein kinase (MAPK), evaluated by Western Blot, increased by 500% in the ischemic striatum 24 h after MCAo. SCH 58261 treatment significantly reduced phospho-p38 MAPK by 70%. Microglia was immunostained using the OX-42 antibody. Phospho-p38 MAPK and OX-42-immunoreactive cells are localized in the ventral striatum and frontoparietal cortex. Furthermore, both OX-42 and phospho-p38 MAPK-immunoreactive cells have overlapping morphological features, typical of reactive microglia. SCH 58261 reduced phospho-p38 MAPK immunoreactivity in the striatum and in the cortex without changing the microglial cell morphology. These results indicate that the protective effect of the adenosine antagonist SCH 58261 during ischemia is not due to reduced microglial activation but involves inhibition of phospho-p38 MAPK and suggest that treatment with the A2A antagonist from the first hour to several hours after ischemia may be a useful therapeutic approach in cerebral ischemia.
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PMID:The selective A2A receptor antagonist SCH 58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia. 1644


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