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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. In animal models of global and focal cerebral ischemia, numerous preclinical studies have demonstrated various agents to be neuroprotective at different steps along this cascade. A wide variety of drugs has also been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They include calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilizad, anti-intercellular adhesion molecule-1 (ICAM-1) antibody, GM-1 ganglioside, clomethiazole, the sodium channel antagonist fosphenytoin, and piracetam. In the future, clinicians may have an armamentarium of treatments for acute ischemic stroke at their disposal, with a combination of agents directed at different sites in the ischemic cascade being the ultimate goal.
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PMID:Neuroprotective therapy. 993 19

On the basis of their promising experimental evidence, calcium channel blockers are today largely used in clinical practice for treatment of patients with cerebrovascular disorders. We propose a meta-analytical evaluation of published clinical trials on nimodipine, a dihydropiridin calcium antagonist, in subarachnoid hemorrhage and in ischemic stroke. In seven trials of subarachnoid hemorrhage, 112 deaths occurred among 682 patients randomized to active treatment compared with 154 deaths among 689 control patients (odds ratio of 0.68, 95% confidence interval of 0.52 to 0.90). Poor outcome due to delayed cerebral ischemia following subarachnoid hemorrhage was also lower in the group allocated to receive nimodipine (odds ratio of 0.47, 95% confidence interval of 0.36 to 0.62). In 12 trials of ischemic stroke, 382 deaths occurred among 2056 patients allocated to receive nimodipine compared to 288 deaths among 1462 control patients (odds ratio of 0.98, 95% confidence interval of 0.82 to 1.18). Pooled results strongly suggest a protective effect of nimodipine in delayed cerebral ischemia following subarachnoid hemorrhage and no effect in ischemic stroke, but the direction and the significance of these results are due to the contribution of a single large trial on subarachnoid hemorrhage and of two trials on ischemic stroke, which account respectively for 40% and 65% of randomized patients. The dissociated effect of nimodipine on these similar conditions could be related to its preventive role in ischemic damage, resembling animal models of ischemic stroke where a beneficial effect of calcium antagonists was clearly shown only when treatment was started before experimental cerebral artery occlusion. In this view, the negative results obtained from the clinical setting of ischemic stroke seem to indicate nimodipine as an aspecific neuroprotective agent without a curative effect.
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PMID:From pharmacological promises to controlled clinical trials to meta-analysis and back: the case of nimodipine in cerebrovascular disorders. 1015 Jan 86

Calcium channel blockers constitute a very important group of drugs that are commonly used in the treatment of cardiovascular and cerebrovascular disorders. Current indications for these medications include hypertension, angina, supraventricular arrhythmias, and prevention of coronary and cerebral vasospasm. Although calcium channel blockers originally held great promise in the treatment of myocardial and cerebral ischemia, clinical results have been discouraging. An understanding of the basic physiological mechanisms of actions for these drugs is important for the practising clinician and may explain the disappointing results for the treatment of ischemia to date. This paper is a narrative review, from a clinician's viewpoint, of the structure and role of calcium channels in cardiac and cerebrovascular tissues, as well as a review of the in vitro and clinical results of calcium channel blockade in myocardial and cerebral ischemia.
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PMID:Calcium channel blockers in myocardial and cerebral ischemia: a clinician's review from bench to bedside. 1020 97

We examined whether the anti-ischemic effect of lamotrigine (LTG), which inhibits the presynapic sodium channel, could be enhanced by the calcium channel blocker-flunarizine (FNR) in cerebral ischemia. Global ischemia was induced in Mongolian gerbils for 5 min under the monitoring of scalp temperature. LTG and FNR were administered intraperitoneally 1 h before ischemia. After 7 days, animals were killed and viable neurons in CA1 area were counted. LTG treated group showed significant protective effects compared to control group (P < 0.01). These effects were more prominent in group treated with LTG and FNR (P = 0.01). Combination of two drugs did not increase the mortality rate compared to single-treated group. These results show that a synergistic reduction of neuronal death can be achieved by combination of LTG and FNR without serious adverse reaction.
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PMID:Neuroprotective effects of lamotrigine enhanced by flunarizine in gerbil global ischemia. 1032 69

The permanent occlusion of bilateral common carotid arteries (2VO) in rats has been shown to cause progressive and long-lasting cognitive deficits which may be due to impairment of memory retention and/or memory recall process. To clarify the function of voltage dependent calcium channels and the receptor binding of nimodipine by chronic cerebral ischemia, we examined specific (+)-[3H]PN 200-110 binding and the effect of oral administration of nimodipine in brain regions and hearts of rats, at 2 weeks to 4 months after permanent 2VO. There was no significant difference in either dissociation constant (Kd) or maximal number of binding sites (Bmax) for (+)-[3H]PN 200-110 in the cerebral cortex, hippocampus, corpus striatum and thalamus between 2VO and sham rats. In addition, in vitro inhibitory effect of nimodipine on cerebral cortical (+)-[3H]PN 200-110 binding in 2VO rats was similar to that in sham rats. Compared to control rats, oral administration of nimodipine to both 2VO and sham rats at 2 months after permanent 2VO brought about a significant increase in Kd values of specific (+)-[3H]PN 200-110 binding in the cerebral cortex, hippocampus, thalamus and myocardium, and the increase in Kd values was much larger in brain regions of 2VO rats than sham rats. However, the increase in Kd values in the myocardium did not differ between 2VO and sham rats. This observation suggests an increased in vivo binding affinity for nimodipine in chronic ischemic brain. In conclusion, the present study has shown that oral administration of nimodipine may cause a greater occupation in vivo of 1,4-dihydropyridine (DHP) calcium channel antagonist receptors in brains of permanent 2VO rats than in sham rats. Thus, nimodipine may be pharmacologically effective in preventing brain dysfunction due to cerebral ischemia in vivo.
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PMID:Increase in receptor binding affinity for nimodipine in the rat brain with permanent occlusion of bilateral carotid arteries. 1075 71

In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia-hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia-hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia-hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent.
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PMID:LY393615, a novel neuronal Ca(2+) and Na(+) channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia. 1114 60

In the mammalian central nervous system, transient global ischemia of specific duration causes selective degeneration of CA1 pyramidal neurons in hippocampus. Many of the ischemia-induced pathophysiologic cascades that destroy the neurons are triggered by pre- and postsynaptic calcium entry. Consistent with this, many calcium channel blockers have been shown to be neuroprotective in global models of ischemia. omega-Conotoxin MVIIA, a selective N-type VGCC blocker isolated from the venom of Conus magus, protects CA1 neurons in the rat model of global ischemia, albeit transiently. The mechanism by which this peptide renders neuroprotection is unknown. We performed high-resolution receptor autoradiography with the radiolabeled peptide and observed highest binding in stratum lucidum of CA3 subfield, known to contain inhibitory neurons potentially important in the pathogenesis of delayed neuronal death. This finding suggested that the survival of stratum lucidum inhibitory neurons might be the primary event, leading to CA1 neuroprotection after ischemia. Testing of this hypothesis required the reproduction of its neuroprotective effects in the gerbil model of global ischemia. Surprisingly, we found that omega-MVIIA did not attenuate CA1 hippocampal injury after 5 min of cerebral ischemia in gerbil. Possible reasons are discussed. Lastly, we show that the peptide can be used as a synaptic marker in assessing short and long-term changes that occur in hippocampus after ischemic injury.
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PMID:Autoradiographic localization of N-type VGCCs in gerbil hippocampus and failure of omega-conotoxin MVIIA to attenuate neuronal injury after transient cerebral ischemia. 1143 Aug 86

Magnesium is involved in multiple physiological processes that may be relevant to cerebral ischaemia, including antagonism of glutamate release, NMDA receptor blockade, calcium channel antagonism, and maintenance of cerebral blood flow. Systemically administered magnesium at doses that double physiological serum concentration significantly reduces infarct volume in animal models of stroke, with a window of up to six hours after onset and favourable dose-response characteristics when compared with previously tested neuroprotective agents. Small clinical trials have reported benefit, but results are not statistically significant in systematic review. A large ongoing trial (IMAGES) will report in 2003-4 and further trials are planned.
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PMID:Magnesium in stroke treatment. 1249 16

The pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline extracted from Uncaria rhynchophylla Miq Jacks were reviewed. The alkaloids mainly act on cardiovascular system and central nervous system including the hypotension, brachycardia, antiarrhythmia, and protection of cerebral ischemia and sedation. The active mechanisms were related to blocking of calcium channel, opening of potassium channel, and regulating of nerve transmitters transport and metabolism, etc.
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PMID:Pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline. 1254 15

The ability of Sipatrigine (BW619c89), a sodium and calcium channel blocker to protect neuronal perikarya, axons and oligodendrocytes from ischaemia has been evaluated in the rat. Sipatrigine (30 mg/kg) was administered 15 min prior to transient (2 h) occlusion of the middle cerebral artery with animals being sacrificed 24 h after induction of ischaemia. Sipatrigine significantly reduced the volumes of neuronal perikarya damage (by 35%) and oligodendrocyte damage (by 54%). Sipatrigine minimally altered axonal damage (median scores: vehicle approximately 30, Sipatrigine approximately 26). The present report provides evidence that neuronal perikarya, axons and oligodendrocytes may be differentially protected by pharmacological intervention in focal cerebral ischaemia.
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PMID:Sipatrigine and oligodendrocyte and axonal pathology following transient focal cerebral ischaemia in the rat. 1263 15


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