Ca 2+ channel antagonists and neuroprotection from cerebral ischemia

Ca 2+ channel antagonists and neuroprotection from cerebral ischemia Stroke is the third leading cause of death and the main disabling neurologic disease. The finding in experimental studies that neuronal death does not occur immediately after ischemic injury has encouraged the development of neuroprotective agents. Various Ca 2+ channel antagonists, that is, L-type-selective or non-selective derivatives from classical Ca 2+ channel antagonists, have been examined for their ability of neuroprotection through improvement of cerebral blood circulation or inhibition of Ca 2+ overload induced by excessive glutamate release. Although some of the antagonists showed efficient neuroprotection in animal models, systemic hypotension limited the utility of these drugs, and none of the compounds showed beneficial effects in treatments for acute ischemic stroke in clinical trials. Drugs other than Ca 2+ channel antagonists developed on the basis of the glutamate–Ca 2+ overload hypothesis were shown also to lack clinical benefit. Recently, some mechanisms have been proposed to interpret neuronal death in relation to hyperexcitability or apoptosis after ischemic insult. In these hypotheses, activation of the Ca 2+ channel types selectively expressed in neuronal tissues is proposed as a critical step of the pathways toward neurodegeneration. Thus, it is increasingly recognized that developing highly selective compounds for neuronal Ca 2+ channels is not only important for treatment of stroke but also for elucidation of mechanisms that underlie neurodegeneration. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Pharmacology Elsevier

Ca 2+ channel antagonists and neuroprotection from cerebral ischemia

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Publisher
Elsevier
Copyright
Copyright © 1998 Elsevier Science B.V.
ISSN
0014-2999
D.O.I.
10.1016/S0014-2999(98)00774-2
Publisher site
See Article on Publisher Site

Abstract

Stroke is the third leading cause of death and the main disabling neurologic disease. The finding in experimental studies that neuronal death does not occur immediately after ischemic injury has encouraged the development of neuroprotective agents. Various Ca 2+ channel antagonists, that is, L-type-selective or non-selective derivatives from classical Ca 2+ channel antagonists, have been examined for their ability of neuroprotection through improvement of cerebral blood circulation or inhibition of Ca 2+ overload induced by excessive glutamate release. Although some of the antagonists showed efficient neuroprotection in animal models, systemic hypotension limited the utility of these drugs, and none of the compounds showed beneficial effects in treatments for acute ischemic stroke in clinical trials. Drugs other than Ca 2+ channel antagonists developed on the basis of the glutamate–Ca 2+ overload hypothesis were shown also to lack clinical benefit. Recently, some mechanisms have been proposed to interpret neuronal death in relation to hyperexcitability or apoptosis after ischemic insult. In these hypotheses, activation of the Ca 2+ channel types selectively expressed in neuronal tissues is proposed as a critical step of the pathways toward neurodegeneration. Thus, it is increasingly recognized that developing highly selective compounds for neuronal Ca 2+ channels is not only important for treatment of stroke but also for elucidation of mechanisms that underlie neurodegeneration.

Journal

European Journal of PharmacologyElsevier

Published: Dec 11, 1998

References

  • Reduction by lifarizine of the neuronal damage induced by cerebral ischaemia in rodents
    Alps, B.J; Calder, C; Wilson, A.D; McBean, D.E; Armstrong, J.M
  • Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands
    Franke, C.L; Palm, R; Dalby, M; Schoonderwaldt, H.C; Hantson, L; Eriksson, B; Lang-Jenssen, L; Smakman, J
  • Viability thresholds and the penumbra of focal ischemia
    Hossmann, K.A
  • Inhibitory effects of a new neuroprotective diltiazem analogue, T-477, on cloned brain Ca 2+ channels expressed in Xenopus oocytes
    Kobayashi, T; Strobeck, M; Schwartz, A; Mori, Y
  • Exploration of P-type Ca 2+ channels as drug targets for the treatment of epilepsy or ischemic stroke
    Lingenhohl, K; Small, D.L; Monette, R; Buchan, A.M; Morley, P; Allegrini, P.R; Frost, L.W; Sauer, D; Schmutz, M; Knopfel, T
  • Effects of Ca 2+ and Na + channel inhibitors in vitro and in global cerebral ischaemia in vivo
    O'Neill, M.J; Bath, C.P; Dell, C.P; Hicks, C.A; Gilmore, J; Ambler, S.J; Ward, M.A; Bleakman, D
  • Temporal profile of neuronal damage in a model of transient forebrain ischemia
    Pulsinelli, W.A; Brierley, J.B; Plum, F
  • Effects of Ca 2+ channel blockers on cortical hypoperfusion and expression of c-Fos-like immunoreactivity after cortical spreading depression in rats
    Shimazawa, M; Hara, H; Watano, T; Sukamoto, T

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