Ca2+ 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 Ca2+ channel antagonists, that is, L-type-selective or non-selective derivatives from classical Ca2+ channel antagonists, have been examined for their ability of neuroprotection through improvement of cerebral blood circulation or inhibition of Ca2+ 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 Ca2+ channel antagonists developed on the basis of the glutamate-Ca2+ 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 Ca2+ 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 Ca2+ channels is not only important for treatment of stroke but also for elucidation of mechanisms that underlie neurodegeneration.
Kobayashi
T
T
Pharmacological Research Laboratory, Tanabe Seiyaku, Toda, Saitama, Japan. kobayasi@tanabe.co.jp
Mori
Y
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002545:Brain Ischemia / Q000517:prevention & control*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018696:Neuroprotective Agents; D018698:Glutamic Acid