Central effect of Ca²⁺ channel blockers : Multiple sites of action

Abstract

To develop a new concept of central acting drugs, the modulation of brain Ca²⁺ flux must be considered as one of the important factors. This is because excessive Ca²⁺ influx to neuronal cells damages or kills these cells, and also because abnormal intracellular Ca²⁺ concentrations induce several types of mental disorders. Recently, both pre-clinical and clinical studies indicated that some Ca²⁺ channel blockers (Ca antagonists) will be useful for the treatment of grand mal, manic depressive insanity, panic disorder and anxiety. Furthermore, it has been estimated by animal studies and clinical pharmacology that ischemia-induced neuronal death can be prevented by the treatment with a Ca antagonist. However, the latter data, especially, has been mainly explained by pharmacological effects on the cerebrovascular system, not because of possible direct central actions. To invoke the notion of direct central action, it must be assumed that Ca antagonists might pass the blood-brain barrier (BBB). This potentiality that some Ca antagonists (i.e., flunarizine, nicardipine, nimodipine, etc.) can pass the BBB has been initially explored. If substantiated, such direct central effects of Ca antagonists may explain both the psychotropic effects and neuronal protection by these agents. To investigate the actual therapeutic effects of Ca²⁺ antagonists on psychotropic disorders and neuronal death, a suitable animal model and reasonable methods and criteria must be established. Then, both preclinical and clinical studies can be expected to relate to atypical central acting drugs modulating the brain Ca²⁺ channels, and also to the development of new pharmacological properties of Ca²⁺ antagonists.