ReviewCa2+ channel antagonists and neuroprotection from cerebral ischemia
Introduction
In late 1960s, nifedipine, verapamil and diltiazem, emerged as a novel group of drugs `Ca2+ channel antagonist', because of their selectivity in blocking voltage-dependent Ca2+ channels (VDCC) (Fleckenstein, 1983). Ca2+ channel antagonists were developed originally for the treatment of angina pectoris by dilation of coronary arteries. However, they proved beneficial also for hypertension, ischemic heart disease, and cardiac arrhythmia (Triggle, 1991).
Stroke, comprised of embolisms, thromboses, or hemorrhages in the brain, interrupts vital blood supply and thereby induces localized ischemic damage in brain tissues. Since stroke is a dysfunction of cerebral blood circulation, the remarkable utility of the Ca2+ channel antagonists in cardiovascular diseases had encouraged the examination of therapeutic potentials of these drugs in cerebrovascular dysfunctions. Although many of these compounds, synthesized to dilate cerebral artery, blocked Ca2+ channels in vascular smooth muscle cells, their clinical effects were disappointing.
From the view point of the glutamate–Ca2+ overload neurotoxicity hypothesis (Choi, 1988; Siesjo and Bengtsson, 1989), inhibition of excessive Ca2+ influx into neurons was considered to be important for neuroprotection. It is natural to apply Ca2+ channel antagonists directly to neuronal tissue, considering the prominent distribution of VDCC in the brain and the physiological importance of Ca2+ in neurons. However, no compounds were proven to be effective in clinical trials of more than 10 years. Therefore, not so many Ca2+ channel antagonists were newly synthesized as neuroprotective drugs, and researchers turned their attention to new candidates based upon glutamate–Ca2+ overload hypothesis such as glutamate receptor (NMDA, AMPA) antagonists, radical scavengers, Na+ overload inhibitors, calpain inhibitors, nitric oxide synthetase inhibitors. Although they showed promising results in animal studies, many compounds developed from the cascade of glutamate–Ca2+ overload hypothesis also proved to be ineffective or caused side effects in clinical trials.
Recently, hyperexcitability and apoptosis have been proposed as novel mechanisms that lead to delayed neuronal death, which has encouraged revision of glutamate–Ca2+ overload hypothesis. In this article, we describe possible relationships between such mechanisms and neuronal VDCCs, and discuss the potential of Ca2+ channel antagonists becoming neuroprotective agents. We also review Ca2+ channel antagonists developed so far and their problems as neuroprotective agents in the clinic.
Section snippets
Blood flow level and types of neuronal death
Eighty percent of strokes are due to blood clots. After onset of stroke, blood clots form focal ischemia that evoke neuronal damage in restricted areas of brain. Three types of neuronal death have been distinguished based on the level of residual blood flow in the ischemic area (Fig. 1). (1) At the center of ischemic region where the cerebral circulation is completely arrested, irreversible cell damage occurs in several minutes. In the core area, neurons cannot be saved by medical treatments
Functional and molecular diversity of Ca2+ channels
VDCCs serve as the only link to transduce depolarization into activities controlled by excitation in various cellular processes including neurosecretion. The basis of this pivotal role of Ca2+ channels is the transient increase of [Ca2+]i. Ca2+ channels, together with Na+ and K+ channels, are also electrogenic. VDCCs are diverse in both biophysical and pharmacological properties. It has been recognized that there exist multiple VDCC types (L-, N-, P-, Q-, R- and T-type) that can be
Ca2+ channel blockade as a potential therapeutic strategy for stroke
Developments of neuronal death described in Section 2involve processes that can be connected to Ca2+ influx through VDCCs. This suggests inhibition of VDCC as a target for therapy of stroke.
Neuroprotection by Ca2+ channel antagonists
Numerous reports have been made on the neuroprotective effects of Ca2+ channel antagonists in anoxia/ischemia. Since duration of the insult, dosing schedule, and age or stage of development of neurons may all be important determining parameters, it is not surprising that different models have yielded somewhat conflicting results in evaluating Ca2+ channel antagonists (for example, see Table 2). In general, L-type or non-selective Ca2+ channel antagonists appear to be more effective in studies
Concluding remarks
Great efforts have been dedicated to application of Ca2+ channel antagonists for the treatment of acute stroke for a long time. Although the researchers were able to show beneficial effects of certain Ca2+ channel antagonists in animal models, few to no compound has been proven effective in clinical trials.
It must be stressed that most of the compounds examined so far are derivatives of conventional Ca2+ channel antagonists, which are similar to each other in functional characteristics. Some of
Acknowledgements
We thank A. Schwartz, S. Komatsubara, N. Suto and F. Mori for encouragement and comments and C. Mahoney for critical reading of the manuscript and helpful discussion.
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