Pharmacology of sodium and calcium channel modulation in neurons: implications for neuroprotection.

It is now clear that the wide variety of neuronal voltage-dependent calcium channels (Table 1) are determinants of transmitter release (N-type, P-type, Q-type channels), repetitive or burst neuronal firing (T-type channels) and perhaps of some aspects of gene expression (L-type channels). However, although the calcium overload hypothesis of neuronal cell death has been around for 14 years, there is little clinical acceptance of a role for calcium channel modulators in the treatment of stroke or other forms of neurodegeneration. Indeed, in a recent article Grosset [ 11 concluded that there was no current useful therapy for acute stroke. In this article, we review why initial approaches have failed to provide robust clinical benefit, but why newer approaches, which are either in early clinical trials or in preclinical evaluation, may be of benefit. These approaches are either ion channel selective or, alternatively, gain selectivity by appropriate kinetics at different ion channel states.