CALCIUM-CHANNEL ANTAGONISTS AND HUMAN-IMMUNODEFICIENCY-VIRUS COAT PROTEIN-MEDIATED NEURONAL INJURY

Recent evidence in vitro has suggested that neuronal injury observed in the acquired immunodeficiency syndrome dementia complex may depend, at least in part, on toxic effects of the human immunodeficiency virus type 1 envelope protein, gp120. This laboratory previously reported that members of the dihydropyridine class of calcium channel antagonists, nimodipine and nifedipine, greatly attenuate the rise in intracellular calcium engendered by gp 120 and prevent subsequent neuronal injury. The relatively low (nanomolar) concentrations of dihydropyridines that were effective suggested that their action might be exerted at the level of the L-type of voltage-dependent calcium channels. In the present study, I tested members of the three other major classes of Ca2+ channel antagonist drugs to determine if they too could prevent neurotoxicity induced by gp 120. At the maximal dose that did not cause neuronal damage in and of itself, a diphenylalkylamine piperazine derivative (flunarizine, 10-mu-M) was the most effective, a phenylalkylamine (verapamil, 100-mu-M) was possibly effective, whereas a benzothiazepine (diltiazem, 1-mu-M) was ineffectual in protecting rat retinal ganglion cells from gp 120-induced toxicity in vitro. To explain these results, previous work has shown that the various classes of Ca2+ channel antagonists may exhibit differential potency in blocking voltage-dependent Ca2+ current in neurons, with dihydropyridines and flunarizine being the most potent at neuronal calcium channels. Moreover, these channels on mammalian central neurons are relatively insensitive to agents such as verapamil and diltiazem compared with other cell types like muscle. The low micromolar concentrations necessary for potency of flunarizine is in keeping with that predicted by binding and electrophysiological studies for block of voltage-dependent calcium channels. Other mechanisms of neuroprotection by flunarizine from gp120, however, cannot be totally excluded.