THE ABILITY OF DIPHENYLPIPERAZINES TO PREVENT NEURONAL DEATH IN DORSAL-ROOT GANGLION NEURONS IN-VITRO AFTER NERVE GROWTH-FACTOR DEPRIVATIONAND IN-VIVO AFTER AXOTOMY

The mechanism of neuroprotection by the calcium channel antagonist flu narizine against neuronal death is unknown. We investigated the abilit y of other calcium channel antagonists (cinnarizine, nimodipine, nicar dipine, diltiazem, and verapamil), calmodulin antagonists, and calpain inhibitors to prevent neuronal death in rat dorsal root ganglion neur ons in vitro after nerve growth factor (NGF) deprivation and the abili ty of cinnarizine and diltiazem to protect in vivo after axotomy. In v itro, only neurons treated with cinnarizine or flunarizine were protec ted from death after withdrawal. In vivo, cinnarizine, but not diltiaz em, protected dorsal root ganglion neurons in rats after unilateral sc iatic nerve crush. Intracellular calcium concentration ([Ca2+](i)) was evaluated with fura 2 after NGF deprivation in vitro. Neurons ''commi tted to die'' 24 h after NGF deprivation displayed a decline in [Ca2+] (i) before visible morphological deterioration consistent with cell de ath. The influx of extracellular calcium was not necessary to produce neuronal death. Neurons deprived of NGF gradually lost the ability to respond to elevated external potassium with an increase in [Ca2+](i) d uring the first 24 h after trophic factor deprivation. After 24 h, neu rons deprived of NGF could not be rescued by readministration of NGF. Neurons protected from cell death with diphenylpiperazines maintained their response to high external potassium, suggesting continued membra ne integrity. We speculate that diphenylpiperazines may protect sensor y neurons via an unknown mechanism that stabilizes cell membranes.