THE ABILITY OF DIPHENYLPIPERAZINES TO PREVENT NEURONAL DEATH IN DORSAL-ROOT GANGLION NEURONS IN-VITRO AFTER NERVE GROWTH-FACTOR DEPRIVATIONAND IN-VIVO AFTER AXOTOMY
Me. Eichler et al., THE ABILITY OF DIPHENYLPIPERAZINES TO PREVENT NEURONAL DEATH IN DORSAL-ROOT GANGLION NEURONS IN-VITRO AFTER NERVE GROWTH-FACTOR DEPRIVATIONAND IN-VIVO AFTER AXOTOMY, Journal of neurochemistry, 62(6), 1994, pp. 2148-2157
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.