The ability of diphenylpiperazines to prevent neuronal death in dorsal root ganglion neurons in vitro after nerve growth factor deprivation and in vivo after axotomy.
The mechanism of neuroprotection by the calcium channel antagonist flunarizine against neuronal death is unknown. We investigated the ability of other calcium channel antagonists (cinnarizine, nimodipine, nicardipine, diltiazem, and verapamil), calmodulin antagonists, and calpain inhibitors to prevent neuronal death in rat dorsal root ganglion neurons in vitro after nerve growth factor (NGF) deprivation and the ability of cinnarizine and diltiazem to protect in vivo after axotomy. In vitro, only neurons treated with cinnarizine or flunarizine were protected from death after withdrawal. In vivo, cinnarizine, but not diltiazem, protected dorsal root ganglion neurons in rats after unilateral sciatic nerve crush. Intracellular calcium concentration ([Ca2+]i) was evaluated with fura 2 after NGF deprivation in vitro. Neurons "committed to die" 24 h after NGF deprivation displayed a decline in [Ca2+]i before visible morphological deterioration consistent with cell death. 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 during the first 24 h after trophic factor deprivation. After 24 h, neurons 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 membrane integrity. We speculate that diphenylpiperazines may protect sensory neurons via an unknown mechanism that stabilizes cell membranes.
Eichler
M E
ME
Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri 78284-7756.
Dubinsky
J M
JM
Tong
J
J
Rich
K M
KM
D000818:Animals; D001369:Axons / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000145:classification / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003714:Denervation; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects*; D007425:Intracellular Membranes / Q000378:metabolism; D009414:Nerve Growth Factors / Q000172:deficiency* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D009414:Nerve Growth Factors; D010879:Piperazines; D011188:Potassium; D002118:Calcium