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Veratridine delays apoptotic neuronal death induced by NGF deprivation through a Na+‐dependent mechanism in cultured rat sympathetic neurons
Author(s) -
Tanaka S.,
Koike T.
Publication year - 1997
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/s0736-5748(96)00082-2
Subject(s) - veratridine , mechanism (biology) , apoptosis , neuroscience , nerve growth factor , chemistry , endocrinology , medicine , microbiology and biotechnology , biology , receptor , sodium , sodium channel , biochemistry , organic chemistry , philosophy , epistemology
Superior‐cervical ganglion (SCG) cells dissociated from newborn rats depend on nerve growth factor (NGF) for survival. Membrane depolarization with elevated K+ is known to prevent neuronal death following NGF deprivation and/or to promote survival via a Ca2+‐dependent mechanism. Here we have exploited the possibility of whether or not a Na+‐dependent pathway for neuronal survival is present in these cells. Veratridine (ec50=40 nM), a voltage‐dependent Na+ channel activator, significantly delayed the onset of apoptotic cell death in NGF‐deprived SCG neurons that had been cultured for 7 days in the presence of NGF. This effect was blocked completely by Na+ channel blockers including tetrodotoxin (TTX, 1 μM), benzamil (25 μM) and flunarizine (1 μM), but was not attenuated by nimodipine (1 μM), an L‐type Ca 2+ channel blocker. The saving effect of veratridine on cultured neurons was observed even in low Ca 2+ media (0–1.0 mM), but was completely abolished in a low Na + medium (38 mM). Sodium‐binding benzofuran isophthalate was employed as a fluorescent probe for monitoring the level of cytoplasmic free Na + , which revealed a sustained increase in its level (12.9 mM, 307% of that of control) in response to veratridine (0.75 μ M). The TTX or flunarizine completely blocked veratridine‐induced Na + influx in these cultured neurons. Moreover, no appreciable increase in intracellular Ca 2+ was detected under these conditions. Though Na + channels were effectual in SCG neurons which were freshly isolated from newborn rats, the Na + ‐dependent saving effect of veratridine was not observed in these young neurons. These lines of evidence suggest that the death‐suppressing effect of veratridine on cultured SCG neurons depends on the Na + influx via voltage‐dependent Na + channels, and suggests the presence of Na + ‐dependent regulatory mechanism(s) in neuronal survival.