期刊
JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY
卷 20, 期 4, 页码 233-240出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/ANA.0b013e31817ec34d
关键词
calcium; apoptosis; anesthetic; caspase
资金
- NIH [NS07375, NS34152, NS050525, HD16596]
Certain anesthetics exhibit neurotoxicity in the brains of immature but not mature animal's. Gamma-aminobutyric acid (GABA). the primary inhibitory neurotransmitter in the adult brain. is excitatory on immature neurons via its action at the GABA(A) receptor. due to a reversed transmembrane chloride gradient. GABA(A) receptor activation in immature neurons is sufficient to open L-type voltage-gated calcium channels. As propofol is a GABA(A) agonist, we hypothesized that it and more specific GAB-AA modulators would increase intracellular free calcium ([Ca2+](i)) resulting in the death of neonatal rat hippocampal neurons. Ncuronal [Ca2+](i) was monitored using Fura2-AM fluorcscence imaging. Cell death was assessed by doable staining with propidium iodide and Hoechst 33258 at 1 hour (acute) and 48 hours (delayed) after 5 hours exposure of neurons to propofol or the GABAA receptor agonist. muscimol. in the presence and absence of the GABA receptor antagonist, bicuculline. or the L-type Ca2+ channel blocker, nifedipine. Fluorescent measurements of caspase-3,-7 activities were performed at I hour after exposure. Both muscimol and propofol induced a rapid increase in [Ca2+]; in days in vitro (DIV) 4, but not in DIV 8 neurons. that was inhibited by nifedipine and bicuculline. Caspase-3-7 activities and cell death increased significantly in DIV 4 but not DIV 8 hippocampal neuronal cultures 1 hour after 5 hours exposure to propofol, but not muscimol. and were inhibited by the presence of bicuculline or nifedipine. We conclude that an increase in [Ca2+](i), due to activation of GABAA receptors and opening of L-type calcium channels. is necessary for propofol-induced death of immature rat hippocampal neurons but that additional mechanisms not elicited by GABAA activation alone also contribute to cell death.
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