Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain.
Short-term exposure of adult rats to nitrous oxide (N2O), an inhalational anesthetic and NMDA (N-methyl-D-aspartate) antagonist, causes a reversible neurotoxic vacuole reaction in neurons of the posterior cingulate/retrosplenial cortex (PC/RSC) which resembles that caused by low doses of other NMDA antagonists. Since high doses or prolonged exposure to other NMDA antagonists can cause neurons to die, we assessed whether prolonged N2O exposure might also cause neuronal cell death. Adult female Sprague-Dawley rats were exposed to 150-vol% N2O (approximately EC50 for N2O anesthesia in rats) for various durations from 1 to 16 h. The time course for onset and disappearance of the reversible vacuole reaction was studied, as was the time course and dose requirement for triggering cell death. A maximum vacuole reaction was observed in PC/RSC neurons in brains examined immediately after 3 h of 150-vol% N2O exposure and the same magnitude of vacuole reaction was observed when brains were examined immediately after a longer period of N2O exposure. When N2O was terminated at 3 h and the rats were killed 1 h later, the vacuole reaction was markedly diminished and if the rats were killed 3 h later the vacuole reaction had completely disappeared. Prolonged exposure to 150-vol% N2O (for 8 h or more) caused neuronal cell death which was detectable by silver staining 32 h later. Concurrently administered GABAergic agents, diazepam (an i.v. anesthetic), or isoflurane (an inhalational anesthetic), prevented this cell death reaction. Our findings demonstrate that short-term exposure of adult rats to N2O causes injury to PC/RSC neurons that is rapidly reversible, and prolonged N2O exposure causes neuronal cell death. These neurotoxic effects, including the cell death reaction, can be prevented by coadministration of GABAmimetic anesthetic agents. Duration of NMDA receptor blockade appears to be an important determinant of whether neurons are reversibly injured or are driven to cell death by an NMDA antagonist drug.
Jevtovic-Todorovic
V
V
Department of Anesthesiology, University of Virginia Health System, P.O. Box 800710, Charlottesville, VA 22908, USA. vj3w@virginia.edu
Beals
J
J
Benshoff
N
N
Olney
J W
JW
D000704:Analysis of Variance; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001784:Blood Gas Analysis; D001921:Brain / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009609:Nitrous Oxide / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining; D013997:Time Factors; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology
D018685:Anesthetics, Inhalation; D018757:GABA Modulators; D007530:Isoflurane; D009609:Nitrous Oxide; D003975:Diazepam