Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain

• Published in: Neuroscience 2003, Vol.122 (3), p.609-616
• Main Authors: Jevtovic-Todorovic, V, Beals, J, Benshoff, N, Olney, J.W
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Anesthetics, Inhalation - toxicity; Animals; Biological and medical sciences; Blood Gas Analysis; Brain - pathology; Cell Death - drug effects; deOlmos silver staining; Diazepam - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Drug toxicity and drugs side effects treatment; Female; GABA Modulators - pharmacology; Isoflurane - pharmacology; laughing gas; Medical sciences; Nerve Degeneration; neuronal necrosis; Neurons - drug effects; Neurons - pathology; neurotoxicity; Nitrous Oxide - toxicity; NMDA antagonist; Pharmacology. Drug treatments; posterior cingulate/retrosplenial cortex; Rats; Rats, Sprague-Dawley; Silver Staining; Time Factors; Toxicity: nervous system and muscle; Vacuoles - drug effects; Vacuoles - pathology
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2003.07.012

Short-term exposure of adult rats to nitrous oxide (N 2O), 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 N 2O exposure might also cause neuronal cell death. Adult female Sprague–Dawley rats were exposed to 150-vol% N 2O (approximately EC 50 for N 2O 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% N 2O exposure and the same magnitude of vacuole reaction was observed when brains were examined immediately after a longer period of N 2O exposure. When N 2O 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% N 2O (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 N 2O causes injury to PC/RSC neurons that is rapidly reversible, and prolonged N 2O 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.