41a Propofol Induces a GABA-Independent Expression of C-Fos and Egr-1 In Neuronal Cells

Srivatsan Kidambi¹, Joel Yarmush², Wayne Fong², Sangeetha Kamath², Joseph SchianodiCola², and Yaakov Nahmias³. (1) Center for Engineering in Medicine, Harvard Medical School, Massachusetts General Hospital, Shriners Hospital, New York Methodist Hospital, 51 Blossom Street, Boston, MA 02114, (2) Department of Anesthesiology, New York Methodist Hospital, Brooklyn, NY 11215, (3) Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, 51 Blossom Street, Boston, MA 02114

Propofol is a commonly used intravenous anesthetic agent, which produce rapid induction of and recovery from general anesthesia. Numerous clinical studies reported that propofol can potentially cause amnesia and memory loss in human subjects. The underlying mechanism for this memory loss is unclear but may potentially be related to the induction of memory-associated genes such as c-Fos and Egr-1 by propofol.

Mouse neuroblastoma (N2A) cells were exposed to varying concentrations of propofol at multiple time intervals. Cellular viability was quantified by fluorescence microscopy and the transcription of the immediate early genes, c-Fos and Egr-1, was quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). GABA-A receptor antagonists and MAPK/ERK inhibitors were used to investigate the mechanism of action. Propofol induces time and dose dependent transcription of c-Fos and Egr-1. At physiologically relevant concentration (3μg/ml) propofol caused a 6-fold and 2.5-fold induction in c-Fos and Egr-1 transcription, respectively. The propofol-induced c-Fos and Egr-1 expression was unaffected by bicuculline, GABA receptor antagonist but was abolished by PD98059, a MAPK/ERK inhibitor, suggesting the possible involvement of the MAPK/ERK pathway. Our study suggests that at physiological concentrations propofol can induce long-term changes of neuronal function by changing gene transcription. Furthermore, the induction of c-Fos and Egr-1 by propofol is mediated via a non GABAergic mechanism involving the MAPK/ERK pathway. Future work will examine the effects of propofol in primary neurons and elucidate the role of the GABA pathway in a more physiologic model of the central nervous system.