Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity.
The commonly used inhaled anesthetic isoflurane has been shown to be both neuroprotective and neurotoxic in various cell cultures and animal models. We hypothesize that, like cerebral ischemia, isoflurane is inherently neurotoxic. Limited exposure of isoflurane provides neuroprotection via induction of endogenous neuroprotective mechanisms (preconditioning), while prolonged exposure of isoflurane induces neurotoxicity directly by its inherent neurotoxic effects. To test this hypothesis, we treated rat primary cortical neurons at different days in vitro (DIV) and rat pheochromocytoma neurosecretory (PC12) cells with or without Alzheimer's mutated presenilin-1 (PS1) with 2.4% isoflurane for 24 h to induce cell damage determined by both MTT (3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) reduction and LDH (lactate dehydrogenase) release assays. For isoflurane preconditioning, we treated the above cells with isoflurane at 0.6%, 1.2% and 2.4% for 60 min, 4 h prior to a prolonged exposure of 2.4% isoflurane for 24 h. One hour of preconditioning with isoflurane dose-dependently inhibited neurotoxicity induced by 2.4% isoflurane for 24 h in both primary cortical neurons and PC12 cells. This neuroprotection was most dramatically observed in matured cortical neurons (DIV 16) and PC12 cells with over expression of Alzheimer's mutated PS1 (L286V). Preconditioning L286V PC12 cells with equivalent two minimal alveolar concentrations (MAC) of halothane (1.5%), but not sevoflurane (4%), also abolished the neurotoxicity induced by 2.4% isoflurane for 24 h. Overall, these results suggest that isoflurane may be both neuroprotective and neurotoxic, depending on the exposure concentrations and duration.
Wei
Huafeng
H
Department of Anesthesiology and Critical Care, University of Pennsylvania, 305 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA. weih@uphs.upenn.edu
Liang
Ge
G
Yang
Hui
H
D018685:Anesthetics, Inhalation / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004622:Embryo, Mammalian; D007530:Isoflurane / Q000008:administration & dosage*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007930:Leucine / Q000235:genetics; D009154:Mutation / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D053764:Presenilin-1 / Q000235:genetics / Q000502:physiology; D051381:Rats; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014633:Valine / Q000235:genetics
D018685:Anesthetics, Inhalation; D053764:Presenilin-1; D013778:Tetrazolium Salts; D013844:Thiazoles; D007530:Isoflurane; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D007930:Leucine; D014633:Valine