title: Isoflurane preconditioning decreases glutamate receptor overactivation-induced Purkinje neuronal injury in rat cerebellar slices.
abstract: A brain slice model was used to test the hypothesis that preconditioning with isoflurane, a commonly used volatile anesthetic in clinical practice, reduces neuronal injury caused by overstimulation of glutamate receptors. Glutamate receptors were stimulated by various concentrations of glutamate for 20 min, N-methyl-d-aspartate (NMDA) for 15 min or alpha-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) for 15 min. Morphology of Purkinje neurons in the cerebellar slices of adult male Sprague-Dawley rats was evaluated 5 h after the agonist stimulation. Glutamate, NMDA and AMPA induced a dose-dependent decrease in the percentage of morphologically normal Purkinje neurons. The concentration to induce the maximal neurotoxic effect was 300 microM for glutamate, 300 microM for NMDA and 30 microM for AMPA. Isoflurane preconditioning (2% isoflurane for 30 min and then a 15-min rest period before the agonist stimulation) significantly reduced the neurotoxicity induced by 300 microM glutamate, 300 microM NMDA or 30 microM AMPA. Isoflurane preconditioning-induced protection against glutamate neurotoxicity was abolished by two protein kinase C (PKC) inhibitors, calphostin C (0.5 microM) and chelerythrine (5 microM), or a nitric oxide synthase (NOS) inhibitor, l-nitro(G)-arginine methyl ester (l-NAME, 1.5 mM), but was not affected by an adenosine A1 receptor inhibitor, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 300 nM), or a Gi protein inhibitor, pertussis toxin (PTX, 200 ng/ml). Isoflurane preconditioning-induced protection against NMDA neurotoxicity was also abolished by calphostin C, chelerythrine or l-NAME. Thus, isoflurane preconditioning reduced glutamate receptor overstimulation-induced neuronal injury/death. This neuroprotection may be PKC- and NOS-dependent.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, One Hospital Drive, P.O. Box 800710, Charlottesville, VA 22908-0710, USA.
authors.forename: Shuqiu
authors.initials: S
authors.lastname: Zheng
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007530:Isoflurane; D037342:Pertussis Toxin