Cyclooxygenase-2 is an obligatory factor in methamphetamine-induced neurotoxicity.
Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. The mechanisms underlying its neurotoxicity are not fully understood, but considerable evidence points to oxidative stress as a probable mechanism. A recent microarray analysis of gene expression changes caused by methamphetamine revealed that cyclooxygenase-2 (COX-2) was induced along with its transcription factor CCAAT/enhancer-binding protein (Thomas DM, Francescutti-Verbeem DM, Liu X, and Kuhn DM, 2004). We report presently that methamphetamine increases striatal expression of COX-2 protein. Cyclooxygenase-1 (COX-1) expression was not changed. Mice bearing a null mutation of the gene for COX-2 were resistant to methamphetamine-induced neurotoxicity. COX-1 knockouts, like wild-type mice, showed extensive dopamine nerve terminal damage. Selective inhibitors of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole (SC-560)], COX-2 [N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulfonamide (NS-398), rofecoxib], or COX-3 (antipyrine) or a nonselective inhibitor of the COX-1/2 isoforms (ketoprofen) did not protect mice from neurotoxicity. Finally, methamphetamine did not change striatal prostaglandin E(2) content. Taken together, these data suggest that COX-2 is an obligatory factor in methamphetamine-induced neurotoxicity. The functional aspect of COX-2 that contributes to drug-induced neurotoxicity does not appear to be its prostaglandin synthetic capacity. Instead, the peroxidase activity associated with COX-2, which can lead to the formation of reactive oxygen species and dopamine quinones, can account for its role.
Thomas
David M
DM
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Kuhn
Donald M
DM
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D051546:Cyclooxygenase 2; D004298:Dopamine / Q000378:metabolism; D005260:Female; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*
D008694:Methamphetamine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D004298:Dopamine