PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment

초록

The present study was designed to evaluate the specific role of protein kinase C (PKC) delta in methamphetamine (MA)-induced dopaminergic toxicity. A multiple-dose administration regimen of MA significantly increases PKC delta expression, while rottlerin, a PKC delta inhibitor, significantly attenuates MA-induced hyperthermia and behavioral deficits. These behavioral effects were not significantly observed in PKC delta antisense oligonucleotide (ASO)-treated- or PKC delta knockout (-/-)-mice. There were no MA-induced significant decreases of dopamine (DA) content or tyrosine hydroxylase (TH) expression in the striatum in rottlerin-treated-, ASO-treated- or PKC delta (-/-)-mice. The administration of MA also results in a significant decrease of TH phosphorylation at set 40, but not ser 31, while the inhibition of PKC delta consistently and significantly attenuates MA-induced reduction in the phosphorylation of TH at ser 40. Therefore, these results suggest that the MA-induced enhancement of PKC delta expression is a critical factor in the impairment of TH phosphorylation at ser 40 and that pharmacological or genetic inhibition of PKC delta may be protective against MA-induced dopaminergic neurotoxicity in vivo. (C) 2011 Elsevier B.V. All rights reserved.

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