Protein kinase Cδ mediates methamphetamine-induced dopaminergic neurotoxicity in mice via activation of microsomal epoxide hydrolase

초록

We previously demonstrated that activation of protein kinase C delta (PKC delta) is critical for methamphetamine (MA)induced dopaminergic toxicity. It was recognized that microsomal epoxide hydrolase (mEH) also induces dopaminergic neurotoxicity. It was demonstrated that inhibition of PKC modulates the expression of mEH. We investigated whether MA-induced PKC delta activation requires mEH induction in mice. MA treatment (8 mg/kg, i.p., x 4; 2 h interval) significantly enhanced the level of phosphorylated PKC delta in the striatum of wild type (WT) mice. Subsequently, treatment with MA resulted in significant increases in the expression of cleaved PKC delta and mEH. Treatment with MA resulted in enhanced interaction between PKC delta and mEH. PKC delta knockout mice exhibited significant attenuation of the enhanced mEH expression induced by MA. MA-induced hyperthermia, oxidative stress, proapoptotic potentials, and dopaminergic impairments were attenuated by PKC delta knockout or mEH knockout in mice. However, treating mEH knockout in mice with PKC delta inhibitor, rottlerin did not show any additive beneficial effects, indicating that mEH is a critical mediator of neurotoxic potential of PKC delta. Our results suggest that MA-induced PKC delta activation requires mEH induction as a downstream signaling pathway and that the modulation of the PKC delta and mEH interaction is important for the pharmacological intervention against MA-induced dopaminergic neurotoxicity.

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