rottlerin and Fever

We previously demonstrated that activation of protein kinase Cδ (PKCδ) 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 PKCδ activation requires mEH induction in mice. MA treatment (8 mg/kg, i.p., × 4; 2 h interval) significantly enhanced the level of phosphorylated PKCδ in the striatum of wild type (WT) mice. Subsequently, treatment with MA resulted in significant increases in the expression of cleaved PKCδ and mEH. Treatment with MA resulted in enhanced interaction between PKCδ and mEH. PKCδ 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 PKCδ knockout or mEH knockout in mice. However, treating mEH knockout in mice with PKCδ inhibitor, rottlerin did not show any additive beneficial effects, indicating that mEH is a critical mediator of neurotoxic potential of PKCδ. Our results suggest that MA-induced PKCδ activation requires mEH induction as a downstream signaling pathway and that the modulation of the PKCδ and mEH interaction is important for the pharmacological intervention against MA-induced dopaminergic neurotoxicity.

Topics: Acetophenones; Animals; Benzopyrans; Dopaminergic Neurons; Epoxide Hydrolases; Fever; Gene Knockout Techniques; Locomotion; Methamphetamine; Mice, Inbred C57BL; Mice, Knockout; Neurotoxicity Syndromes; Oxidative Stress; Protein Kinase C-delta