Critical interplay between PAF receptor and PKCδ is involved in dopaminergic insult evoked by methamphetamine in mice

Abstract

Methamphetamine (MA)-induced neurodegeneration has been reported to resemble behavioral and neurochemical changes in patients with Parkinson's disease. Although it is recognized that platelet-activating factor receptor (PAFR) is involved in the neurodegenerative change, little is known about the role of PAFR in the MA-induced neurodegeneration. Thus, we investigated the mechanistic role of PAFR in MA-induced neurodegeneration. Simultaneously, we asked whether PAFR can interplay with another inflammatory/proapoptotic factor protein kinase Cδ (PKCδ). A single dose of MA (35 mg/kg, i.p.) caused significant increases in PAFR and phospho-protein kinase Cδ (p-PKCδ) expression in the striatum of wild-type mice. MA also increased the interaction between PAFR and p-PKCδ, as assessed by co-immunoprecipitation. Furthermore, triple labelling immunocytochemical analysis showed that PAFR-immunoreactivity (IR) and p-PKCδ-IR were localized in the same Iba-1-labeled microglial cells, suggesting that they express PAFR and PKCδ. Consistently, rottlerin, a PKCδ inhibitor or ginkgolide B, a PAFR inhibitor significantly attenuated MA-induced pro-apoptotic changes (i.e., TUNEL-positive cells and cleaved caspase-3/Bax expression) in Taconic ICR mice. Genetic and pharmacological inhibition of PAFR or PKCδ reduced the MA-caused dopaminergic degenerative effects (i.e., a decrease in tyrosine hydroxylase expression, an increase in dopamine turnover rate, microgliosis, and behavioral impairments), suggesting that PAFR and PKCδ mediate dopaminergic neurodegeneration. MA-induced increases in PAFR and p-PKCδ were attenuated by rottlerin or PKCδ gene knockout. However, ginkgolide B or PAFR gene knockout failed to affect the increase in p-PKCδ expression after MA treatment. Therefore, we suggest that PKCδ is an upstream molecule that increases PAFR for activating the morbid signaling cascade induced by MA.