PP2 and piceatannol inhibit PrP106-126-induced iNOS activation mediated by CD36 in BV2 microglia

Prion diseases are a group of transmissible fatal neurodegen- erative disorders of humans and animals, including bovine spongiform encephalopathy, scrapie, and Creutzfeldt- Jakob disease. Microglia, the resident macrophages of the central nervous system, are exquisitely sensitive to patho- logical tissue alterations, altering their morphology and phenotype to adopt a so-called activated state and perform immunological functions in response to pathophysiological brain insults. Although recent findings have provided valu- able insights into the role microglia play in the proinflamma- tory events observed in prion, the intracellular signaling molecules responsible for the initiation of these responses remain to be elucidated. It seems that microglial activation involve PrP106-126 binding and the activation of cell surface immune and adhesion molecules such as CD36 and integ- rins, with the subsequent recruitment of Src family tyrosine kinases such as Fyn, Lyn, and Syk kinases. In the present study, we show that CD36 is involved in PrP106-126-induced microglial activation and that PP2 and piceatannol （Pic） can abrogate neurotoxic prion peptides-induced inducible nitric oxide synthase activation in microglia. These findings unveil a previously unrecognized role of PP2 and Pic as Src family kinase Fyn and the tyrosine kinase Syk inhibitor involved in neurotoxic prion peptides-microglia interactions, thus pro- viding new insights into mechanisms underlying the activa- tion of microgiia by neurotoxic prion peptides.