Methamphetamine exposure induces neuronal programmed necrosis by activating the receptor-interacting protein kinase 3 -related signalling pathway.

Abstract

Methamphetamine (METH) is a synthetic drug with severe neurotoxicity, however, the regulation of METH-induced neuronal programmed necrosis remains poorly understood. The aim of this study was to identify the molecular mechanisms of METH-induced neuronal programmed necrosis. We found that neuronal programmed necrosis occurred in the striatum of brain samples from human and mice that were exposed to METH. The receptor-interacting protein kinase 3 (RIP3) was highly expressed in the neurons of human and mice exposed to METH, and RIP3-silenced or RIP1-inhibited protected neurons developed neuronal programmed necrosis in vitro and in vivo following METH exposure. Moreover, the RIP1-RIP3 complex causes cell programmed necrosis by regulating mixed lineage kinase domain-like protein (MLKL)-mediated cell membrane rupture and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Together, these data indicate that RIP3 plays an indispensable role in the mechanism of METH-induced neuronal programmed necrosis, which may represent a potential therapeutic target for METH-induced neurotoxicity.