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Methamphetamine exposure induces neuronal programmed necrosis by activating the receptor‐interacting protein kinase 3 ‐related signalling pathway
Author(s) -
Zhao Xu,
Lu Jiancong,
Chen Xuebing,
Gao Zhengxiang,
Zhang Cui,
Chen Chuanxiang,
Qiao Dongfang,
Wang Huijun
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100188r
Subject(s) - meth , methamphetamine , neurotoxicity , programmed cell death , necrosis , microbiology and biotechnology , protein kinase a , necroptosis , biology , kinase , apoptosis , chemistry , pharmacology , biochemistry , toxicity , genetics , monomer , organic chemistry , acrylate , polymer
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.