Methamphetamine (METH) is a widely abused and highly addictive psychoactive stimulant that can induce neuronal apoptosis. Lipocalin-2 (LCN2) is a member of the lipocalin family, and its upregulation is involved in cell death in the adult brain. However, the role of LCN2 in METH-induced neurotoxicity has not been reported. In this study, we found that LCN2 was predominantly expressed in hippocampal astrocytes after METH exposure and that recombinant LCN2 (Re LCN2) can induce neuronal apoptosis in vitro and in vivo. The inhibition of LCN2 and LCN2R, a cell surface receptor for LCN2, reduced METH-and Re LCN2-induced mitochondrion-related neuronal apoptosis in cultures of primary rat neurons and animal models. Our study supports the role of reactive oxygen species (ROS) generation and the PRKR-like ER kinase (PERK)-mediated signaling pathway in the upregulation of astrocyte-derived LCN2 after METH exposure. Additionally, the serum and cerebrospinal fluid (CSF) levels of LCN2 were significantly upregulated after METH exposure. These results indicate that upregulation of astrocyte-derived LCN2 binding to LCN2R is involved in METH-induced mitochondrionrelated neuronal apoptosis.
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 METHinduced 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.
K E Y W O R D Sdynamin-related protein 1, methamphetamine, mixed lineage kinase domain-like protein, programmed necrosis, the receptor-interacting protein kinase 3The shRNA synthesis and stereotaxic injection protocol was based on our recent previous studies. 8,9,45 A short
Methamphetamine (MA) is a widely abused psychoactive drug that primarily damages the nervous system. However, the involvement of MA in the survival of microglia remains poorly understood. CCAAT-enhancer binding protein (C/EBP-β) is a transcription factor and an important regulator of cell apoptosis. Lipocalin2 (lcn2) is a known apoptosis inducer and is involved in many cell death processes. We hypothesized that C/EBP-β is involved in MA-induced lcn2-mediated microglial apoptosis. To test this hypothesis, we measured the protein expression of C/EBP-β after MA treatment and evaluated the effects of silencing C/EBP-β or lcn2 on MA-induced apoptosis in BV-2 cells and the mouse striatum after intrastriatal MA injection. MA exposure increased the expression of C/EBP-β and stimulated the lcn2-mediated modulation of apoptosis. Moreover, silencing the C/EBP-β-dependent lcn2 upregulation reversed the MA-induced microglial apoptosis. The
in vivo
relevance of these findings was confirmed in mouse models, which demonstrated that the microinjection of anti-C/EBP-β into the striatum ameliorated the MA-induced decrease survival of microglia. These findings provide a new insight regarding the specific contributions of C/EBP-β-lcn2 to microglial survival in the context of MA abuse.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.