Astrocyte-Derived Lipocalin-2 Is Involved in Mitochondrion-Related Neuronal Apoptosis Induced by Methamphetamine

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 mitochondrion-related neuronal apoptosis.