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Astrocyte-Derived Lipocalin-2 Is Involved in Mitochondrion-Related Neuronal Apoptosis Induced by Methamphetamine
Xuebing Chen1, Feng Qiu2, Xu Zhao1
1School of Forensic Medicine, Southern Medical University, Guangzhou 510515, China.
Abstract:
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.
Insights
Methamphetamine (METH) neurotoxicity involves astrocyte-derived Lipocalin-2 (LCN2). Inhibiting LCN2 or its receptor (LCN2R) protects neurons from METH-induced cell death, suggesting a novel therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Methamphetamine (METH) is a potent psychoactive stimulant linked to significant neurotoxicity and addiction.
- Lipocalin-2 (LCN2) is implicated in adult brain cell death, but its specific role in METH neurotoxicity was previously unknown.
Purpose of the Study:
- To investigate the role of Lipocalin-2 (LCN2) in methamphetamine-induced neurotoxicity.
- To elucidate the cellular mechanisms and pathways involved in LCN2-mediated neuronal apoptosis.
Main Methods:
- Examined LCN2 expression in hippocampal astrocytes following METH exposure.
- Utilized recombinant LCN2 (Re LCN2) to induce apoptosis in vitro and in vivo.
- Assessed the effects of inhibiting LCN2 and its receptor (LCN2R) on neuronal apoptosis.
- Investigated the involvement of reactive oxygen species (ROS) and the PERK signaling pathway.
- Measured LCN2 levels in serum and cerebrospinal fluid (CSF) of METH-exposed subjects.
Main Results:
- LCN2 expression was significantly upregulated in hippocampal astrocytes after METH exposure.
- Recombinant LCN2 induced neuronal apoptosis both in vitro and in vivo.
- Inhibition of LCN2 and LCN2R attenuated METH- and Re LCN2-induced mitochondrion-related neuronal apoptosis.
- Astrocyte-derived LCN2 upregulation was linked to ROS generation and the PERK signaling pathway.
- Elevated LCN2 levels were observed in serum and CSF following METH exposure.
Conclusions:
- Astrocyte-derived LCN2 plays a critical role in METH-induced mitochondrion-related neuronal apoptosis.
- The LCN2-LCN2R axis is a key mediator of METH neurotoxicity.
- Targeting the LCN2 pathway presents a potential therapeutic strategy for METH abuse and neurotoxicity.
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