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Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial
Jie Chao1,2, Yuan Zhang1, Longfei Du1
1Department of Pharmacology, Medical School of Southeast University, Southeast University, Nanjing, China.
Abstract:
Our previous study demonstrated that the sigma-1 receptor is involved in methamphetamine-induced microglial apoptosis and death; however, whether the sigma-1 receptor is involved in microglial activation as well as the molecular mechanisms underlying this process remains poorly understood. The aim of this study is to demonstrate the involvement of the sigma-1 receptor in methamphetamine-mediated microglial activation. The expression of σ-1R, iNOS, arginase and SOCS was examined by Western blot; activation of cell signaling pathways was detected by Western blot analysis. The role of σ-1R in microglial activation was further validated in C57BL/6 N WT and sigma-1 receptor knockout mice (male, 6-8 weeks) injected intraperitoneally with saline or methamphetamine (30 mg/kg) by Western blot combined with immunostaining specific for Iba-1. Treatment of cells with methamphetamine (150 μM) induced the expression of M1 markers (iNOS) with concomitant decreased the expression of M2 markers (Arginase) via its cognate sigma-1 receptor followed by ROS generation. Sequential activation of the downstream MAPK, Akt and STAT3 pathways resulted in microglial polarization. Blockade of sigma-1 receptor significantly inhibited the generation of ROS and activation of the MAPK and Akt pathways. These findings underscore the critical role of the sigma-1 receptor in methamphetamine-induced microglial activation.
Insights
The sigma-1 receptor drives methamphetamine-induced microglial activation by promoting M1 polarization through ROS generation and MAPK/Akt/STAT3 pathway activation. Blocking this receptor inhibits these effects, highlighting its critical role.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Previous research linked the sigma-1 receptor to methamphetamine-induced microglial apoptosis.
- The role of the sigma-1 receptor in microglial activation and its underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the sigma-1 receptor's involvement in methamphetamine-mediated microglial activation.
- To elucidate the molecular mechanisms by which the sigma-1 receptor influences microglial activation.
Main Methods:
- Western blot analysis to assess the expression of sigma-1 receptor (σ-1R), iNOS, arginase, and SOCS.
- Detection of cell signaling pathway activation (MAPK, Akt, STAT3) using Western blot.
- Validation in wild-type and sigma-1 receptor knockout mice using Western blot and Iba-1 immunostaining.
Main Results:
- Methamphetamine treatment increased M1 marker (iNOS) and decreased M2 marker (Arginase) expression via the sigma-1 receptor, leading to ROS generation.
- Activation of MAPK, Akt, and STAT3 pathways sequentially occurred, resulting in microglial polarization.
- Sigma-1 receptor blockade significantly reduced ROS generation and the activation of MAPK and Akt pathways.
Conclusions:
- The sigma-1 receptor plays a critical role in methamphetamine-induced microglial activation.
- Methamphetamine-induced microglial polarization is mediated by the sigma-1 receptor through ROS generation and downstream signaling pathways.
- Targeting the sigma-1 receptor may offer a therapeutic strategy for methamphetamine-induced neuroinflammation.
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