Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization

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.

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

“…Studies in animals and humans have shown that a significant rise in peripheral and brain inflammation signals exists following the chronic intake of most drugs of abuse [56][57][58][59]. The activation of microglia and/or astrocytes has been shown in animal models of every drug studied including amphetamines [60,61], cocaine [62], ethanol [63][64][65][66], opioids [67], cannabinoids [68,69], and nicotine [65,66]. Interestingly, though the different drugs of abuse exert different mechanisms to promote the release of dopamine in nucleus accumbens, and motivate consumption (Table 1), they exert similar mechanisms to increase both brain oxidative stress and neuroinflammation.…”

The Main Molecular Mechanisms Underlying Methamphetamine- Induced Neurotoxicity and Implications for Pharmacological Treatment

“…The underlying mechanism of microglial activation induced by METH is related to the Toll-like receptor 4 (TLR4) located on microglia, which is involved in the immune surveillance of pathogens and exogenous small molecules ( Bachtell et al, 2015 ). Activation of microglia may also be mediated through the sigma-1 receptor, which involves ROS generation and activation of the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways in the neurotoxicity of METH ( Chao et al, 2017 ).…”

Sigma-1 Receptor-Modulated Neuroinflammation in Neurological Diseases

“…Evidence shows that Sig-1R may regulate microglia polarization. Chao reported that pretreating BV-2 cells with the Sig-1R antagonist BD1047 significantly reduced the methamphetamine-induced increased the ratio of M1 marker (iNOS) and M2 marker (Chao et al, 2017 ). An in vitro study shows that Sig-1Rs stimulation suppressed the morphological, migratory and the inflammatory responses of microglia to LPS (Hall et al, 2009 ).…”