NLRP3 Inflammasome Blockade Reduces Cocaine-Induced Microglial Activation and Neuroinflammation.

Abstract

Cocaine use disorder is a major health crisis that is associated with increased oxidative stress and neuroinflammation. While the role of NLRP3 inflammasome in mediating neuroinflammation is well-recognized, whether cocaine induces this response remains unexplored. Based on the premise that cocaine induces both reactive oxygen species (ROS) as well as microglial activation, we hypothesized that cocaine-mediated microglial activation involves both ROS and NLRP3 signaling pathways. We examined activation of the NLRP3 pathway in microglia exposed to cocaine, followed by validation in mice administered either cocaine or saline for 7 days, with or without pretreatment with the NLRP3 inhibitor, MCC950, and in postmortem cortical brain tissues of chronic cocaine-dependent humans. We found that microglia exposed to cocaine exhibited significant induction of NLRP3 and mature IL-1β expression. Intriguingly, blockade of ROS (Tempol) attenuated cocaine-mediated priming of NLRP3 and microglial activation (CD11b). Blockade of NLRP3 by both pharmacological (MCC950) as well as gene silencing (siNLRP3) approaches underpinned the critical role of NLRP3 in cocaine-mediated activation of inflammasome and microglial activation. Pretreatment of mice with MCC950 followed by cocaine administration for 7 days mitigated cocaine-mediated upregulation of mature IL-1β and CD11b, in both the striatum and the cortical regions. Furthermore, cortical brain tissues of chronic cocaine-dependent humans also exhibited upregulated expression of the NLRP3 pathway mediators compared with non-cocaine dependent controls. Collectively, these findings suggest that cocaine activates microglia involving the NLRP3 inflammasome pathway, thereby contributing to neuroinflammation. NLRP3 can thus be considered as a potential therapeutic target for alleviating cocaine-mediated neuroinflammation.

• Authors: Ernest T Chivero, Annadurai Thangaraj, Ashutosh Tripathi, Palsamy Periyasamy, Ming-Lei Guo, Shilpa Buch
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 58 Issue 5 Pg. 2215-2230 (May 2021) ISSN: 1559-1182 [Electronic] United States
• PMID: 33417223 (Publication Type: Journal Article)

Chemical References

• Dopamine Uptake Inhibitors
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Caspase 1
• Cocaine

Topics

• Animals
• Caspase 1 (metabolism)
• Cell Line
• Cocaine (pharmacology)
• Dopamine Uptake Inhibitors (pharmacology)
• Frontal Lobe (drug effects, metabolism)
• Humans
• Inflammasomes (drug effects, metabolism)
• Interleukin-1beta (metabolism)
• Mice
• Microglia (drug effects, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)