TY - JOUR
T1 - NLRP3 Inflammasome Blockade Reduces Cocaine-Induced Microglial Activation and Neuroinflammation
AU - Chivero, Ernest T.
AU - Thangaraj, Annadurai
AU - Tripathi, Ashutosh
AU - Periyasamy, Palsamy
AU - Guo, Minglei
AU - Buch, Shilpa
N1 - Funding Information:
We thank the Douglas-Bell Canada Brain Bank (DBCBB) for providing the postmortem brain samples of cocaine abusers and controls. The DBCBB is supported by the Quebec Suicide Research Network of the Fonds de Recherche du Quebec - Sante (FRQS) and by the Douglas Institute Foundation. We are grateful to Natasha K. Ferguson, Maria E. Burkovetskaya, Fang Niu, and Shannon Callen for technical assistance.
Funding Information:
This work was supported by NIH grant R01DA050545 (SB & MG), R01DA050545-02S1 (PI: SB & ETC as Research Supplement recipient), R21DA046831 (ETC), R01DA047156 (MG & SB) and the Nebraska Centre for Substance Abuse Research (NCSAR).
Funding Information:
We thank the Douglas-Bell Canada Brain Bank (DBCBB) for providing the postmortem brain samples of cocaine abusers and controls. The DBCBB is supported by the Quebec Suicide Research Network of the Fonds de Recherche du Quebec - Sante (FRQS) and by the Douglas Institute Foundation. We are grateful to Natasha K. Ferguson, Maria E. Burkovetskaya, Fang Niu, and Shannon Callen for technical assistance.
Publisher Copyright:
© 2021, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - Cocaine
KW - IL-1β
KW - MCC950
KW - NLRP3
KW - Reactive oxygen species
KW - Tempol
UR - http://www.scopus.com/inward/record.url?scp=85099113132&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099113132&partnerID=8YFLogxK
U2 - 10.1007/s12035-020-02184-x
DO - 10.1007/s12035-020-02184-x
M3 - Article
C2 - 33417223
AN - SCOPUS:85099113132
VL - 58
SP - 2215
EP - 2230
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
IS - 5
ER -