2. Academic Validation
  3. The NRF2 activator RTA-408 ameliorates chronic alcohol exposure-induced cognitive impairment and NLRP3 inflammasome activation by modulating impaired mitophagy initiation

The NRF2 activator RTA-408 ameliorates chronic alcohol exposure-induced cognitive impairment and NLRP3 inflammasome activation by modulating impaired mitophagy initiation

  • Free Radic Biol Med. 2024 Apr 26:220:15-27. doi: 10.1016/j.freeradbiomed.2024.04.236.
Xinrou Lin 1,  Hongxuan Wang 2,  Lubin Zou 1,  Biying Yang 3,  Wanru Chen 2,  Xiaoming Rong 2,  Xiaoni Zhang 2,  Lei He 2,  Xiangpen Li 4,  Ying Peng 5
Affiliations

Affiliations

  • 1 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510000, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China.
  • 2 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510000, China.
  • 3 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510000, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
  • 4 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510000, China; Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shanwei, 516400, China. Electronic address: lixiangp@mail.sysu.edu.cn.
  • 5 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510000, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510000, China. Electronic address: pengy2@mail.sysu.edu.cn.
PMID: 38679301 DOI: 10.1016/j.freeradbiomed.2024.04.236
Abstract

Background: Chronic alcohol exposure induces cognitive impairment and NLRP3 inflammasome activation in the mPFC (medial prefrontal cortex). Mitophagy plays a crucial role in neuroinflammation, and dysregulated Mitophagy is associated with behavioral deficits. However, the potential relationships among Mitophagy, inflammation, and cognitive impairment in the context of alcohol exposure have not yet been studied. NRF2 promotes the process of Mitophagy, while alcohol inhibits NRF2 expression. Whether NRF2 activation can ameliorate defective Mitophagy and neuroinflammation in the presence of alcohol remains unknown.

Methods: BV2 cells and primary microglia were treated with alcohol. C57BL/6J mice were repeatedly administered alcohol intragastrically. BNIP3-siRNA, PINK1-siRNA, CCCP and bafilomycin A1 were used to regulate Mitophagy in BV2 cells. RTA-408 acted as an NRF2 activator. Mitochondrial dysfunction, Mitophagy and NLRP3 inflammasome activation were assayed. Behavioral tests were used to assess cognition.

Results: Chronic alcohol exposure impaired the initiation of both receptor-mediated Mitophagy and PINK1-mediated Mitophagy in the mPFC and in vitro microglial cells. Silencing BNIP3 or PINK1 induced mitochondrial dysfunction and aggravated alcohol-induced NLRP3 inflammasome activation in BV2 cells. In addition, alcohol exposure inhibited the NRF2 expression both in vivo and in vitro. NRF2 activation by RTA-408 ameliorated NLRP3 inflammasome activation and Mitophagy downregulation in microglia, ultimately improving cognitive impairment in the presence of alcohol.

Conclusion: Chronic alcohol exposure-induced impaired Mitophagy initiation contributed to NLRP3 inflammasome activation and cognitive deficits, which could be alleviated by NRF2 activation via RTA-408.

Keywords

Alcohol; Cognitive impairment; Mitophagy; NLRP3; NRF2.

Figures
Products