• Tanzhen Xu, Lingling Sun, Xiaoyan Shen, Yali Chen, Yanyan Yin, Junyan Zhang, Dake Huang, Weiping Li, and Weizu Li.
• Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China.
• Int. Immunopharmacol. 2019 Apr 1; 69: 60-70.

AbstractOxidative stress and inflammation are closely related to neuron ageing. NADPH oxidase 2 (NOX2) is a major source of reactive oxygen species (ROS) generation in brain. The nucleotide-binding oligomerisation domain (NOD)-like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of proinflammatory molecules in neurons. We hypothesize that NOX2-derived ROS accumulation mediates activation of NLRP1 inflammasome, which is involved in age-related neuronal damage. In the present study, we investigated the changes of NOX2-NLRP1 signaling pathway in primary hippocampal neurons cultured for different time (6, 9 and 12 days, d). Meanwhile, we further examined the effect of ROS inhibitor and NLRP1-siRNA on neuronal senescence. The results showed that, compared with 6 d group, the neuronal apoptosis and β-Galactosidase (β-Gal) expression were significantly increased, and the microtubule-associated protein 2 (MAP2) expression significantly decreased in primary hippocampal neurons cultured for 12 d. In addition, the results also showed that the production of ROS, the expressions of NOX2 and NLRP1 inflammasome were significantly increased with the prolongation of culture time in hippocampal neurons. Moreover, the NOX inhibitor (apocynin) and ROS scavenger (tempol) significantly decreased ROS production and alleviated neuronal damage. Meanwhile, the tempol and apocynin treatment significantly decreased the expression of NLRP1 inflammasome in hippocampal neurons. Furthermore, the NLRP1-siRNA and caspase-1 inhibitor treatment also alleviated neuronal damage. These results suggest that NOX2-derived ROS generation may induce brain inflammation via NLRP-1 inflammasome activation and lead to age-related neuronal damage. The NADPH oxidase and NLRP1 inflammasome may be important therapeutic targets for age-related neuronal damage.Copyright © 2019 Elsevier B.V. All rights reserved.

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