Nrf2/antioxidant defense pathway is involved in the neuroprotective effects of Sirt1 against focal cerebral ischemia in rats after hyperbaric oxygen preconditioning

• Published in: Behavioural brain research Vol. 309; pp. 1 - 8
• Main Authors: Xue, Fen, Huang, Jin-wen, Ding, Pei-yan, Zang, Hong-gang, Kou, Zhi-jian, Li, Ting, Fan, Juan, Peng, Zheng-wu, Yan, Wen-jun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-08-2016
• Subjects: Animals; Antioxidants - metabolism; Brain - blood supply; Brain - metabolism; Brain - pathology; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - therapy; Disease Models, Animal; HBO-PC; Heme Oxygenase-1 - metabolism; Hyperbaric Oxygenation; Ischemic Preconditioning; Malondialdehyde - metabolism; MCAO; Neuroprotection; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative stress; Oxidative Stress - physiology; Random Allocation; Rats, Sprague-Dawley; RNA, Small Interfering; Signal Transduction; Sirt1; Sirtuin 1 - antagonists & inhibitors; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Superoxide Dismutase-1 - metabolism; MCAO; Oxidative stress; eNOS; tPA; HBO-PC; HO-1; siRNA; PGC-1α; MDA; HT; FOXOs; SOD1; Nrf2; ROS; Sirt1
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2016.04.045

•HBO-PC reduced infarct volume ratio and neurobehavioral deficit in MCAO rats.•It also increased the expression of Sirt1 and Nrf2/antioxidant defense pathway.•The neuroprotective effects of HBO-PC were inhibited by Sirt1 or Nrf2 siRNA.•Sirt1 siRNA inhibited Nrf2 expression, but Nrf2 siRNA had no effect on Sirt1 expression.•The findings suggest possible therapeutic avenues in cases of cerebral ischemia.
Sirtuin 1 (Sirt1) is a class III histone deacetylase involved in neuroprotection induced by hyperbaric oxygen preconditioning (HBO-PC) in animal models of ischemia. However, the underlying mechanisms remain to be illustrated. In the present study, rats exposed to middle cerebral artery occlusion (MCAO) were used to establish an ischemic stroke model. The infarct volume ratio, neurobehavioral score, and expressions of Sirt1, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and superoxide dismutase 1 (SOD1) were evaluated at 7 days after reperfusion, and the level of malondialdehyde (MDA) was used to assess oxidative stress. HBO-PC increased the expression of Sirt1 and reduced infarct volume ratio and neurobehavioral deficit in MCAO rats. Meanwhile, HBO-PC also increased expression of Nrf2, HO-1, and SOD1 and decreased MDA content. Furthermore, either Sirt1 or Nrf2 knockdown by short interfering RNA (siRNA) inhibited the expression of Nrf2, HO-1, and SOD1 and eliminated the neuroprotective effects of HBO-PC. Taken together, the results suggest that the Nrf2/antioxidant defense pathway is involved in the long lasting neuroprotective effects of Sirt1 induced by HBO-PC against transient focal cerebral ischemia.