A novel nuclear factor erythroid 2-related factor 2 (Nrf2) activator RS9 attenuates brain injury after ischemia reperfusion in mice. (1st October 2016)

• Record Type: Journal Article
• Authors: Yamauchi, Keita; Nakano, Yusuke; Imai, Takahiko; Takagi, Toshinori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Iwama, Toru; Hara, Hideaki
• Is Part Of: Neuroscience. Volume 333(2016)
• Page Start: 302
• Page End: 310
• Publication Date: 2016-10-01
• Subjects: ANOVA analysis of variance -- AREs antioxidant-response elements -- BARD bardoxolone methyl -- CCA common carotid artery -- HO-1 heme oxygenase-1 -- IRI ischemia–reperfusion injury -- Keap-1 Kelch-like ECH-associated protein 1 -- MCAO middle cerebral artery occlusion -- NF-κB nuclear factor-kappa B -- NQO-1 NADPH quinone oxidoreductase-1 -- Nrf2 nuclear factor erythroid 2-related factor 2 -- PBS phosphate-buffered saline -- ROS reactive oxygen species -- rt-PA recombinant tissue plasminogen activator -- TNF-α tumor necrosis factor-α -- TTC 2, 3, 5-triphenyltetrazolium chloride -- TTW therapeutic time window; heme oxygenase-1 -- ischemia reperfusion injury -- nuclear factor erythroid 2-related factor 2 -- nuclear factor-kappa B -- oxidative stress; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2016.07.035
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: A novel Nrf2 activator, RS9, protected the brain from ischemia–reperfusion injury. The efficacy of post-onset treatment is because of rapid Nrf2 activation by RS9. RS9 attenuated not only oxidative stress but also neuroinflammation. RS9 protected the brain in both the acute and sub-acute phase of ischemia. Abstract: Recanalization of occluded vessels leads to ischemia–reperfusion injury (IRI), with oxidative stress as one of the main causes of injury, despite the fact that recanalization therapy is the most effective treatment for ischemic stroke. The nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the transcription factors which has an essential role in protection against oxidative stress. RS9 is a novel Nrf2 activator obtained from bardoxolone methyl (BARD), an Nrf2 activator that has already been tested in a clinical trial, using a biotransformation technique. RS9 has been reported to lead to higher Nrf2 activation and less cytotoxicity than BARD. In this study, we investigated the effects of RS9 on IRI. Mice were intraperitoneally treated immediately after 2 h of transient middle cerebral artery occlusion (MCAO) with a vehicle solution or 0.2 mg/kg of RS9. Post-onset treatment of RS9 attenuated the infarct volume and improved neurological deficits 22 h after reperfusion. RS9 activated Nrf2 2 and 6 h after reperfusion and activated heme oxygenase-1 at 6 and 22 h after reperfusion. RS9 also attenuated the phosphorylation of NF-κB p65 2 and 6 h after reperfusion. Finally, RS9 improved the survival rate and neurological deficits 7 days after MCAO. Our results suggest that the activation of Nrf2 by RS9 has a neuroprotective effect, mediated by attenuating both oxidative stress and neuroinflammation, and that RS9 is an effective therapeutic candidate for the treatment of IRI.