Neuroprotective effects of trilobatin, a novel naturally-occurring Sirt3 agonist from Lithocarpus polystachyus Rehd., mitigates cerebral ischemia/reperfusion injury: Involvement of TLR4/NF-κB and Nrf2/ Keap-1 signaling.

Neuroinflammation and oxidative stress are deemed the prime causes of brain injury after cerebral ischemia-reperfusion (I/R). Since Sirt3 pathway plays an imperative role in protecting against neuroinflammation and oxidative stress and has been verified as a target to treat ischemia stroke. Therefore, we desired to seek novel Sirt3 agonist and explore its underlying mechanism for stroke treatment both in vivo and in vitro.Trilobatin (TLB) not only dramatically suppressed neuroinflammation and oxidative stress injury after middle cerebral artery occlusion (MCAO) in rats, but also effectively mitigated oxygen and glucose deprivation/reoxygenation (OGD/R) injury in primary cultured astrocytes. These beneficial effects along with reduced pro-inflammatory cytokines via suppressing TLR4 signaling pathway, as well as lessened oxdative injury via activating Nrf2 signaling pathways, in keeping with the findings in vivo. Intriguingly, the TLB-mediated neuroprotection on cerebral I/R injury was modulated by reciprocity between TLR4-mediated neuroinflammatory responses and Nrf2 antioxidant responses as evidenced by molecular docking and silencing TLR4 and Nrf2, respectively. Most importantly, TLB not only directly bond to Sirt3, but also, increased Sirt3 expression and activity, indicating that Sirt3 might be a promising therapeutic target of TLB.TLB is a naturally-occurring Sirt3 agonist with potent neuroprotective effects both in vivo and in vitro, via regulation of TLR4/NF-κB and Nrf2/Keap-1 signaling pathways.Our findings indicate that TLB protects against cerebral I/R-induced neuroinflammation and oxidative injury through the regulation of neuroinflammatory and oxidative responses via TLR4, Nrf2 and Sirt3, suggesting TLB might be a promising Sirt3 agonist against ischemic stroke.