β-Nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice

Abstract

Sepsis-associated encephalopathy (SAE) is one of the common serious complications in sepsis, and the pathogenesis of SAE remains unclear. Sirtuin 1 (SIRT1) has been reported to be downregulated in the hippocampus and SIRT1 agonists can attenuated the cognitive dysfunction in septic mice. Nicotinamide adenine dinucleotide (NAD+) is a key substrate to maintain the deacetylation activity of SIRT1. As an intermediate of NAD+, β-Nicotinamide Mononucleotide (NMN) has been reported to be promising in treating neurodegenerative diseases and cerebral ischemic injury. Thus we sought to investigate the potential role of NMN in SAE treatment. The SAE model was established by cecal ligation and puncture (CLP) in vivo, and neuroinflammation model was established with LPS-treated BV-2 cells in vitro. Memory impairment was assessed by Morris water maze and fear conditioning tests. As a result, the levels of NAD+, SIRT1 and PGC-1α were significantly reduced in the hippocampus of septic mice, while the acetylation of total lysine, phosphorylation of P38 and P65 were enhanced. All these changes induced by sepsis were inverted by NMN. Treating with NMN resulted in improved behavior performance in the fear conditioning tests and Morris water maze. Apoptosis, inflammatory and oxidative responses in the hippocampus of septic mice were attenuated significantly after NMN administration. These protective effect of NMN against memory dysfunction, inflammatory and oxidative injuries were reversed by the SIRT1 inhibitor, EX-527. Similarly, LPS-induced activation of BV-2 cells were attenuated by NMN, EX-527 or SIRT1 knockdown could reverse such effect of NMN in vitro. In conclusion, NMN is protective against sepsis-induced memory dysfunction, and the inflammatory and oxidative injuries in the hippocampus region of septic mice. The NAD+/SIRT1 pathway might be involved in one of the mechanisms of the protective effect.