Protective effect and mechanism of nicotinamide adenine dinucleotide against optic neuritis in mice with experimental autoimmune encephalomyelitis.

Patients with multiple sclerosis (MS) are commonly accompanied by optic neuritis (ON) that causes retinal ganglion cell (RGC) death and even vision loss. Nicotinamide adenine dinucleotide (NAD+) can protect against cell apoptosis and attenuate MS-triggered symptoms. However, the effect of NAD+ on MS-triggered ON remains unclear. Herein, experimental autoimmune encephalomyelitis (EAE) was established by immunizing female C57BL/6 mice with MOG35-55 peptide. To investigate the effect of NAD+ on ON prevention and treatment, EAE mice received 250 mg/kg NAD+ daily via intraperitoneal injection after immunization and EAE onset, respectively. EX-527 (10 mg/kg, SIRT1 inhibitor) was intraperitoneally injected every two days to explore the role of SIRT1 in NAD+-induced therapeutic effect on EAE. NAD+ intervention attenuated the severity of EAE in mice. NAD+ intervention relieved inflammatory infiltration and CD3+ and CD4+ cell infiltration and decreased the number and activation of microglia and astrocytes in the optic nerve. NAD+ intervention also attenuated demyelination, axonal loss, oligodendrocyte apoptosis and oligodendrocyte progenitor cell recruitment and proliferation in the optic nerve and protected against RGC apoptosis in the retina. NAD+ intervention decreased pro-inflammatory cytokine mRNA and pro-apoptotic protein expression and enhanced anti-inflammatory cytokine mRNA expression and the SIRT1 signaling in the optic nerve and retina and regulated the Th1/Th17/Tregs immune response in the spleen. In addition, EX-527 reversed the therapeutic effect of NAD+ on EAE, suggesting that NAD+ prevented MS-triggered ON by activating the SIRT1 signaling pathway. This study shows the potential of NAD+ to be used as a drug in preventing and treating MS-related ON.