Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms

This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNFα: NAM LD: −35%; NAM HD: −46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: −29%; NAM HD: −50%; p-value < 0.05; BDKRB1: NAM LD: −36%; NAM HD: −37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFκB (p65) signaling in treated diabetic mice (NFκB (p65): NAM LD: −38%; NAM HD: −53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFκB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: −48%; NAM HD: −63%, p-value < 0.05) and inversely correlated with NAD+ content (r = −0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling.