Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms
Jeimy Katherine Torres-Méndez, Julia Niño-Narvión, Patricia Martinez-Santos, Elena María Goretti Diarte-Añazco, Karen Alejandra Méndez‐Lara, Tania Vázquez del Olmo, Noemí Rotllán, María Teresa Julián, Núria Alonso, Dı́dac Mauricio, Mercedes Camacho, Juan Pablo Muñoz, Joana Rossell, Josep Julve
Abstract
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.