Nicotinamide reverses deficits in puberty-born neurons and cognitive function after maternal separation

• Published in: Journal of neuroinflammation 2022-09, Vol.19 (1), p.1-232, Article 232
• Main Authors: Hao, Keke, Wang, Huiling, Zhang, Yuejin, Xie, Xinhui, Huang, Huan, Chen, Cheng, Xu, Shilin, Xu, Rui, Shu, Chang, Liu, Zhongchun, Zhou, Yuan, Reynolds, Gavin P, Wang, Gaohua
• Format: Article
• Language: English
• Subjects: Adolescence; Adolescents; Animal cognition; Animal models; Behavior; Child development; Children; Cognitive ability; Cognitive impairment; Cytokines; Development and progression; Early life stress; Estrogens; Experiments; Females; Health aspects; Hippocampus; IL-1β; Immunofluorescence; Inflammation; Interleukin 6; Laboratory animals; Maternal separation; Mental disorders; Metabolism; Mother and child; NAD; Neurogenesis; Neuroinflammation; Neuronal loss; Neurons; Niacinamide; Phenotypes; Psychological aspects; Puberty; Recovery of function; Risk factors; Rodents; Schizophrenia; Superoxide dismutase; Tumor necrosis factor-α; Western blotting
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-022-02591-y

Background Early life stress (ELS) is associated with the development of schizophrenia later in life. The hippocampus develops significantly during childhood and is extremely reactive to stress. In rodent models, ELS can induce neuroinflammation, hippocampal neuronal loss, and schizophrenia-like behavior. While nicotinamide (NAM) can inhibit microglial inflammation, it is unknown whether NAM treatment during adolescence reduces hippocampal neuronal loss and abnormal behaviors induced by ELS. Methods Twenty-four hours of maternal separation (MS) of Wistar rat pups on post-natal day (PND)9 was used as an ELS. On PND35, animals received a single intraperitoneal injection of BrdU to label dividing neurons and were given NAM from PND35 to PND65. Behavioral testing was performed. Western blotting and immunofluorescence staining were used to detect nicotinamide adenine dinucleotide (NAD.sup.+)/Sirtuin3 (Sirt3)/superoxide dismutase 2 (SOD2) pathway-related proteins. Results Compared with controls, only MS animals in the adult stage (PND56-65) but not the adolescent stage (PND31-40) exhibited pre-pulse inhibition deficits and cognitive impairments mimicking schizophrenia symptoms. MS decreased the survival and activity of puberty-born neurons and hippocampal NAD.sup.+ and Sirt3 expression in adulthood. These observations were related to an increase in acetylated SOD2, microglial activation, and significant increases in pro-inflammatory IL-1[beta], TNF-[alpha], and IL-6 expression. All the effects of MS at PND9 were reversed by administering NAM in adolescence (PND35-65). Conclusions MS may lead to schizophrenia-like phenotypes and persistent hippocampal abnormalities. NAM may be a safe and effective treatment in adolescence to restore normal hippocampal function and prevent or ameliorate schizophrenia-like behavior. Keywords: Schizophrenia, Early life stress, Maternal separation, Cognitive impairment, Neuroinflammation, Neuronal loss, Nicotinamide, Sirt3