The role of overdose folic acid in promoting neuroinflammation, oxidative stress, and apoptosis in SOD1-G93A mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that involves the targeted degeneration of motor neurons. The precise pathogenetic mechanisms are still largely unclear. In this study, we utilized the SOD1-G93A mouse model of ALS to investigate the effects of folic acid (FA), an important factor involved in homocysteine metabolism. Our results indicated that a little FA prolonged the lifespan of the SOD1-G93A mice and medium and high-dose FA significantly shortened the lifespan of the SOD1-G93A mice. Furthermore, we observed that an overdose of FA significantly elevated inflammation levels in the cerebellum, as evidenced by increased concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cluster of differentiation 68 (CD68), cluster of differentiation 86 (CD86), and monocyte chemoattractant protein-1 (MCP-1), facilitating microglial activation. The low-dose FA effects were the opposite of the overdose FA. Additionally, high-dose FA increased the levels of phosphorylated p65 (p-p65)/p65, thereby promoting the NF-κB signaling pathway. Conversely, high-dose FA inhibited the expression of total superoxide dismutase (T-SOD) while increasing the level of malondialdehyde (MDA) in the cerebellum; these effects were not observed in muscle tissue. Moreover, high-dose FA elevated the levels of Bax2/Bcl-2. Concurrently, high-dose FA induced increased apoptosis in SOD1-G93A mice, as demonstrated by TUNEL staining. Notably, the brain iron content of SOD1-G93A mice remained unchanged following FA treatment. These findings provide evidence that an overdose of FA supplementation may exert pro-inflammatory effects by promoting the NF-κB pathway, oxidative stress, and apoptosis in the context of ALS.