Aerobic Exercise Modulates RIPK1-mediated MAP3K5/JNK and NF-κB Pathways to Suppress Microglia Activation and Neuroinflammation in the Hippocampus of D-gal-Induced Accelerated Aging mice

Microglia activation-induced neuroinflammation is a risk factor for cognitive dysfunction in the hippocampus during the early stages of neurodegenerative diseases. Exercise is an intrinsic remedy that plays a crucial role in enhancing the survival of neurons and reducing neuroinflammation in the brain. Among these theories, alterations in intracellular signaling pathways associated with neuronal growth and inflammation have been emphasized. Based on these observations and recent evidence demonstrating the beneficial effects of exercise on suppressing brain inflammation in the elderly, we examined cellular signaling pathways in the hippocampal formation of D-galactose-induced accelerated aging mice that underwent 8 weeks of treadmill exercise. To accomplish this, we utilized immunohistochemistry and Western blotting to detect the expression of hippocampal proteins, and qPCR to detect the expression of mRNA. We found that aerobic exercise significantly promoted the survival of hippocampal neurons, inhibited microglia activation, and decreased the expression of inflammatory cytokines TNF-α, IL-1α, IL-1β, and chemokines CXCL-1, CXCR-2 in D-galactose model mice. Furthermore, exercise contributed to decreasing the microglia activation marker Iba1-positive cell count and average optical density and increasing the number of NeuN-immunopositive cells. Exercise also reduced RIPK1 and MAP3K5 expression in the hippocampus. Surprisingly, aerobic exercise significantly decreased the expression ratios of p-p65/p65, p-IκBα/IκBα, and p-JNK/JNK. Therefore, we hypothesized that exercise has an anti-inflammatory effect on the hippocampus of mice in the D-galactose-induced aging model. This effect may be attributed to the ability of aerobic exercise to down-regulate the RIPK1-mediated NF-κB and JNK pathways.