Hippocampal neuronal death induced by kainic acid and restraint stress is suppressed by exercise

The present study investigated whether chronic exercise suppressed hippocampal neuronal death due to repeated stress followed by i.c.v. kainic acid (KA) injection, and whether cAMP response element-binding protein (CREB), mitogen-activated protein kinase (MAPKs), and calcium/calmodulin-dependent protein kinase II (CaMKII) activation contributed to the neuroprotective effect in this experimental paradigm. To achieve the objective, mice were subjected to treadmill running for 8 weeks (19 m/min, 1 h/d, 5 d/wk) followed by seven consecutive days of repeated restraint stress (2 h/d), and then i.c.v. injection of KA (0.05 μg/5 μL). Hippocampal neuronal death was assessed using Nissl staining, and protein levels were measured using Western blot and immunohistochemical analysis. Hippocampal neuronal loss in mice subjected to restraint stress and KA injection was exacerbated compared with KA injection alone, which was reversed in the hippocampal CA3 region with prior chronic exercise. To further identify the neuroprotective effects of chronic exercise administration on hippocampal insults by repeated stress, levels of stress-related factors were measured. First, there was no significant difference in serum corticosterone and glucocorticoid (Gc) receptor levels in mice with restraint alone and restraint combined with prior chronic exercise. Second, malondialdehyde (MDA) and nitrite levels were significantly enhanced in restrained mice and were revered in restraint with chronic exercise. However, pCREB levels in the hippocampus in restraint mice with chronic exercise were profoundly increased compared with levels in restraint-alone mice. Among the MAPKs, pERK1/2 levels in restraint mice with chronic exercise were significantly higher than levels in mice with restraint alone. Furthermore, pCaMKII levels in restraint mice with chronic exercise were markedly elevated compared with levels in mice after restraint alone. Prior chronic exercise suppressed KA-induced hippocampal neuronal death in hippocampal CA3 region in restrained mice via declined ROS levels, which was lower MDA and nitrite levels, and activation of CREB, which was mediated by ERK1/2 and CaMKII, suggesting that chronic exercise exerts a protective effect on excitatory neurodegenerative disorders including epileptic seizure.