Author(s): OUYANG, W., GAN, T.T., LIAO, Q., WANG, J.H., FAN, Z.H., CAO, J., PAN, H.J., LOU, G.F., DONG, X.F. , Institution: ZHEJIANG NORMAL UNIVERSITY, Country: CHINA, Abstract-ID: 133

INTRODUCTION:
While studies have shown exercise to improve cognitive performance and provide neuroprotection in animal models of traumatic brain injury (TBI), understanding the effects of exercise on autophagy, astrogliosis, and inflammation in TBI remains limited. Additionally, the effectiveness of TNF inhibitors like etanercept in treating TBI patients is unclear. This study aimed to evaluate the effects of preconditioning exercise (PE) and/or post-TBI TNF inhibitor Yisaipu on neurological and motor function, including locomotion coordination, balancing and gait deficits in a TBI mouse model.
METHODS:
Seventy-six male C57BL/6J mice were divided into six groups: Sham, TBI+Saline, TBI+Yisaipu, Sham+Exercise, TBI+Exercise, and TBI+Exercise+Yisaipu. Exercise group mice performed a voluntary exercise regimen for 6 weeks, and TBI was induced with 2.5‒2.8 atm percussion force on the right motorsensory cortex. Yisaipu was administered intraperitoneally immediately following the injury and 24 hours post-injury. Various behavioral, molecular, and biochemical approaches were used to evaluate neurological function, motor coordination, gait, cytokine levels, autophagy, astrogliosis, and neuronal injuries.
RESULTS:
At 2 h post-TBI, the neurological severity score (NSS) in TBI+Exe mice was significantly lower (p<0.01) than in TBI+Sal mice, and it consistently remained lower than that in TBI+Sal mice at 1- and 2-days post-injury. Compared to TBI+Yis mice, TBI+Exe and TBI+Exe+Yis mice showed increased fall latency on the rotarod. The improved beam and grid walk performance was more evident in TBI+Exe+Yis mice than in TBI+Exe or TBI+Yis mice. The maximum speed of foot, ankle, and knee joint movement in TBI+Exe+Yis mice was significantly larger than in TBI+Yis and TBI+Exe mice and notably larger than in TBI+Sal mice (foot: p<0.01, ankle: p<0.01, knee: p<0.05). Both PE and Yisaipu treatments reduced post-TBI TNF-α levels, and the beneficial effect of the combination of the two treatments was more evident than with Yisaipu alone. The serum levels of IL-4 in TBI+Yis and TBI+Exe mice increased compared with sham and sham+Exe mice, respectively, and were significantly elevated in TBI+Exe+Yis mice (p<0.05) compared with sham+Exe mice. The combination of PE and Yisaipu treatment remarkably improved autophagic flux evidenced by reduced LC3-II levels, reduced astrogliosis evidenced by reduced LC3-II and GFAP levels, and mitigated injured cortical volume [(18.4 ± 7.1) mm3] compared to either TBI+Sal mice [(59.9 ± 13.8) mm3, p<0.001)] or TBI+Exe mice [(50.3 ± 11.8) mm3, p<0.01].
CONCLUSION:
The combination of PE and post-TBI Yisaipu treatments was more effective than single treatments in reducing sensorimotor and gait deficits in mice. These functional improvements were associated with reduced systemic inflammation, mainly via serum TNF-α, improved autophagic flux, and mitigated lesions after TBI.