1. 2022;25;E1137-E1151Exercise Facilitates the M1-to-M2 Polarization of Microglia by Enhancing Autophagy via the BDNF/AKT/mTOR Pathway in Neuropathic Pain
   Randomized Controlled Study
   Jie Bai, PhD, Bin Geng, PhD, Xingwen Wang, PhD, Shenghong Wang, PhD, Qiong Yi, PhD, Yuchen Tang, PhD, and Yayi Xia, PhD.

BACKGROUND: In neuropathic pain following peripheral nerve injury, microglia are rapidly activated and accumulated in the spinal cord. Physical exercise can alleviate neuropathic pain. However, the exact mechanism underlying this analgesic effect is not fully understood.

OBJECTIVES: We aimed to investigate the molecular mechanisms by which exercise alleviates neuropathic pain in relation to brain-derived neurotrophic factor (BDNF), microglia polarization, and autophagy.

STUDY DESIGN: A randomized controlled animal study divided into 2 stages. The first stage comprised 4 groups each with 6 mice, and the second stage comprised 6 groups, 3 with 18 mice and 3 with 12 mice.

SETTING: Department of Anesthesiology, Lanzhou University Second Hospital, Orthopaedics Key Laboratory of Gansu Province, Lanzhou University.

METHODS: Von Frey filaments, Western blotting, immunofluorescence, and transmission electron microscopy analyses were conducted to detect relevant markers.

RESULTS: After peripheral nerve injury, exercise training downregulated BDNF expression and reversed microglial activation, as indicated by the increased expression of the M2 marker CD206 and decreased expression of the M1 marker CD86 in the spinal dorsal horn of mice. Autophagy flux was enhanced after exercise training, as suggested by the increased expression of the autophagy markers LC3-II/LC3-I and Beclin1 and decreased expression of the autophagy adaptor protein p62. Furthermore, autophagy inhibition by 3-methyladenine aggravated M1 polarization and hyperalgesia, whereas autophagy induced by rapamycin promoted M2 polarization and reduced hyperalgesia. Intrathecal injection of BDNF significantly upregulated BDNF expression, inhibited autophagy, triggered M1 polarization of spinal microglia, and aggravated hyperalgesia. Furthermore, BDNF regulated autophagy through the AKT/mTOR pathway, thereby participating in exercise training-mediated polarization of microglia after nerve injury.

LIMITATIONS: The effect of exercise on autophagy and pain cannot be assessed in an in vitro model. The influence of intrathecal injection of BDNF on the metabolic changes in other neuronal cells and the subsequent effects on pain should be investigated. Further studies on how exercise training modulates microglial autophagy to alleviate neuropathic pain are needed.

CONCLUSIONS: Exercise training promoted the recovery of sciatic nerve injury in mice, possibly by regulating microglial polarization through BDNF/AKT/mTOR signaling-mediated autophagy flux. We confirmed the efficacy of exercise training in alleviating neuropathic pain and suggest a new therapeutic target for neuropathic pain.   

KEY WORDS: Autophagy, brain-derived neurotrophic factor, exercise, microglial polarization, neuropathic pain