sirolimus and Peripheral-Nerve-Injuries

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.. 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.. 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.. Department of Anesthesiology, Lanzhou University Second Hospital, Orthopaedics Key Laboratory of Gansu Province, Lanzhou University.. Von Frey filaments, Western blotting, immunofluorescence, and transmission electron microscopy analyses were conducted to detect relevant markers.. 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.. 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.. 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.

Topics: Analgesics; Animals; Autophagy; Beclin-1; Brain-Derived Neurotrophic Factor; Hyperalgesia; Mice; Microglia; Neuralgia; Peripheral Nerve Injuries; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sirolimus; Spinal Cord Dorsal Horn; TOR Serine-Threonine Kinases

This preliminary research determines whether a combination of reverse end-to-side neurorrhaphy and rapamycin treatment achieves a better functional outcome than a single application after prolonged peripheral nerve injury. We found that the tibial nerve function of the reverse end-to-side + rapamycin group recovered better, with a higher tibial function index value, higher amplitude recovery rate, and shorter latency delay rate (

Topics: Animals; Anti-Bacterial Agents; Combined Modality Therapy; Disease Models, Animal; Electromyography; Female; Muscle Denervation; Muscle, Skeletal; Nerve Regeneration; Neurosurgical Procedures; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Sirolimus; Tibial Neuropathy

The functional outcome after peripheral nerve repair is often unpredictable for many reasons, e.g., the severity of neuronal death and scarring. Axonal degeneration significantly affects outcomes. Post-injury axonal degeneration in peripheral nerves is accompanied by myelin degradation initiated by Schwann cells (SCs), which activate autophagy, a ubiquitous cytoprotective process essential for degrading and recycling cellular constituents. Scar formation occurs concomitantly with nerve insult and axonal degeneration. The association between SC autophagy and the mechanisms of nerve scar formation is still unknown. A rat model of peripheral nerve lesions induced by sciatic nerve transection injuries was used to examine the function of autophagy in fibrosis reduction during the early phase of nerve repair. Rats were treated with rapamycin (autophagy inducer) or 3-methyladenine (autophagy inhibitor). One week after the nerve damage, fibrosis was potently inhibited in rapamycin-treated rats and, based on gait analysis, yielded a better functional outcome. Immunohistochemistry showed that the autophagic activity of SCs and the accumulation of neurofilaments were upregulated in rapamycin-treated rats. A deficiency of SC autophagic activity might be an early event in nerve scar formation, and modulating autophagy might be a powerful pharmacological approach for improving functional outcomes.

Topics: Adenine; Animals; Autophagy; Cicatrix; Male; Nerve Regeneration; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Schwann Cells; Sciatic Nerve; Sirolimus