Translocator protein alleviates allodynia and improves Schwann cell function against diabetic peripheral neuropathy via activation of the Nrf2‐dependent antioxidant system and promoting autophagy

Abstract Aims In diabetes, autophagy and the nuclear factor erythroid‐derived‐2‐like 2 (Nrf2)‐dependent antioxidant system are impaired. Translocator protein (TSPO) agonist Ro5‐4864 alleviates neuropathic pain, including diabetic peripheral neuropathy (DPN). However, the precise mechanisms remain unclear. Thus, we investigated the effects of Ro5‐4864 on autophagy and the Nrf2‐dependent antioxidant system in the sciatic nerves of DPN rats. Methods All rats were randomly assigned to Sham or DPN group. After type 2 diabetes modelling (established by high‐fat diet and streptozotocin injection) followed by behavioural tests, established DPN rats were randomly assigned to the DPN group, the Ro (TSPO agonist Ro5‐4864) group, the Ro + 3‐MA (autophagy inhibitor) group and the Ro + ML385 (Nrf2 inhibitor) group. Behavioural assessments were performed at baseline, on days 3, 7, 14, 21 and 28. Sciatic nerves were collected on day 28 for immunofluorescence, morphological and western blot analyses. Results Ro5‐4864 alleviated allodynia and increased myelin sheath thickness and myelin protein expression after DPN. Beclin‐1 ( p < 0.01) and LC3‐II/LC3‐I ratio ( p < 0.01) decreased and p62 ( p < 0.01) accumulated in the DPN rats. Ro5‐4864 administration increased the Beclin‐1 and LC3‐II/LC3‐I ratio and decreased p62 accumulation. Furthermore, nuclear Nrf2 contents ( p < 0.01) and cytoplasmic HO‐1 ( p < 0.01) and NQO1 ( p < 0.01) expressions were significantly inhibited in the DPN rat, which was also improved by Ro5‐4864. All the beneficial effects were abrogated by 3‐MA or ML385. Conclusion TSPO exhibited a potent analgesic effect and improved Schwann cell function and regeneration against DPN by activating the Nrf2‐dependent antioxidant system and promoting autophagy.