Curcumin attenuates microglia-mediated chronic neuropathic pain through CDK5 /p35 signaling pathway

Curcumin is a phenolic compound derived from turmeric, one of the main ingredients of curry powder, which is widely used for its antioxidant, anti-inflammatory and immunomodulatory effects. Curcumin has been reported to help relieve pain, such as neuropathic pain caused by injury or disease, but the specific mechanism of its antinociceptive effect on pathological pain is unclear. Cyclin-dependent kinase 5 (Cdk5) is a key control point for the release of neurotransmitters from presynaptic vesicles. Cdk5 and its activator p35 couple to regulate key signaling cascades, thereby participating in the pain process. In this study, we established a NP model by chronic constriction injury (CCI) of the bilateral sciatic nerve in rats and evaluated behavioral hyperalgesia using mechanical and hot and cold tests. Protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that Iba-1 and Cdk5/p35 were co-localized in the dorsal horn and dorsal root ganglia, respectively. After CCI, the expression of Cdk5 and p35 was upregulated in the dorsal horn and dorsal root ganglia, while intraperitoneal injection of curcumin significantly reversed the activation of Cdk5/p35 protein and alleviated the hyperalgesia in rats. In addition, the injection of curcumin reduced the co-localization expression of Iba-1 and Cdk5/p35, indicating that curcumin inhibited the activation of Cdk5/p35 protein in the dorsal horn and dorsal root ganglia, thereby affecting the activation of microglia, thereby having a destructive effect on the neuronal cell plasticity and synaptic structure remodeling in the development of NP. Our study provides new evidence that Cdk5/p35 in the dorsal horn and dorsal root ganglia is related to the occurrence of NP, introduces microglia as the basis for the long-term maintenance of NP, and provides insights into the molecular mechanisms involved in the analgesic effect of curcumin. Graphical Abstract