Puerarin Alleviates Vincristine-Induced Neuropathic Pain and Neuroinflammation Via Inhibition of Nuclear Factor-Κb and Activation of the TGF-β/Smad Pathway in Rats

Chemotherapy-induced neuropathic pain harms the quality of life patients. Vincristine is an often used chemotherapeutic drug that evokes neuralgia via inflammation. Puerarin (Pue) extracted from Puerariae Lobatae Radix has analgesic and anti-inflammatory effects; however, its possible effect and mechanism in vincristine (Vin)-induced neuropathic pain has not been investigated. The present research aimed to explore whether Pue could relieve chemotherapy-evoked neuropathic pain and the underlying mechanism actions. Rat neuropathic pain was established by intraperitoneal injection of vincristine. Pue was orally administered in two dose levels (25 or 50 mg/kg/d) for three weeks. The paw withdrawal latency and paw withdrawal threshold were performed to evaluate the pain behaviors. Inflammatory cytokines in the spinal cord and dorsal root ganglion were measured by ELISA kits. qRT-PCR, western blot, and immunofluorescence staining were employed to measure the level and expression feature of inflammatory cytokines. Our findings showed that Pue improved hyperalgesia and allodynia. Treatment with Pue restored the levels of tumor necrosis factor-alpha (TNF-alpha), and IL-1 beta and increased the levels of transforming growth factor-beta (TGF-beta), and interleukin-10 (IL-10). On the molecular level, treatment with Pue down-regulated the protein levels of IL-1 beta, and NF-kappa Bp65 and up-regulated the protein levels of TGF-beta, p-Smad2, and p-Smad3 (TGF-beta/Smad) in the spinal cord and DRG. Immunofluorescence staining further demonstrated that Pue decreased the NF-kappa Bp65 protein. Our findings imply that Pue relieved chemotherapy-induced neuropathic pain might be attributable to the suppression of inflammation cytokines. The anti-inflammation action of Pue might be associated with the activation of the TGF-beta/Smad pathway, a novel mechanism exploring its prophylactic effect in vincristine-induced neuropathic pain.