Resveratrol inhibits paclitaxel-induced neuropathic pain by the activation of PI3K/Akt and SIRT1/PGC1α pathway

Background: Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is one of the essential signaling pathways for the development and maintenance of neuropathic pain.

Objective: To investigate the effect of resveratrol (RES) on paclitaxel-induced neuropathic pain in rats and elucidate the underlying molecular mechanisms.

Method: Male Sprague Dawley rats were randomly divided into seven groups (n=10/group): Group C, Group P, Group R, Group R+P, Group LY + R+P, Group LY (the specific inhibitor of PI3K), Group E (the specific inhibitor of Sirtuin 1 [SIRT1]). Paw withdrawal mechanical threshold (PWT) and thermal withdrawal latency (TWL) were recorded. Mitochondrial histomorphology was performed by transmission electron microscope. PI3K, p-Akt, and t-Akt expressions were tested using immunohistochemistry. Western blot was used to detect p-Akt, t-Akt, SIRT1, and PGC1α expressions. The Apoptosis in the striatum, spinal dorsal horns (SDH), and dorsal root ganglions (DRG) tissues was assayed by TUNEL. ELISA was used to detect the contents of IL-β, IL-10, malondialdehyde (MDA), and superoxide dismutase (SOD) in striatum, SDH, and DRG tissues.

Results: Compared to the control group, PWT and TWL in the P and LY +R+P groups were significantly decreased on 8th and 14th day after paclitaxel administration (P<0.05). The expressions of p-Akt, SIRT1, and PGC1α were decreased in paclitaxel-induced neuropathic rats; however, the expressions of p-Akt, SIRT1, and PGC1α were significantly increased after RES treatment (P<0.05). Furthermore, the expression of p-Akt was decreased by LY294002 (P<0.05), and amount of SIRT1 and PGC1α expression was inhibited by EX-527 (P<0.05). The t-Akt level was not significantly changed in all groups. RES prevented paclitaxel-induced mitochondrial damage by PI3K/Akt. RES improves the pain symptoms of paclitaxel neuralgia rats by increasing the IL-10 and decreasing the expression of IL-1β. RES increases the SOD and reduces the MDA. RES reduces Apoptosis by SIRT1/PGC1α signal pathway.

Conclusion: Our results suggest that RES may inhibit paclitaxel-induced neuropathic pain via PI3K/Akt and SIRT1/PGC1α pathways.