Effect of resveratrol on paclitaxel-induced neuropathic pain and its relationship with phosphatidylinositol 3 kinase/protein kinase B signaling pathway

Objective To investigate the effect of resveratrol (Res) on paclitaxel-induced neuropathic pain in rats and its relationship with phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway. Methods Fifty pathogen-free male Sprague-Dawley rats (weighing 180-200 g) with intrathecal catheters were randomly assigned into five groups (n=10): paclitaxel group (P group), Res pretreated group (R+ P group), LY294002 (the specific inhibitor of PI3K)+ Res pretreated group (LY+ R+ P group), Res group (R group) and control group (C group). Paclitaxel (2 mg/kg) was intraperitoneally injected at the same point on the 1st, 3rd, 5th, and 7th day. Res (intraperitoneal injection, 40 mg/kg) and LY294002 (intrathecal injection, 2.5 μg/10 μl) were administered at the same point on the 2nd, 4th, 6th, 8th, 10th, 12th, and 14th day. It’s worth noting that LY294002 was injected one h before Res. We measured 50% paw withdrawal mechanical threshold (PWT) at the point T0 (one day before chemotherapy), T1 (8 days after chemotherapy) and T2 (14 days after chemotherapy) respectively. The corpus striatum was harvested after euthanization at the 15th day. Transmission electron microscope (TEM) was applied to observe the mitochondrial histomorphology of all groups. The expression of p-Akt and t-Akt was detected using Western blotting. Results At points T1 and T2, as compared with C group, PWT in the P group and LY+ R+ P group was significantly reduced (P=0.000, 0.000), while as compared with P group, PWT in R+ P group was significantly increased (P=0.000). Under the TEM, we observed swollen and vacuolated mitochondria in P group and LY+ R+ P group. Nevertheless, the histomorphological changes were alleviated in R+ P group. As compared with C group (0.42±0.03), the expression levels of p-Akt in the R group (0.53±0.05) were increased (P=0.000), and those in P group (0.28±0.01), R+ P group (0.36±0.04) and LY+ R+ P group (0.21±0.03) were decreased (P=0.000, 0.019, 0.000). As compared with R group, the expression levels of p-Akt in the P group, R+ P group, LY+ R+ P group were decreased (P=0.000, 0.000, 0.000). As compared with P group, the expression levels of p-Akt in the R+ P group was significantly increased (P=0.002), and those in LY+ R+ P group were significantly reduced (P=0.006). The t-Akt had no significant change (P=0.551). Conclusion Res had the potential to prevent paclitaxel-induced neuropathic pain by protecting mitochondrial pathway, in which the PI3K/Akt signaling pathway was involved. Key words: Paclitaxel; Neuropathic pain; Resveratrol; Mitochondrial; Phosphatidylinositol 3 kinase/protein kinase B signaling pathway