Effect Of Resveratrol On Paclitaxel-inducedneuropathic Pain:the Relationship With PI3K/Akt Signaling Pathway

Objective:As a commonly used chemotherapy drug in clinic,paclitaxel has a significant effect on various malignant tumors.However,the effective treatment against peripheral neuropathic pain induced by paclitaxel has not yet been found.With the increase of dosage,the pain symptoms are getting worse,which seriously affects the quality of life of patients.Therefore,it has very important clinical value to clarify its specific physiological and pathological processes.In this experiment,rats with neuropathic pain model was established by intraperitoneal injection of paclitaxel,and the effect of resveratrol?Res?was evaluated by intraperitoneal injection on paclitaxel-induced neuropathic pain in rats,and the role of phosphatidylinositol 3 kinase?PI3K?/protein kinase B?Akt?signaling pathwaywas explored by intrathecal injection of LY294002.Methods:Fifty pathogen-free male Sprague-Dawley rats?weighing180-200g?with intrathecal catheters wererandomly 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 intraperitoneal injected at the same point on the 1,3,5,7 days.Res?intraperitoneal injection,40 mg/kg?and LY294002?intrathecal injection,2.5?g/10?l?were administered at the same point on the 2,4,6,8,10,12,14 days.It's worth noting that LY294002 was injected one hour before Res.We measured 50%paw withdrawal mechanical threshold?MWT?and thermal withdrawal latency?TWL?at the point T0?one day before chemotherapy?,T1?eight days after chemotherapy?and T2?14 days after chemotherapy?respectively.The corpus striatum was harvested after euthanized at the 15th day.Transmission electron microscope?TEM?was applied to observe the mitochondrial histomorphology of all groups.The p-Akt and t-Akt positive cell count in corpus striatum were detected by immuno-histochemistry.The expression of p-Akt and t-Akt were measured using Western blot.Results:1.Behavioral results:at point T₁ and T₂,compared with C group,MWTand TWL of the P group and LY+R+P group weredecreased?P<0.05?,which were not significantly changedin the R group?P>0.05?.Compared with P group,MWTand TWL of R+P group were increased,while decreased in the LY+R+P group?P<0.05?.Compared withR+P group,MWTand TWL of the LY+R+P group weredecreased?P<0.05?2.Transmission electron microscope results:under the TEM,we observed swollen and vacuolatedmitochondrial in P group and LY+R+P group.Nevertheless,the histomorphological changes was alleviated in R+P group.3.Immuno-histochemistry results:compared with positive cell count of p-Akt in corpus striatum in C group,the positive cell count of p-Akt in the R groupwasincreased?P<0.05?,whilethat in P group?R+P groupand LY+R+P groupwere decreased?P<0.05?.Compared with p-Akt positive cell count in corpus striatum in R group,the positive cell count of p-Aktin theP group?R+P group and LY+R+P group were decreased?P<0.05?.Compared with positive cell of p-Akt count in P group,positive cell count of p-Akt in the R+P group was significantly increased?P<0.05?,while that in LY+R+P group was significantly decreased?P<0.05?.The positive cell count of t-Akt was not significantly changed?P>0.05?.4.Western blot results:compared with C group,the expression levels of p-Akt in the R groupwasincreased?P<0.05?,whilethat in P group?R+P groupand LY+R+P groupwere decreased?P<0.05?.Compared with R group,the expression levels of p-Akt in theP group/R+P group/LY+R+P group were decreased?P<0.05?.Compared with P group,the expression levels of p-Akt in the R+P group was significantly increased?P<0.05?,while that in LY+R+P group was significantly decreased?P<0.05?.The t-Akt was not significantly changed?P>0.05?.Conclusion:Res has the potential to prevent paclitaxel-induced neuropathic pain by protecting mitochondrial pathway,in which the PI3K/Akt signaling pathway was involved.