| BackgroundTrigeminal neuralgia(TN)is a most common type of neuropathic pain which is distributed at branches of the trigeminal nerve.It is characterized by unilateral pain attacks which are sharp,shooting,lancinating,electric shock-like,burning and excruciating in nature.Therefore,TN is known as one of the most painful complaints of the human kind.However,underlying mechanisms of TN have not been completely elucidated,and the outcomes of pharmacological or surgical treatments are often disappointing.Increasing evidences have shown that microglia and astrocytes play important roles in the development of TN.Upound activation,microglia and astrocytes release the proinflammatory cytokines interleukin-1?(IL-1?)and tumor necrosis factor-?(TNF-?),which cause central sensitization.Therefore,targeting neuroglia may provide more opportunities for disease management by aborting neurobiological alterations.Our previous study found AMPK activation may regulate glial activation.Resveratrol is a natural plant antibiotic found in various plants and fruits,especially abundant in grapes and red wine.In the present study,we determined that resveratrol could significantly attenuate trigeminal neuralgia behaviors in the chronic constriction injury(CCI)model.Moreover,activated microglia and astrocytes markedly increased in the CCI model,whereas resveratrol was associated with decreased activation of microglia and astrocytes and release of inflammatory cytokines in CCI rat.Finally,we found that the analgesic effect of resveratrol was involved in mitogen-activated protein kinase(MAPK)signal pathway.Methods(1)Chronic constriction injury model was established in rats.Effects of AMPK activation on the CCI-induced mechanical hyperalgesia were tested with Von Frey test.(2)To investigate the role of resveratrol on TN.The expressions of GFAP and IBA-1 in spinal cord were detected by western blot.And immunofluorescence was used to identify the distribution and location of GFAP and IBA-1.Meanwhile,the proinflammatory cytokines interleukin-1?(IL-1?)and tumor necrosis factor-a(TNF-a)in the spinal cord was determined with western blot.(3)To investigate the mechanisms of resveratrol on CCI-induced glia activation.Effects of resveratrol CCI-induced the actvation of MAP Kinase family were tested with western blot(4)In order to clarify the role of resveratrol on inhibition of glial cell activation in TN.Western blot was used to determine effects of resveratrol on proinflammatory cytokines TNF-a plus IL-1?-induced astrocyte and BV-2 cell activation.Immunofluorescence was used to determine effects of resveratrol on proinflammatory cytokines TNF-a plus IL-1?-induced astrocyte proliferation.(5)To investigate the role of resveratrol on inhibition of phosphorylation of MAPK.Results(1)Resveratrol suppressed CCI-induced mechanical hyperalgesia in a dose dependment manner.Repetitive administration of resveratrol almost reversed TN.(2)Resveratrol inhibits phosphorylation of c-fos and CGRP in the spinal trigeminal nuclues(STN).(3)Resveratrol inhibited the activation of the glial cells and the increase of inflammatory cytokines IL-1? and TNF-a in the spinal cord in CCI rats.(4)Resveratrol reduces CCI-induced production of pro-inflammatory factors and phosphorylation of NR1 and PKCy in the STN.(5)Resveratrol inhibited CCI-induced upregulation of p-JNK,p-p38 and p-ERK levels in STN.These effects were reversed by the co-administration of the AMPK inhibitor compound C.(6)Resveratrol inhibited TNF-a and IL-1?-induced astrocyte and BV-2 cell activation.(7)TAK1 inhibitor declined TNF-a and IL-1?-induced activation and proliferation of astrocytes and phosphorylation of MAPK.Conclusion(1)We have demonstrated that resveratrol suppresses mechanical allodynia of the trigeminal nerve by inhibiting activation of astrocytes and microglia and decreased the expression level of proinflammatory cytokine in TN..(2)The effect of resveratrol may depend on AMPK activation and is associated with inhibition on MAPK signaling in the spinal cord. |
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