Spinal SIRT1Activation As A Novel Mechanism Underlying The Prevention Of Neuropathic Pain In Mice

BackgroundNeuropathic pain is a big problem in the treatment of pain. Epigenetic gene silencingunderlies neuronal plasticity in neuropathic pain, and the NAD-dependent deacetylasesilent information regulator1(SIRT1) plays complex systemic roles in a variety ofprocesses through deacetylating its specific acetylated-protein substrates. Theanatomical analysis of SIRT1immunoreactivity highlights the presence of SIRT1inboth rodent and human spinal cord. SIRT1has been implicated in molecular pathwaysassociated with pain or nerve injury. Our current data show that EX-527, a SIRT1inhibitor, aggravates spontaneous pain by formalin injected into the plantar surface ofthe left hind paw in mice, indicating that SIRT1inaction plays some roles ininflammatory pain process. Our hypothesis is that CCI surgery induces neuropathicpain through inactivating SIRT1and SIRT1activation may be a new strategy intreatment of neuropathic pain. MethodsAll the studies were performed with CCI mice model and the terminal indicatorsincluded the content of SIRT1，SIRT1activity reflected by acetylation levels of theSIRT1substrate H4-k16Ac, and thermal hyperalgesia and mechanical allodynia.1After animals were allowed to acclimate for one week, they received PSNL surgeryor sham surgery. We observed the effect of CCI surgery on SIRT1and its activity,thermal hyperalgesia and mechanical allodynia before and1、3、7、14、21days aftersham or CCI surgery.2Then we observed the effect of lentivirus expressing Nmnat1, exogenous NAD orresveratrol on neuropathic pain induced by CCI in mice. Lentivirus expressingNmnat1intrathecally injected3days before CCI surgery delays the production ofthermal hyperalgesia and mechanical allodynia; Lentivirus expressing Nmnat1intrathecally injected3days after CCI surgery attenuates the development of thermalhyperalgesia and mechanical allodynia; Exogenous NAD intrathecally injected1hbefore and1day after CCI surgery, or resveratrol intrathecally injected1h before CCIsurgery delays the production of thermal hyperalgesia and mechanical allodynia.3Lastly, we observed the effect of lentivirus expressing SIRT1siRNA or EX-527onthe anti-nociceptive effect of increased nuclear NAD in spine cord. Lentivirusexpressing SIRT1siRNA intrathecally injected3days before CCI surgery reverses theprotection of exogenous NAD intrathecally injected1h before and1day after CCIsurgery; EX-527intrathecally injected2h before CCI surgery reverses the protectionof exogenous NAD intrathecally injected1h and1day after EX-527injection. Results In this study we report that spinal SIRT1expression and its deacetylationactivity decrease in mice following CCI surgery. Furthermore, we demonstrate thatincreased spinal nuclear NAD biosynthesis by gene recombination or addingexogenous NAD and SIRT1activation can be epigenetically modulating ways whichdelay the onset and attenuate the development of mechanical allodynia and thermalhyperalgesia induced by CCI in mice. Most importantly, SIRT1activation is essentialfor the anti-nociceptive activity of increased nuclear NAD in spine.Conclusions The study provides potentially novel therapeutic strategies directed atincreasing the supply of NAD and/or SIRT1activation for treatment of neuropathicpain.