Spinal SIRT1 Activation Attenuates Neuropathic Pain in Mice

Abstract

Abnormal histone acetylation occurs during neuropathic pain through an epigenetic mechanism. Silent information regulator 1 (sir2 or SIRT1), a NAD-dependent deacetylase, plays complex systemic roles in a variety of processes through deacetylating acetylated histone and other specific substrates. But the role of SIRT1 in neuropathic pain is not well established yet. The present study was intended to detect SIRT1 content and activity, nicotinamide (NAM) and nicotinamide adenine dinucleotide (NAD) in the spinal cord using immunoblotting or mass spectroscopy over time in mice following chronic constriction injury (CCI) or sham surgery. In addition, the effect of intrathecal injection of NAD or resveratrol on thermal hyperalgesia and mechanical allodynia was evaluated in CCI mice. Finally, we investigated whether SIRT1 inhibitor EX-527 could reverse the anti-nociceptive effect of NAD or resveratrol. It was found that spinal SIRT1 expression, deacetylase activity and NAD/NAM decreased significantly 1, 3, 7, 14 and 21 days after CCI surgery as compared with sham group. In addition, daily intrathecal injection of 5 µl 800 mM NAD 1 h before and 1 day after CCI surgery or single intrathecal injection of 5 µl 90 mM resveratrol 1 h before CCI surgery produced a transient inhibitory effect on thermal hyperalgesia and mechanical allodynia in CCI mice. Finally, an intrathecal injection of 5 µl 1.2 mM EX-527 1 h before NAD or resveratrol administration reversed the anti-nociceptive effect of NAD or resveratrol. These data indicate that the reduction in SIRT1 deacetylase activity may be a factor contributing to the development of neuropathic pain in CCI mice. Our findings suggest that the enhancement of spinal NAD/NAM and/or SIRT1 activity may be a potentially promising strategy for the prevention or treatment of neuropathic pain.

HMG-CoA synthase isoenzymes 1 and 2 localize to satellite glial cells in dorsal root ganglia and are differentially regulated by peripheral nerve injury

“…It is reported that HMGCS1 is significantly up-nitrosylated after spared nerve injury, and HMGCS1 is also a substrate of NAD-dependent protein deacetylase sirtuin-1 (SIRT1) (Hirschey et al, 2011) and decreased SIRT1 deacetylase activity in the spinal cord is a contributing factor for the development of neuropathic pain (Shao et al, 2014). However in the peripheral sensory system, the biological significance of these various modifications of HMGCS1 remains to be determined.…”

Epigenetics and Personalized Pain Management

“…SIRT1 is a class III NAD + -dependent HDAC that plays an important role in cell survival, inflammation, energy metabolism, and aging [92]. Using a pharmacological approach, this study also showed that upregulating SIRT1 activity may be a useful therapeutic intervention strategy for treating neuropathic pain [94]. Resveratrol treatment, which is a classic agonist of SIRT1, increased SIRT1 expression, suppressed global H3 acetylation compared to the group with morphine tolerance, and reversed morphine antinociceptive tolerance [93].…”

The pharmacology of resveratrol in animals and humans

“…Spinal Sirt1 expression and deacetylase activity decrease after CCI surgery. RSV pretreatment alleviated CCI-induced neuropathic pain in mice, associated with thermal hyperalgesia and mechanical allodynia, which was reversed by intrathecal injection of the Sirt1 inhibitor EX-527, suggesting that the analgesic effect of RSV is mediated by Sirt1 deacetylase activity [313]. …”