SIRT1 attenuates neuropathic pain by epigenetic regulation of mGluR1/5 expressions in type 2 diabetic rats

Abstract

Accumulating evidence has demonstrated that epigenetic modification-mediated changes in pain-related gene expressions play an important role in the development and maintenance of neuropathic pain. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is involved in the development of chronic pain. Moreover, SIRT1 may be a novel therapeutic target for the prevention of type 2 diabetes mellitus (T2DM). But the role of SIRT1 in T2DM-induced neuropathic pain remains unknown. In this study, we found that spinal SIRT1 expression and activity were downregulated significantly in high-fat-fed/low-dose streptozotocin-induced neuropathic pain rats. SIRT1 localized in spinal neurons but not in astrocytes or microglia. Furthermore, the expressions of metabotropic glutamate receptor (mGluR1) and mGluR5, which play a key role in central sensitization and neuropathic pain, and H3 acetylation levels at Grm1/5 (encoding mGluR1/5) promoter regions were increased in diabetic neuropathic pain rats. SIRT1 activator SRT1720 reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal activation in diabetic neuropathic pain rats. Concurrently, increased expressions of mGluR1/5 and H3 acetylation levels at Grm1/5 promoter regions were reversed by SIRT1 activation. In addition, knockdown of SIRT1 by Ad-SIRT1-shRNA induced pain behaviors and spinal neuronal activation in normal rats, which was accompanied by the increased expressions of mGluR1/5 and H3 acetylation levels at Grm1/5 promoter regions. Therefore, we concluded that SIRT1-mediated epigenetic regulation of mGluR1/5 expressions was involved in the development of neuropathic pain in type 2 diabetic rats.

NeuroHeal Treatment Alleviates Neuropathic Pain and Enhances Sensory Axon Regeneration

“…SIRT1 modulates autophagy in different ways [47]. Although unexplored here, SIRT1 may be the primary mediator of the autophagy and analgesic effects of NeuroHeal within dorsal neurons, because its deacetylase activity reduces neuropathic pain after PNI [48,49]. In this way, a recent article described that the SIRT1-activator resveratrol increases KCC2 levels in human Rett syndrome neurons, which fits with our results [50].…”

The etiological changes of acetylation in peripheral nerve injury–induced neuropathic hypersensitivity

“…Various receptors, transporters, and enzymes involved in glutamatergic and γ-aminobutyric acid (GABA)ergic synaptic transmission are affected by acetylation in neuropathic pain. For example, in Zhou et al.’s study, 15 increased histone H3 acetylation in mGrm1/5 (encoding mGluR1/5) promoter regions upregulated mGluR1/5 expression in rats with diabetic neuropathy. Indeed, experts have observed decreased glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) expression in the spinal dorsal horn after spinal nerve ligation (SNL), which HDAC inhibitor (HDACI) valproate could restore, followed with pain behaviors improvement.…”

“…Sirt1 activator SRT1720 and Sirt1 shRNA could reverse or induce spinal neuronal activation and pain phenotype, respectively. 15 Other than glutamatergic receptors, a downregulation or knockdown of GLAST and GLT-1 in the spinal dorsal horn potentiates the spontaneous nociceptive phenotype and contributes to the neuropathic pain development. 30 …”

Role of N-Acylethanolamines in the Neuroinflammation: Ultramicronized Palmitoylethanolamide in the Relief of Chronic Pain and Neurodegenerative DiseasesRole of N-Acylethanolamines in the Neuroinflammation: Ultramicronized Palmitoylethanolamide in the Relief of Chronic Pain and Neurodegenerative Diseases

“…Silent information regulator 1 (Sirt1), a NADdependent deacetylase, through deacetylating acetylated histone and other specific substrates plays a relevant role in many physiopathological conditions such as diabetes, cardiovascular disorders, cancer, neurodegeneration and neuropathic pain [140,141]. Abnormal histone acetylation is suggested to be a characteristic gene modification and a transcription factor-mediated epigenetic mechanism underlying neuropathic pain [143][144]. The role of Sirt1 and Sirt1 activator (resveratrol) in alleviating neuropathic pain is more and more emerging [140,142,146].…”