Authors
Xintong Hao, Junkang Leng, Jianjun Tan
Published in
Frontiers in physiology. Volume 17. Pages 1888004. Epub Aug 06, 2026.
Abstract
Neuropathic pain arises from lesions or dysfunction within the somatosensory system, leading to chronic disability and scarce effective therapies. The NAD⁺-dependent deacetylase SIRT6 participates in aging and inflammatory responses, yet its involvement in neuropathic pain has remained unexplored. Using two selective SIRT6 activators-UBCS039 and MDL-800-in a rat model of chronic constriction injury (CCI), we asked whether pharmacological SIRT6 activation could ameliorate pain behaviors and, if so, through what molecular route.
CCI surgery was performed in male Sprague-Dawley rats, and SIRT6 expression in the spinal dorsal horn was assessed post-operatively. From day 3 to day 9 after injury, rats received daily intraperitoneal injections of UBCS039 (20 mg/kg) or MDL-800 (10 mg/kg). On day 10, paw withdrawal thresholds (PWT) and paw withdrawal latencies (PWL) were measured. Spinal cord tissues were harvested for assessment of oxidative stress markers (TBARS, SOD, GSH-Px), pro-inflammatory cytokines (IL-1β, IL-18), NLRP3 inflammasome components (NLRP3, ASC, cleaved caspase-1), and Nrf2/HO-1 protein levels. An additional cohort received the Nrf2 inhibitor ML385 (30 mg/kg) 30 minutes before each MDL-800 dose to verify pathway specificity.
CCI markedly reduced SIRT6 mRNA and protein levels in the spinal dorsal horn (n=6 per group, P<0.001). Both UBCS039 and MDL-800 significantly elevated PWT and PWL (n=8, P<0.001), reduced TBARS content, restored SOD and GSH-Px activities (n=6, P<0.01), and suppressed IL-1β and IL-18 production at both transcript and protein levels. Western blotting revealed that SIRT6 activation inhibited NLRP3, ASC, and cleaved caspase-1 expression while reversing the CCI-induced decline of Nrf2 and HO-1. Co-administration of ML385 abolished these protective effects, rendering all measured parameters-including NLRP3 protein, cytokine levels, and pain thresholds-statistically indistinguishable from the untreated CCI group (P>0.05).
Activating SIRT6 dampens neuropathic pain and NLRP3 inflammasome activation by restoring Nrf2 signaling. This positions SIRT6 as a previously unrecognized therapeutic target for neuropathic pain.
PMID:
42625583
Bibliographic data and abstract were imported from PubMed on 21 Aug 2026.
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