Divanillyl sulfone suppresses NLRP3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice

Abstract

Background Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Divanillyl sulfone (DS), a novel structural derivative of 4,4′-dihydroxydibenzyl sulfoxide from a traditional Chinese medicine Gastrodia elata with anti-nociceptive effects, significantly alleviated neuropathic pain following intrathecal injection. Here, we aimed to investigate the underlying mechanisms of DS against neuropathic pain. Methods A chronic constrictive injury (CCI) mouse model of neuropathic pain induced by sciatic nerve ligation was performed to evaluate the effect of DS by measuring the limb withdrawal using Von Frey filament test. Immunofluorescence staining was used to assess the cell localizations and expressions of Iba-1, ASC, NLRP3, and ROS, the formation of autolysosome. The levels of NLRP3-related proteins (caspase-1, NLRP3, and IL-1β), mitophagy-related proteins (LC3, Beclin-1, and p62), and apoptosis-related proteins (Bcl-XL and Bax) were detected by Western blotting. The apoptosis of BV-2 cell and caspase activity were evaluated by flow cytometry. Results DS significantly alleviated the neuropathic pain by increasing the mechanical withdrawal threshold and inhibiting the activation of NLRP3 in CCI-induced model mice. Our findings indicated that DS promoted the mitophagy by increasing the LC3II and Beclin 1 and decreasing the levels of p62 protein in BV-2 cell. This is accompanied by the inhibition of NLRP3 activation, which was shown as inhibited the expression of NLRP3 in lysates as well as the secretion of mature caspase-1 p10 and IL-1β p17 in supernatants in cultured BV-2 microglia. In addition, DS could promote mitophagy-induced improvement of dysfunctional mitochondria by clearing intracellular ROS and restoring mitochondrial membrane potential. Conclusion Together, our findings demonstrated that DS ameliorate chronic neuropathic pain in mice by suppressing NLRP3 inflammasome activation induced by mitophagy in microglia. DS may be a promising therapeutic agent for chronic neuropathic pain.

Neuroprotective Effect of Dexmedetomidine against Postoperative Cognitive Decline via NLRP3 Inflammasome Signaling Pathway

“…However, the level of NLRP3 expression was not affected. These results are consistent with a previous report suggesting that MCC950 blocks the assembly and formation of NLRP3, ASC, and caspase-1complex [ 15 ].…”

“…The NLR family pyrin domain containing 3 (NLRP3) inflammasome consists of NLRP3 protein, apoptosis-associated speck-like protein (ASC), and pro-caspase-1, which regulates IL-1β activation and secretion by active caspase-1. Thus, the dysregulation of the NLRP3 inflammasome is associated with various diseases, including ischemic stroke, diabetes, multiple sclerosis, atherosclerosis, Alzheimer’s disease, and other inflammatory-related diseases [ 13 , 14 , 15 , 16 ]. In addition, recent studies have revealed that dysregulation of NLRP3 inflammasome was associated with cognitive impairment [ 17 ], and the impairment could be reversed by inhibiting the NLRP3 inflammasome [ 18 ].…”

Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis

“…However, the exact regulatory mechanism between autophagy and pyroptosis in CFA-induced inflammatory pain is still elusive. Autophagy plays an important role in eliminating misfolded proteins, ROS, ATP and proinflammatory cytokines which induces NLRP3 inflammasome activation [ 47 ]. What's more, increasing evidence has shown that autophagy-related proteins can package and degrade the NLRP3 inflammasome components ASC and NLRP3 [ 48 ].…”

Bilirubin impacts microglial autophagy via the Akt–mTOR signaling pathway

“…Some indirect mechanisms by which autophagy suppresses inflammasome activation were also reported. Autophagy eliminates damaged or irreversibly depolarized mitochondria, thereby preventing the accumulation of endogenous inflammasome agonists, such as reactive oxygen species and damaged mitochondrial DNA (Plaza‐Zabala et al., 2017; Shao et al., 2021). Recent evidence indicates that autophagy plays a direct role in the regulation of inflammasomes.…”