Abstract
BackgroundChronic 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.MethodsA 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.ResultsDS 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.ConclusionTogether, 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.
Highlights
Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function
IL-1β secreted by the activated NLR family pyrin domaincontaining 3 (NLRP3) inflammasome relays pain signals by binding to the IL-1 receptor (IL-1R) expressed on neurons, and the analgesic effect of Divanillyl sulfone (DS) may be related to blocking NLRP3 inflammasome activation and IL-1β/IL-1R signaling in the spinal cord
In summary, we reported that DS effectively improved the chronic neuropathic pain in constrictive injury (CCI)-induced neuropathic pain model mice
Summary
Chronic neuropathic pain is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Neuralgia is a type of chronic pain that manifests as spontaneous pain, hyperalgesia, and allodynia [1, 2] It is caused by injury or disease in the somatosensory nervous system that includes the central nerves, spinal cord, posterior root of the spinal cord, and peripheral nerves. Some non-neuronal cells of the central nervous system (CNS), especially microglia, have been implicated in triggering neuropathic pain [5,6,7,8]. Chronic neuropathic pain is characterized by infiltration of immune cells into the dorsal root ganglia (DRG), and the activation of microglia in spinal cord and brain, eventually leading to a neuroinflammatory response [12]. Multiple mechanisms participate in the central neuronal excitation mediated by microglial inflammation in peripheral nerve injury (PNI)-induced neuropathic pain. Thereby, the NLRP3 inflammasome is the most recognized contributor and plays an irreplaceable role to the transmission of pain signals [19, 20]
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