Targeting TANK-binding kinase 1 attenuates painful diabetic neuropathy via inhibiting microglia pyroptosis.

BACKGROUND: Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. METHODS: PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. RESULTS: In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. CONCLUSIONS: Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN.

Defective autophagy contributes to bupivacaine-induced aggravation of painful diabetic neuropathy in db/db mice.

Current evidence suggests that hyperactivated or impaired autophagy can lead to neuronal death. The effect of local anesthetics on painful diabetic neuropathy (PDN) and the role of autophagy in the above pathological process remain unclear, warranting further studies. So, PDN models were established by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in leptin gene-mutation (db/db) mice. Wild type (WT) and PDN mice received intrathecal 0.75% bupivacaine or/with intraperitoneal drug treatment (rapamycin or bafilomycin A1). Subsequently, the PWT and PWL were measured to assess hyperalgesia at 6 h, 24 h, 30 h, and 48 h after intrathecal bupivacaine. Also, sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) were measured before and 48 h after intrathecal bupivacaine treatment. The spinal cord tissue of L4-L6 segments and serum were harvested to evaluate the change of autophagy, oxidative stress, oxidative injury, and apoptosis. We found that bupivacaine induced the activation of autophagy but did not affect the pain threshold, SNCV and MNCV in WT mice at predefined time points. Conversely, bupivacaine lowered autophagosome generation and degradation, slowed SNCV and aggravated spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. The autophagy activator (rapamycin) could decrease spinal dorsal horn neuron oxidative injury, alleviate the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Meanwhile, the autophagy inhibitor (bafilomycin A1) could exacerbate spinal dorsal horn neuron oxidative injury, the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Our results showed that bupivacaine could induce defective autophagy, slowed SNCV and aggravate spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. Restoring autophagy may represent a potential therapeutic approach against nerve injury in PDN patients with local anesthesia and analgesia.

Survival analysis of a comprehensive treatment strategy for internal carotid artery blowout syndrome by nasopharyngeal carcinoma.

OBJECTIVE: To retrospectively analyze the comprehensive treatment strategy for internal carotid artery blowout syndrome (CBS) by nasopharyngeal carcinoma (NPC). METHODS: Of the 311 patients of NPC with carotid artery blowout syndrome admitted at our center from April 2018 to August 2022, 288 were enrolled. RESULTS: The patients were divided into two groups: treatment group (266 cases) and control group (22 cases). After comprehensive treatment, the survival rate of the treatment group was significantly higher than that of the control group, especially within 6 months to the 1 year. Preventive intervention for CBS I type may have considerable benefits. And in the long run, this treatment strategy did not significantly increase the incidence of stroke in the treatment group. CONCLUSION: The comprehensive treatment strategy for ICA-CBS of patients with NPC significantly reduced the mortality of asphyxia due to epistaxis, reduced the incidence of CBS during nasal endoscopy, and finally improved survival rate.

Poly (ADP-ribose) polymerase 1-mediated defective mitophagy contributes to painful diabetic neuropathy in the db/db model.

Studies have shown that poly (ADP-ribose) polymerase 1 (PARP1) is involved in the pathological process of diabetes. Mitophagy is widely acknowledged to be a key regulatory process in maintaining reactive oxygen species homeostasis via lysosome degradation of damaged mitochondria. However, the regulatory role of PARP1 in mitophagy-related mitochondrial oxidative injury and progression of painful diabetic neuropathy (PDN) is unclear. In this study, we studied the in vitro and in vivo mechanisms of PARP1-mediated mitophagy blockade in a leptin gene-mutation (db/db) mouse model of PDN. Db/db mice models of PDN were established by assessing the sciatic nerve conduction velocity (SNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). The results showed that PARP1 activity and mitochondrial injury of dorsal root ganglion (DRG) neurons were increased, and mitophagy was impaired in PDN mice. PARP1 was found to mediate the impairment of mitophagy in DRG neurons isolated from PDN mice. PARP1 inhibitors (PJ34 or AG14361) attenuated diabetes-induced peripheral nerve hyperalgesia, restored DRG neuron mitophagy function and decreased mitochondrial oxidative injury. Mitophagy impairment induced by lysosome deacidificant (DC661) aggravated diabetes-induced DRG neuron mitochondrial oxidative stress and injury. Taken together, our data revealed that PARP1-induced defective mitophagy of DRG neurons is a key mechanism in diabetes-induced peripheral neuropathic injury. Inhibition of PARP1 and restoration of mitophagy function are potential therapeutic targets for PDN.