Dexmedetomidine Reduces the Lidocaine-Induced Neurotoxicity by Inhibiting Inflammasome Activation and Reducing Pyroptosis in Rats

• Published in: Biological & pharmaceutical bulletin Vol. 44; no. 7; pp. 902 - 909
• Main Authors: Ding, Xu-dong, Cao, Yan-yan, Li, Lu, Zhao, Guang-yi
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.07.2021; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Adrenergic alpha-2 Receptor Agonists - pharmacology; Adrenergic alpha-2 Receptor Agonists - therapeutic use; Anesthetics, Local; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apoptosis; Caspase-1; dexmedetomidine; Dexmedetomidine - pharmacology; Dexmedetomidine - therapeutic use; inflammasome; Inflammasomes; Inflammasomes - metabolism; Inflammation; Interleukin 18; Kinases; Lidocaine; Male; Microglia; Neurons - drug effects; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurotoxicity; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - metabolism; Phosphorylation; Phosphorylation - drug effects; Protein kinase C; Protein Kinase C-delta - metabolism; Pyroptosis; Pyroptosis - drug effects; Rats; Rats, Sprague-Dawley; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal cord injuries; pyroptosis; caspase 1; dexmedetomidine; inflammasome
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.b20-00482

Local anesthetic toxicity is closely related to neuronal death and activation of the inflammatory response. Dexmedetomidine (Dex) is an adrenergic α2 receptor agonist that can reduce the neurotoxicity induced by lidocaine. It also has anti-inflammatory effects. However, the mechanism underlying the neuroprotective effects of Dex against lidocaine-induced toxicity remains to be defined. We hypothesized that Dex exerts its neural protective effect through inhibiting inflammasome activation and through anti-pyroptosis effects against local anesthetic-induced nerve injury. In a rat model of lidocaine-induced spinal cord injury, we studied the protective effect of Dex on lidocaine-induced changes in spinal cord function, inflammasome formation and pyroptosis, pro-inflammatory cytokine expression, and protein kinase C (PKC)-δ phosphorylation. Dex reduced lidocaine-induced neurotoxicity and inhibited PKC-δ phosphorylation in the spinal cord of rats. Furthermore, Dex inhibited pyroptosis and inflammasome formation (caspase-1, NLRP3, and apoptosis-associated speck-like protein (ASC)). Finally, Dex attenuated interleukin (IL)-1β and IL-18 expression, as well as microglia response. In conclusion, Dex can reduce the severity of lidocaine-induced spinal cord injury in rats by inhibiting priming and inflammasome activation and reducing pyroptosis via PKC-δ phosphorylation.