Dexmedetomidine attenuates perioperative neurocognitive disorders by suppressing hippocampal neuroinflammation and HMGB1/RAGE/NF-κB signaling pathway

Biomed Pharmacother. 2022 Jun:150:113006. doi: 10.1016/j.biopha.2022.113006. Epub 2022 Apr 26.

Abstract

Surgical trauma can induce an inflammatory response in the central nervous system. Neuroinflammation is a crucial pathological mechanism of perioperative neurocognitive disorders (PND). Dexmedetomidine (Dex) is an alpha (α)-2 adrenoceptor agonist that is widely used in the perioperative period. Previous studies have shown that Dex has neuroprotection in various nerve injury models, but its role in PND remains unclear. Our study aimed to observe the neuroprotective effect of Dex pretreatment on postoperative cognitive change and explore the effects of hippocampal neuroinflammation, microglial polarization and HMGB1/RAGE/NF-κB signaling pathway involved in Dex on PND in rats. Rats were pretreated with Dex alone or in combination with yohimbine (α-2 adrenoceptor antagonist) before surgery. Behavioral tests results showed that Dex ameliorated surgery-induced cognitive impairment in rats. Nissl, immunohistochemistry and TUNEL-NeuN staining results indicated that Dex reduced hippocampus damage and neuronal apoptosis caused by surgery. Dex preconditioning reduced the expression of the proinflammatory cytokines IL-1β, TNF-α and IL-6 in hippocampus. Immunohistochemical and immunofluorescence results showed that Dex preconditioning inhibited the activation of glial cells induced by surgery. Western blot analysis showed that Dex preconditioning downregulated the expression of M1 phenotype markers (CD86 and iNOS), HMGB1, RAGE and nuclear NF-κB and upregulated the expression of M2 phenotype markers (Arginase 1 and CD206) and cytoplasmic NF-κB. Yohimbine could inhibit the neuroprotective effect of Dex. These results indicated that Dex pretreatment could improve postoperative short-term cognitive impairment, and the neuroprotective mechanism may involve the suppression of hippocampal neuroinflammation, regulation of M1/M2 polarization, and inhibition of HMGB1/RAGE/NF-κB signal transduction.

Keywords: Dexmedetomidine; HMGB1; Microglial polarization; Neuroinflammation; Perioperative neurocognitive disorders.

MeSH terms

  • Animals
  • Dexmedetomidine* / pharmacology
  • HMGB1 Protein* / metabolism
  • Hippocampus / metabolism
  • NF-kappa B / metabolism
  • Neurocognitive Disorders
  • Neuroinflammatory Diseases
  • Neuroprotective Agents* / pharmacology
  • Rats
  • Receptor for Advanced Glycation End Products / metabolism*
  • Receptors, Adrenergic / metabolism
  • Signal Transduction
  • Yohimbine

Substances

  • HMGB1 Protein
  • NF-kappa B
  • Neuroprotective Agents
  • Receptor for Advanced Glycation End Products
  • Receptors, Adrenergic
  • Yohimbine
  • Dexmedetomidine