Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice

Leng K. Lai, Martin Valdearcos, Kazuhito Morioka, Sarah Saxena, Xiaomei Feng, Rong Li, Yosuke Uchida, An Lijun, Wei Li, Jonathan Pan, Suneil Koliwad, Ralph Marcucio, Heike Wulff, Mervyn Maze

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Background: Postoperative cognitive decline (PCD) requires microglial activation. Voltage-gated Kv1.3 potassium channels are involved in microglial activation. We determined the role of Kv1.3 in PCD and the efficacy and safety of inhibiting Kv1.3 with phenoxyalkoxypsoralen-1 (PAP-1) in preventing PCD in a mouse model. Methods: After institutional approval, we assessed whether Kv1.3-deficient mice (Kv1.3–/–) exhibited PCD, evidenced by tibial-fracture surgery-induced decline in aversive freezing behaviour, and whether PAP-1 could prevent PCD and postoperative neuroinflammation in PCD-vulnerable diet-induced obese (DIO) mice. We also evaluated whether PAP-1 altered either postoperative peripheral inflammation or tibial-fracture healing. Results: Freezing behaviour was unaltered in postoperative Kv1.3–/– mice. In DIO mice, PAP-1 prevented postoperative (i) attenuation of freezing behaviour (54 [17.3]% vs 33.4 [12.7]%; P=0.03), (ii) hippocampal microglial activation by size (130 [31] pixels vs 249 [49]; P<0.001) and fluorescence intensity (12 000 [2260] vs 20 800 [5080] absorbance units; P<0.001), and (iii) hippocampal upregulation of interleukin-6 (IL-6) (14.9 [5.7] vs 25.6 [10.4] pg mg−1; P=0.011). Phenoxyalkoxypsoralen-1 neither affected surgery-induced upregulation of plasma IL-6 nor cartilage and bone components of the surgical fracture callus. Conclusions: Microglial-mediated PCD requires Kv1.3 activity, determined by genetic and pharmacological targeting approaches. Phenoxyalkoxypsoralen-1 blockade of Kv1.3 prevented surgery-induced hippocampal microglial activation and neuroinflammation in mice known to be vulnerable to PCD. Regarding perioperative safety, these beneficial effects of PAP-1 treatment occurred without impacting fracture healing. Kv1.3 blockers, currently undergoing clinical trials for other conditions, may represent an effective and safe intervention to prevent PCD.

Original languageEnglish (US)
JournalBritish Journal of Anaesthesia
DOIs
StateAccepted/In press - 2020

Keywords

  • Kv1.3
  • microglial activation
  • neuroinflammation
  • phenoxyalkoxypsoralen-1
  • postoperative cognitive decline
  • potassium channel
  • wound healing

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Fingerprint

Dive into the research topics of 'Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice'. Together they form a unique fingerprint.

Cite this