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

Ieng 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

doi:10.1016/j.bja.2020.05.018

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

Br J Anaesth. 2020 Sep;125(3):298-307. doi: 10.1016/j.bja.2020.05.018. Epub 2020 Jul 2.

Authors

Ieng K Lai¹, Martin Valdearcos², Kazuhito Morioka³, Sarah Saxena⁴, Xiaomei Feng⁵, Rong Li⁶, Yosuke Uchida⁷, An Lijun⁸, Wei Li⁹, Jonathan Pan¹⁰, Suneil Koliwad², Ralph Marcucio³, Heike Wulff¹¹, Mervyn Maze¹²

Affiliations

¹ Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
² Diabetes Center and Department of Medicine, University of California, San Francisco, CA, USA.
³ Orthopaedic Trauma Institute, Department of Orthopaedic Surgery, University of California, San Francisco, CA, USA.
⁴ Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Department of Anesthesia, University Hospital Center CHU-Charleroi, Charleroi, Belgium.
⁵ Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA.
⁶ Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁷ Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA; Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁸ Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco, CA, USA; Department of Anesthesiology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, China.
⁹ Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco, CA, USA; Department of Anesthesia, Shandong Provincial Hospital, Jinan, China.
¹⁰ Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco, CA, USA.
¹¹ Department of Pharmacology University of California, Davis, CA, USA.
¹² Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. Electronic address: [email protected].

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognitive Dysfunction / prevention & control*
Disease Models, Animal
Encephalitis / prevention & control*
Kv1.3 Potassium Channel / antagonists & inhibitors*
Mice
Postoperative Complications / prevention & control*
Wound Healing / physiology*

Substances

Kv1.3 Potassium Channel

Abstract

Publication types

MeSH terms

Substances

Grants and funding