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

Autor:	Lai IK; Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA., Valdearcos M; Diabetes Center and Department of Medicine, University of California, San Francisco, CA, USA., Morioka K; Orthopaedic Trauma Institute, Department of Orthopaedic Surgery, University of California, San Francisco, CA, USA., Saxena S; 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., Feng X; 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., Li R; 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., Uchida Y; 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., Lijun A; 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., Li W; 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., Pan J; Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), Department of Neurological Surgery, University of California, San Francisco, CA, USA., Koliwad S; Diabetes Center and Department of Medicine, University of California, San Francisco, CA, USA., Marcucio R; Orthopaedic Trauma Institute, Department of Orthopaedic Surgery, University of California, San Francisco, CA, USA., Wulff H; Department of Pharmacology University of California, Davis, CA, USA., Maze M; Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. Electronic address: Mervyn.Maze@UCSF.edu.
Jazyk:	angličtina
Zdroj:	British journal of anaesthesia [Br J Anaesth] 2020 Sep; Vol. 125 (3), pp. 298-307. Date of Electronic Publication: 2020 Jul 02.
DOI:	10.1016/j.bja.2020.05.018
Abstrakt:	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. (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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