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Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice.
Lai, Ieng K; Valdearcos, Martin; Morioka, Kazuhito; Saxena, Sarah; Feng, Xiaomei; Li, Rong; Uchida, Yosuke; Lijun, An; Li, Wei; Pan, Jonathan; Koliwad, Suneil; Marcucio, Ralph; Wulff, Heike; Maze, Mervyn.
Afiliação
  • 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.
Br J Anaesth ; 125(3): 298-307, 2020 09.
Article em En | MEDLINE | ID: mdl-32624183
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Complicações Pós-Operatórias / Cicatrização / Encefalite / Canal de Potássio Kv1.3 / Disfunção Cognitiva Limite: Animals Idioma: En Revista: Br J Anaesth Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Complicações Pós-Operatórias / Cicatrização / Encefalite / Canal de Potássio Kv1.3 / Disfunção Cognitiva Limite: Animals Idioma: En Revista: Br J Anaesth Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos