Protective effects of omega-3 fatty acids in a blood-brain barrier-on-chip model and on postoperative delirium-like behaviour in mice

Ting Yang; Ravikanth Velagapudi; Cuicui Kong; Unghyeon Ko; Vardhman Kumar; Paris Brown; Nathan O Franklin; Xiaobei Zhang; Ana I Caceres; Hyunjung Min; Anthony J Filiano; Ramona M Rodriguiz; William C Wetsel; Shyni Varghese; Niccolò Terrando

doi:10.1016/j.bja.2022.05.025

Protective effects of omega-3 fatty acids in a blood-brain barrier-on-chip model and on postoperative delirium-like behaviour in mice

Br J Anaesth. 2023 Feb;130(2):e370-e380. doi: 10.1016/j.bja.2022.05.025. Epub 2022 Jun 29.

Authors

Affiliations

¹ Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, NC, USA. Electronic address: ting.yang2@duke.edu.
² Department of Anesthesiology, Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC, USA.
³ Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA.
⁴ Department of Biomedical Engineering, Duke University, Durham, NC, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.
⁶ Department of Neurosurgery, Duke University, Durham, NC, USA.
⁷ Department of Neurosurgery, Duke University, Durham, NC, USA; Department of Immunology, Duke University Medical Center, Durham, NC, USA.
⁸ Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
⁹ Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, USA; Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA.
¹⁰ Department of Anesthesiology, Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC, USA; Department of Immunology, Duke University Medical Center, Durham, NC, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.

Abstract

Background: Peripheral surgical trauma can trigger neuroinflammation and ensuing neurological complications, such as delirium. The mechanisms whereby surgery contributes to postoperative neuroinflammation remain unclear and without effective therapies. Here, we developed a microfluidic-assisted blood-brain barrier (BBB) device and tested the effects of omega-3 fatty acids on neuroimmune interactions after orthopaedic surgery.

Methods: A microfluidic-assisted BBB device was established using primary human cells. Tight junction proteins, vascular cell adhesion molecule 1 (VCAM-1), BBB permeability, and astrocytic networks were assessed after stimulation with interleukin (IL)-1β and in the presence or absence of a clinically available omega-3 fatty acid emulsion (Omegaven®; Fresenius Kabi, Bad Homburg, Germany). Mice were treated 1 h before orthopaedic surgery with 10 μl g^-1 body weight of omega-3 fatty acid emulsion i.v. or equal volumes of saline. Changes in pericytes, perivascular macrophages, BBB opening, microglial activation, and inattention were evaluated.

Results: Omega-3 fatty acids protected barrier permeability, endothelial tight junctions, and VCAM-1 after exposure to IL-1β in the BBB model. In vivo studies confirmed that omega-3 fatty acid treatment inhibited surgery-induced BBB impairment, microglial activation, and delirium-like behaviour. We identified a novel role for pericyte loss and perivascular macrophage activation in mice after surgery, which were rescued by prophylaxis with i.v. omega-3 fatty acids.

Conclusions: We present a new approach to study neuroimmune interactions relevant to perioperative recovery using a microphysiological BBB platform. Changes in barrier function, including dysregulation of pericytes and perivascular macrophages, provide new targets to reduce postoperative delirium.

Keywords: blood–brain barrier; delirium; microglia; neurovascular unit; omega-3 fatty acid; organ-on-chip; pericyte; perivascular macrophage.

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MeSH terms

Animals
Blood-Brain Barrier / metabolism
Emergence Delirium*
Emulsions / metabolism
Fatty Acids, Omega-3* / metabolism
Fatty Acids, Omega-3* / pharmacology
Fatty Acids, Omega-3* / therapeutic use
Humans
Mice
Neuroinflammatory Diseases
Vascular Cell Adhesion Molecule-1 / metabolism

Substances

Emulsions
Vascular Cell Adhesion Molecule-1
Fatty Acids, Omega-3

Abstract

Publication types

MeSH terms

Substances

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