Long-term dietary supplementation with plant-derived omega-3 fatty acid improves outcome in experimental ischemic stroke

Nicole R Bonetti; Luca Liberale; Alexander Akhmedov; Lisa Pasterk; Sara Gobbato; Yustina M Puspitasari; Ana Vukolic; Seyed Soheil Saeedi Saravi; Bernd Coester; Carla Horvath; Elena Osto; Fabrizio Montecucco; Thomas F Lüscher; Jürg H Beer; Giovanni G Camici

doi:10.1016/j.atherosclerosis.2021.04.005

Long-term dietary supplementation with plant-derived omega-3 fatty acid improves outcome in experimental ischemic stroke

Atherosclerosis. 2021 May:325:89-98. doi: 10.1016/j.atherosclerosis.2021.04.005. Epub 2021 Apr 20.

Authors

Affiliations

¹ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland.
² Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.
³ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.
⁴ Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.
⁵ Institute of Food, Nutrition and Health, Laboratory of Translational Nutrition Biology, ETH Zurich, Schwerzenbach, Switzerland.
⁶ University and University Hospital Zurich, Institute of Clinical Chemistry, Zurich, Switzerland; University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
⁷ First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy.
⁸ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Royal Brompton and Harefield Hospitals and Imperial College, London, United Kingdom.
⁹ Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; University Heart Center, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland; Department of Research and Education, University Hospital Zurich, Zurich, Switzerland. Electronic address: giovanni.camici@uzh.ch.

PMID: 33915355
DOI: 10.1016/j.atherosclerosis.2021.04.005

Abstract

Background and aims: Early revascularization -the gold standard therapy for ischemic stroke- is often withheld in the elderly population due to high risk of complications. Thus, safe and effective preventive and therapeutic options are needed. The plant-derived omega-3-fatty-acid alpha-linolenic-acid (ALA) has emerged as a novel cardiovascular-protective agent. As of yet, little is known about its potential therapeutic effects on stroke. We hereby aimed to investigate the impact of a clinically relevant long-term dietary intervention with ALA on stroke outcome.

Methods: Six month-old C57BL/6 wildtype males were either fed an ALA-rich (high ALA) or a control diet (low ALA) for 12 months. At 18 months, brain ischemia/reperfusion was induced by transient middle cerebral artery occlusion (tMCAO). Stroke size and neurological function were assessed. Functional blood-brain-barrier-(BBB) permeability and protein expression were assessed by immunohistochemistry. Baseline inflammatory markers were measured at 18 months.

Results: High ALA-fed animals displayed decreased circulating TNF-α levels and Neutrophil-to-Lymphocyte Ratios at 18 months. Stroke size and neurological dysfunction were significantly reduced in high ALA-fed animals. Coherently to the reduced stroke size, functional BBB integrity and occludin endothelial expression were maintained by high ALA supplementation. Additionally, ALA reduced endothelial activation and thus recruitment and activation of macrophages and resident microglia. Finally, high ALA diet reduced the expression of BBB-degrading and neurotoxic MMP-3 and MMP-9.

Conclusions: We demonstrate the beneficial effects of a clinically relevant and feasible dietary intervention with a safe and readily available compound in the setting of stroke. The protective effects observed with ALA supplementation may relate to blunting of inflammation and might pave the way for novel stroke treatments.

Keywords: Dietary intervention; Inflammation; Ischemic stroke; Omega-3 fatty acid; α-linolenic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Brain Ischemia* / drug therapy
Dietary Supplements
Fatty Acids, Omega-3*
Humans
Infant
Ischemic Stroke*
Male
Stroke* / drug therapy
alpha-Linolenic Acid

Substances

Fatty Acids, Omega-3
alpha-Linolenic Acid