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

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 potential 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 sizes 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 expression of BBB-degrading and neurotoxic MMP-3 and MMP-9 expression. 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.