Abstract
Background and aimsEarly 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. MethodsSix 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. ResultsHigh 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. ConclusionsWe 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.
Highlights
Ischemic stroke annually affects more than 15 million people worldwide with massive impact on quality of life and health care ex penditures [1]
We assessed the levels of ALA-derived n-3 fatty acids and showed that levels of EPA, docosapentaenoic acid (DPA), and DHA were increased in high-ALA group suggesting that conversion from ALA to n-3 long chain poly unsaturated fatty acids was taking place (0.03 ± 0.01 vs 2.04 ± 0.43, 0.12 ± 0.01 vs 0.64 ± 0.07 and 4.37 ± 0.43 vs 11.11 ± 0.58, p < 0.01 for EPA and p < 0.0001 for DPA and DHA, Table 1)
ALA supplementation has shown the ability to positively modulate different cardiovascular conditions [5,8,9,10,11]. It remains un known whether dietary ALA supplementation affects outcome after ischemic stroke
Summary
Ischemic stroke annually affects more than 15 million people worldwide with massive impact on quality of life and health care ex penditures [1]. Its targeted treatment remains an unmet clinical need and re-canalization strategies – the current therapeutic gold stan dard - are often withheld due to the narrow therapeutic window and numerous contraindications [2]. Such limitations concern the highly susceptible elderly population [3]. The cardio- and cerebrovascular protective effects of fish-derived dietary long-chain omega-3 (n-3) fatty acids eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids have been extensively investigated with often conflicting clinical results [4]. Stroke size and neurological dysfunction were significantly reduced in high ALA-fed animals. To the reduced stroke size, functional BBB integrity and occludin endothelial expression were maintained by high ALA supplementation. The protective effects observed with ALA supple mentation may relate to blunting of inflammation and might pave the way for novel stroke treatments
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