Publication: Alpha-Linolenic Acid: a pleiotropic option for protecting the brain from Ischemic stroke and managing metabolic comorbidities

Présentation

Introduction Despite progress in understanding cell death in ischemic stroke, stroke-related death and disability continue to progress. While protecting the brain remains a challenge, recent research indicates that nutrition could be a crucial part of the solution. Specifically, the composition of daily diets may either weaken or strengthen the brain’s resistance to stroke and triggers its comorbidities like obesity and type 2 diabetes (T2D). Over the last 30 years, the health benefits of omega-3 polyunsaturated fatty acids have gained widespread attention, initially through epidemiological studies and rapidly endorsed by the public, even before robust scientific validation emerged. With the public already open to consuming omega-3 supplements, we have evaluated the potential benefits of alpha-linolenic acid (C18:3 3, ALA) in the context of stroke and T2D. Methods We used an appropriately designed combination of in vitro approaches and more integrative in vivo animal model of stroke to explore ALA, and its dihydroxylated derivatives (called linotrins) not just as a nutrient supplement but also as a potential therapeutic agent. Results Our research demonstrates ALA’s neuroprotective effects, extending to the whole neurovascular unit. ALA has shown pleiotropic capabilities, including neuronal protection, stimulation of neuroplasticity, vasodilation of brain arteries, and reduction of neuroinflammation. Moreover, dietary modification to include ALA has been shown to reduce stroke-induced cerebral damage in mouse models, suggesting that ALA could serve as a valuable adjunctive treatment against stroke. Moreover, ALA can be metabolized by 15-LOX into linotrins, akin to the well-known Protectin DX (PDX) derived from docosahexaenoic acid (C22:6 3, DHA). In collaboration with Dr. Durand, head of the « Bioactive Lipid Synthesis » team at IBMM, we achieved the first stereoselective chemical synthesis of linotrins. We then demonstrated the anti-inflammatory effects of linotrins on glial cells, CNS resident immune cells, and the anti-apoptotic effect and pro-survival effect on beta pancreatic cells. Conclusion Our results suggest that ALA, through its converging beneficial effects on shared therapeutic targets, may serve as a valuable adjunctive treatment to address the overlapping needs in stroke and diabetes care, such as protecting various cell types, and mitigating inflammation.