α-linolenic omega-3 fatty acid for stroke protection: from brain preconditioning paradigm to nutrition

Abstract

Stroke is the third leading cause of death, due to its high incidence, the severity of the insult, and lack of treatment options. The only therapeutic is restoration of cerebral blood flow achieved by recombinant tissue plasminogen activator treatment, but only approximately 5% of patients receive it. In addition, therapeutics aimed at achieving neuroprotection by blocking the ischemic cascade, as identified in numerous preclinical studies, failed in clinical trials. This failure in translation from experimental models to clinical trials led to a re-evaluation of properties which would constitute the ‘‘best-in class’’ therapeutics to be used against stroke. Given that neuroprotection appears ineffective per se, an emerging direction is to identify therapies, probably combinatorial in nature, which protect the whole neurovascular unit and target timedependent neurotoxic mechanisms. Molecules that activate complex cellular signaling cascades that render the brain resistant to subsequent ischemia, known as preconditioners, offer a novel perspective in stroke protection. Preconditioning elicits complex endogenous neuroprotective responses that act by pleiotropic mechanisms to block death pathways, promote survival pathways and increase resistance. In addition to chemical preconditioners, natural/endogenous compounds such as adenosine, glutamate, lysophospholipids, and omega-3 polyunsaturated fatty acids have been demonstrated to be excellent preconditioners. Consequently, a major new concept in preconditioning to combat stroke is introduced, which is preconditioning achieved through supplementation of an essential item in diet or as a nutraceutical. Several epidemiologic studies suggested a beneficial effect of a seafood/omega-3-enriched diet in cerebral diseases, but the omega-3-induced protective mechanisms are still poorly identified. This review highlights how α-linolenic acid (ALA), the omega-3 polyunsaturated fatty acid precursor, protects the brain from in vivo and in vitro models of stroke, thus potentially fulfilling the goal of identifying the ‘‘best-in class’’ therapeutics against stroke. Also described is the surprising pleiotric nature of ALA in protecting neurons, vasodilating brain arteries and stimulating neuroplasticity. Importantly, feasibility of delivery has been demonstrated, since ALA supplementation can be achieved through modification of the daily diet, for which prevention of stroke-induced mortality and cerebral damage has been confirmed. Therefore evaluating ALA as an interesting preconditioner against stroke represents a novel and extremely relevant concept in the context of nutraceutical and functional food development.