Alpha-linolenic omega-3 fatty acid for stroke protection: from brain preconditioning paradigm to nutrition
Résumé
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 a-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.
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