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

Stroke is the third leading cause of death, due to its high incidence, theseverity of the insult, and lack of treatment options. The only therapeutic is restoration ofcerebral blood flow achieved by recombinant tissue plasminogen activator treatment,but only approximately 5% of patients receive it. In addition, therapeutics aimed atachieving neuroprotection by blocking the ischemic cascade, as identified in numerouspreclinical studies, failed in clinical trials. This failure in translation from experimentalmodels 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 neuroprotectionappears ineffective per se, an emerging direction is to identify therapies, probablycombinatorial in nature, which protect the whole neurovascular unit and target timedependentneurotoxic mechanisms. Molecules that activate complex cellular signalingcascades that render the brain resistant to subsequent ischemia, known aspreconditioners, offer a novel perspective in stroke protection. Preconditioning elicitscomplex endogenous neuroprotective responses that act by pleiotropic mechanisms toblock death pathways, promote survival pathways and increase resistance. In addition tochemical preconditioners, natural/endogenous compounds such as adenosine,glutamate, lysophospholipids, and omega-3 polyunsaturated fatty acids have beendemonstrated to be excellent preconditioners. Consequently, a major new concept inpreconditioning to combat stroke is introduced, which is preconditioning achievedthrough supplementation of an essential item in diet or as a nutraceutical. Severalepidemiologic studies suggested a beneficial effect of a seafood/omega-3-enriched dietin cerebral diseases, but the omega-3-induced protective mechanisms are still poorlyidentified. This review highlights how a-linolenic acid (ALA), the omega-3 polyunsaturatedfatty 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 againststroke. Also described is the surprising pleiotric nature of ALA in protecting neurons,vasodilating brain arteries and stimulating neuroplasticity. Importantly, feasibility ofdelivery has been demonstrated, since ALA supplementation can be achieved throughmodification of the daily diet, for which prevention of stroke-induced mortality andcerebral damage has been confirmed. Therefore evaluating ALA as an interestingpreconditioner against stroke represents a novel and extremely relevant concept in thecontext of nutraceutical and functional food development.