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Review
. 2015;2015:519830.
doi: 10.1155/2015/519830. Epub 2015 Feb 19.

Alpha-linolenic Acid: An omega-3 Fatty Acid With Neuroprotective Properties-Ready for Use in the Stroke Clinic?

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Free PMC article
Review

Alpha-linolenic Acid: An omega-3 Fatty Acid With Neuroprotective Properties-Ready for Use in the Stroke Clinic?

Nicolas Blondeau et al. Biomed Res Int. .
Free PMC article

Abstract

Alpha-linolenic acid (ALA) is plant-based essential omega-3 polyunsaturated fatty acids that must be obtained through the diet. This could explain in part why the severe deficiency in omega-3 intake pointed by numerous epidemiologic studies may increase the brain's vulnerability representing an important risk factor in the development and/or deterioration of certain cardio- and neuropathologies. The roles of ALA in neurological disorders remain unclear, especially in stroke that is a leading cause of death. We and others have identified ALA as a potential nutraceutical to protect the brain from stroke, characterized by its pleiotropic effects in neuroprotection, vasodilation of brain arteries, and neuroplasticity. This review highlights how chronic administration of ALA protects against rodent models of hypoxic-ischemic injury and exerts an anti-depressant-like activity, effects that likely involve multiple mechanisms in brain, and may be applied in stroke prevention. One major effect may be through an increase in mature brain-derived neurotrophic factor (BDNF), a widely expressed protein in brain that plays critical roles in neuronal maintenance, and learning and memory. Understanding the precise roles of ALA in neurological disorders will provide the underpinnings for the development of new therapies for patients and families who could be devastated by these disorders.

Figures

Figure 1
Figure 1
Structure of α-linolenic acid. α-Linolenic acid is an 18-carbon, polyunsaturated fatty acid that is essential for normal health. Because humans do not possess the enzymes to synthesize the compound, it must be obtained from dietary sources.
Figure 2
Figure 2
Interplay between NMDA and TrkB receptors mediated by ALA-induced lipid rafts in neuronal plasma membranes. An increase in the nutraceutical ALA is hypothesized to markedly increase membrane fluidity leading to the efficient formation of lipid rafts [5] in neuronal plasma membranes. Lipid rafts are the functional domains of the plasma membrane and play a crucial role in the regulation of transmembrane signaling [6]. TrkB receptors and some NMDA receptors are constituents of lipid rafts [–10] and one of the major nonprotein components of lipid rafts is cholesterol [6]. The enhanced formation and/or efficiency of transmembrane signaling is hypothesized to result in enhanced activation (phosphorylation) of NMDA and TrkB receptors via the binding of BDNF to its cognate receptor, TrkB. Activation of NMDA receptors results in enhanced calcium influx and activation of signal transduction pathways leading to activation of nuclear factor kappa B (NF-κB) via the canonical pathway (phosphorylation of I-κB leads to its dissociation from the dimer (p65/p50) which then translocates to the nucleus where it binds to κB sites to regulate gene expression) which in turn increases BDNF mRNA and protein levels [–14]. Enhanced intracellular BDNF protein expression would lead to an increase in secretion, thereby maintaining its availability to bind to TrkB in an autocrine fashion [14, 15] as well as to stimulate neurogenesis, synaptogenesis, and synaptic function at distant sites (paracrine function).
Figure 3
Figure 3
In vivo subchronic ALA treatment increases mature BDNF levels in neurons of the cortex and hippocampus, but not in striatum. BDNF increase in these specific brain regions is consistent with well-known properties for the efficiency of antidepressant drugs and with the level of brain protection offered by the subchronic ALA treatment. Mature BDNF expression was measured 10 days after the subchronic treatment by Western blots in cortex, hippocampus (* P > 0.05), and striatum (P < 0.05) of mice injected with ALA or vehicle. Subchronic treatment consisted of three i.v. injections of 500 nmol/kg of α-linolenic acid on days 1, 3, and 7.

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