Omega-3 polyunsaturated fatty acids are known to have therapeutic potential in several neurological and psychiatric disorders. However, the molecular mechanisms of action underlying these effects are not well elucidated. We previously showed that alpha-linolenic acid (ALA) reduced ischemic brain damage after a single treatment. To follow-up this finding, we investigated whether subchronic ALA treatment promoted neuronal plasticity. Three sequential injections with a neuroprotective dose of ALA increased neurogenesis and expression of key proteins involved in synaptic functions, namely, synaptophysin-1, VAMP-2, and SNAP-25, as well as proteins supporting glutamatergic neurotransmission, namely, V-GLUT1 and V-GLUT2. These effects were correlated with an increase in brain-derived neurotrophic factor (BDNF) protein levels, both in vitro using neural stem cells and hippocampal cultures and in vivo, after subchronic ALA treatment. Given that BDNF has antidepressant activity, this led us to test whether subchronic ALA treatment could produce antidepressant-like behavior. ALA-treated mice had significantly reduced measures of depressive-like behavior compared with vehicletreated animals, suggesting another aspect of ALA treatment that could stimulate functional stroke recovery by potentially combining acute neuroprotection with long-term repair/compensatory plasticity. Indeed, three sequential injections of ALA enhanced protection, either as a pretreatment, wherein it reduced post-ischemic infarct volume 24 h after a 1-hour occlusion of the middle cerebral artery or as post-treatment therapy, wherein it augmented animal survival rates by threefold 10 days after ischemia.

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Background: Stroke is a devastating disorder that strikes approximately 15 million people worldwide. While most patients survive stroke, many are left with lifelong impairments, thereby making stroke the leading cause of permanent neurological disability. Despite this, there are a few options for treatment of acute stroke. Restoration of blood flow using clot-dissolving drugs has produced impressive benefits in some patients. However, for these drugs to be effective, they must be given soon after stroke onset and relatively only a few stroke patients reach hospital within this time. Side effects of these compounds further limit their use. Summary: Enhancing the brain's endogenous capacity for reorganization and self-repair offers the most promise for victims of stroke. Indeed, many stroke patients show considerable spontaneous functional improvement. Findings in the last 15 years suggest that stroke and related injury create a cerebral milieu similar to that of early brain development, a period characterized by rapid neuronal growth and neuroplasticity. A variety of interventions (e.g., stem cells, delivery of growth factors) are currently being explored in order to enhance neuroplasticity and reorganizational processes that are important for recovery of function. An emerging concept is that combinational or ‘cocktail' therapies are more effective than single interventions in improving stroke recovery. Among these, one of the most promising therapies is enriched rehabilitation, a combination of environmental enrichment and task-specific therapy (e.g., reach training). Key Messages: Neurorestorative approaches to brain reorganization and repair are providing new insights into how neural circuits respond to injury and how this knowledge can be used for optimizing stroke rehabilitation practice.

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