Docosahexaenoic acid signaling modulates cell survival in experimental ischemic stroke penumbra and initiates long-term repair in young and aged rats

• Published in: PloS one Vol. 7; no. 10; p. e46151
• Main Authors: Eady, Tiffany N, Belayev, Ludmila, Khoutorova, Larissa, Atkins, Kristal D, Zhang, Changde, Bazan, Nicolas G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.10.2012; Public Library of Science (PLoS)
• Subjects: Activation; Aging; AKT protein; Animals; Apoptosis; Astrocytes; Behavior - drug effects; Biological activity; Biology; Biosynthesis; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - therapy; Cell survival; Cell Survival - drug effects; Cerebral blood flow; Circuit protection; Cortex; Disabilities; Disease Models, Animal; Docosahexaenoic acid; Docosahexaenoic Acids - administration & dosage; Docosahexaenoic Acids - biosynthesis; Edema; Fatty acids; Gene Expression Regulation - drug effects; Humans; Infarction, Middle Cerebral Artery; Infiltration; Inflammation; Ischemia; Kinases; Lipid peroxidation; Lipids; Male; Medicin och hälsovetenskap; Medicine; Metabolism; Microglia; Monounsaturated fatty acids; Neuroprotection; Occlusion; Omega 3 fatty acids; Oxidative stress; Phosphorylation; Physiological aspects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Recovery of function; Recovery of Function - drug effects; Restoration; Rodents; Signal Transduction; Signaling; Stroke; Stroke - metabolism; Stroke - pathology; Stroke - therapy; Survival; Traumatic brain injury; Wildlife conservation; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0046151

Docosahexaenoic acid, a major omega-3 essential fatty acid family member, improves behavioral deficit and reduces infarct volume and edema after experimental focal cerebral ischemia. We hypothesize that DHA elicits neuroprotection by inducing AKT/p70S6K phosphorylation, which in turn leads to cell survival and protects against ischemic stroke in young and aged rats. Rats underwent 2 h of middle cerebral artery occlusion (MCAo). DHA, neuroprotectin D1 (NPD1) or vehicle (saline) was administered 3 h after onset of stroke. Neurological function was evaluated on days 1, 2, 3, and 7. DHA treatment improved functional recovery and reduced cortical, subcortical and total infarct volumes 7 days after stroke. DHA also reduced microglia infiltration and increased the number of astrocytes and neurons when compared to vehicle on days 1 and 7. Increases in p473 AKT and p308 AKT phosphorylation/activation were observed in animals treated with DHA 4 h after MCAo. Activation of other members of the AKT signaling pathway were also observed in DHA treated animals including increases in pS6 at 4 h and pGSK at 24 h. DHA or NPD1 remarkably reduced total and cortical infarct in aged rats. Moreover, we show that in young and aged rats DHA treatment after MCAo potentiates NPD1 biosynthesis. The phosphorylation of p308 AKT or pGSK was not different between groups in aged rats. However, pS6 expression was increased with DHA or NPD1 treatment when compared to vehicle. We suggest that DHA induces cell survival, modulates the neuroinflammatory response and triggers long term restoration of synaptic circuits. Both DHA and NPD1 elicited remarkable protection in aged animals. Accordingly, activation of DHA signaling might provide benefits in the management of ischemic stroke both acutely as well as long term to limit ensuing disabilities.