Docosahexaenoic Acid Signaling Modulates Cell Survival in Experimental Ischemic Stroke Penumbra and Initiates Long-Term Repair in Young and Aged Rats

Abstract

BackgroundDocosahexaenoic 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.Methods and ResultsRats 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.ConclusionsWe 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.

Omega-3 polyunsaturated fatty acids enhance cerebral angiogenesis and provide long-term protection after stroke

“…In line with the latter view, n-3 PUFAs are thought to confer protection against cerebral ischemia through multiple mechanisms. In addition to the acute effects, such as the attenuation of oxidative stress (Bazan, 2005), anti-inflammatory effects (Zhang et al, 2010), induction of heme oxygenase 1 (Zhang et al, 2014), and pro-survival functions (Eady et al, 2012), we recently reported potent neurorestorative properties of n-3 PUFAs, such as the promotion of endogenous neurogenesis and oligodendrogenesis (Hu et al, 2013). Transgenic overexpression of n-3 PUFAs significantly increased neural stem cell proliferation and differentiation, and increased neuroblast migration to the injury site (Hu et al, 2013).…”

Enriched endogenous omega-3 fatty acids in mice protect against global ischemia injury

“…The defi ciency in -3 PUFAs is considered to be a risk factor for human mental and neurological disorders ( 13,31,32 ). Exogenous application of -3 PUFAs slowed the progression of Alzheimer's disease in mice ( 33,34 ), prevented Huntington's disease ( 35 ), showed therapeutic potential for spinal cord injury (36)(37)(38)(39), and improved neurological and histological outcomes in the focal cerebral ischemia model ( 5,(40)(41)(42). However, these beneficial effects of -3 PUFAs are not consistently detected ( 13,43 ).…”

Time to Cooling Is Associated with Resuscitation Outcomes

“…Furthermore, blood analysis (White et al , 2006) showed that, although 3 hours after resuscitation arterial neuroprotectin D1 (NPD1) increased in all animals, it was three times higher in hypothermic animals. Unlike NSE and S-100B, which are markers of injury (Calderon et al , 2014), NPD1 is an endogenous lipid mediator that reduces inflammation and apoptosis in neurons undergoing oxidative stress (Eady et al , 2012). These findings suggest that cooling beyond the 3-hour postresuscitation window may miss an important mechanism of neuroprotection.…”