Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke

Abstract

We examined the neuroprotective efficacy of docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, in acute ischemic stroke; studied the therapeutic window; and investigated whether DHA administration after an ischemic stroke is able to salvage the penumbra. In each series described below, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo). In series 1, DHA or saline was administered i.v. at 3, 4, 5, or 6 h after stroke. In series 2, MRI was conducted on days 1, 3 and 7. In series 3, DHA or saline was administered at 3 h, and lipidomic analysis was conducted on day 3. Treatment with DHA significantly improved behavior and reduced total infarct volume by a mean of 40% when administered at 3 h, by 66% at 4 h, and by 59% at 5 h. Total lesion volumes computed from T2-weighted images were reduced in the DHA group at all time points. Lipidomic analysis showed that DHA treatment potentiates neuroprotectin D1 (NPD1) synthesis in the penumbra 3 days after MCAo. DHA administration provides neurobehavioral recovery, reduces brain infarction and edema, and activates NPD1 synthesis in the penumbra when administered up to 5 h after focal cerebral ischemia in rats.

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 ).…”

Docosahexaenoic acid (DHA) in stroke, Alzheimer’s disease, and blinding retinal degenerations: coping with neuroinflammation and sustaining cell survival

“…annualreviews.org leads to apoptosis and debris removal. This demonstrates the anti-inflammatory properties of DHA during cellular stress (Belayev et al, 2011).…”

“…one hour after two hours of middle cerebral artery occlusion [MCAO] leads to penumbra protection with an extended time window of protection (up to five hours) and with concomitant NPD1 synthesis (Belayev et al, 2011). Anti-apoptotic, BCL-2 protein family availability is positively modulated by NPD1, whereas pro-apoptotic BCL-2 proteins are negatively regulated, as is the arrival of leukocytes due to neurovascular unit breakdown.…”

“…Recently low-and medium-dose DHA therapy has been shown to improve neurological and histological outcomes after focal cerebral ischemia (Belayev et al, 2009). Non-invasive magnetic resonance imaging [MRI] and mass spectrometry, in conjunction with behavioral, histological and immunostaining methods, were used to provide evidence for DHA protection of the ischemic penumbra (Belayev et al, 2011).…”

A novel therapeutic strategy for experimental stroke using docosahexaenoic acid complexed to human albumin

“…An early increase in unesterified (free) DHA during brain ischemia initiates a pathway for docosanoid biosynthesis, specifically neuroprotectin D1 (NPD1) (Bazan, 2003;Marcheselli et al, 2003). We have shown that NPD1 inhibits brain ischemia-reperfusion-mediated leukocyte infiltration and proinflammatory gene expression, and promotes cell survival both in vitro and in vivo (Bazan, 2007;Belayev et al, 2011;Marcheselli et al, 2003). Our recent studies demonstrated that DHA therapy in medium (5 mg/kg) dose improved neurological and histological outcome when treatment is initiated as late as 5 h after onset of stroke (Belayev et al, 2009(Belayev et al, , 2001).…”