Abstract 94: Protection Against Blood-Brain Barrier Disruption in Focal Cerebral Ischemia by Docosahexaenoic Acid

Abstract

INTRODUCTION: Docosahexaenoic acid (DHA; 22:6n-3) is an omega-3 essential fatty acid family member and the precursor of neuroprotectin D1, a lipid mediator which downregulates apoptosis and promotes cell survival. Recently, we have shown that DHA therapy improves functional and histological outcomes following experimental stroke. We examined the effect of DHA on blood-brain barrier (BBB) integrity after middle cerebral artery occlusion (MCAo) in rats. Damage to the BBB was judged by extravasation of Evans Blue (EB) dye. METHODS: Male SD rats were anesthetized with isoflurane and subjected to 2 h of MCAo by retrograde insertion of an intraluminal suture. DHA (5 mg/kg) or vehicle (saline) was administered IV at 3 h after the onset of MCAo and animals were sacrificed at 6, 24 or 72 h. Behavioral tests were performed at 5, 24, 48 or 72 h. EB (2% in saline, 4 ml/kg) was administered IV either at 5, 23 or 71 h after onset of MCAo. Fluorometric quantitation of EB was performed 1 h later in six brain regions. RESULTS: Physiological variables were stable and showed no significant differences between groups. In the 6 h series (n=9 per group), DHA decreased EB extravasation in the posterior ischemic hemisphere compared to saline (9.2±1.1 vs. 14.3± 1.5, respectively). In the 24 h series (n=8-9 per group), DHA improved behavioral scores on day 1 and decreased EB extravasation in the posterior ischemic hemisphere (4.9±0.41 vs. 8.5±1.0) and cortical area (3.0±0.4 vs. 8.6± 2.0, respectively) compared to saline. In the 72 h series (n=12 per group), DHA improved behavioral scores on days 1, 2 and 3, and decreased EB extravasation in the anterior (6.1±0.8 vs. 9.6±0.9), posterior (5.6±0.7 vs. 9.1±1.2, respectively) ischemic hemispheres compared to saline. In addition, EB extravasation was decreased by DHA in the cortical area (6.2±1.0 vs. 10.1±1.1) and total hemisphere (11.7±1.3 vs. 18.7±1.9, respectively) compared to vehicle. CONCLUSION: These data have demonstrated that DHA is an effective neuroprotective drug, diminishing BBB damage in a model of severe focal ischemia. Thus, it is reasonable to hypothesize that DHA may have potential use in treating focal ischemic stroke in the clinical setting. This study was supported by NIH, NINDS grant R01 NS065786 (LB) and R01 NS046741 (NGB).