Abstract 2964: A Novel Therapeutic Strategy For Experimental Stroke Using Docosahexaenoic Acid Complexed To Human Albumin
Background and Purpose: Recently we have shown that docosahexaenoic acid (DHA; 22:6, n-3) and human albumin (Alb) is neuroprotective after experimental stroke. However, administration of high-dose Alb by expanding intravascular volume may lead to pulmonary edema and congestive heart failure. We suspected that if Alb were complexed with DHA, it might be possible to achieve neuroprotection at lower Alb doses.
Methods: Male Sprague-Dawley rats were anesthetized with isoflurane/nitrous oxide and mechanically ventilated; rectal and cranial temperatures were regulated at 36-37.5°C. Rats received 2 h MCAo by retrograde insertion of an intraluminal suture. Animals received either DHA (5mg/kg), Alb (0.63g/kg), DHA-Alb (0.32, 0.63, 1.25g/kg) or an equivalent volume of vehicle (saline), which was administered at 3 h after onset of stroke into the femoral vein over 3 min using an infusion pump (n=8-10 per group). The neurological status was evaluated during occlusion (60 min), and on days 1, 2, 3 and 7 after MCAo; a grading scale of 0-12 was employed. Seven days after MCAo, brains were perfusion-fixed, and infarct areas and volumes were determined. Number of GFAP (reactive astrocytes), ED-1 (activated microglia/microphages) and NeuN (neurons)-positive cells were counted in the cortex and striatum at the level of the central lesion.
Results: The physiological variables were entirely comparable among all groups. Animals treated with moderate doses of DHA-Alb (0.63 and 1.25g/kg) significantly improved the neurological score compared to Alb-treated rats by 21 and 26% on day 1; by 28 and 29% on day 2; by 36 and 40% on day 3; and by 42 and 35% on day 7 (respectively). The lowest dose of DHA-Alb (0.32g/kg) was not significantly different from the Alb-treated group. In addition, DHA treatment improved behavioral score compared to the Alb-treated rats, but only on day 2 (by 19%) and day 3 (by 26%). All doses of DHA-Alb (0.32, 0.63 and 1.25g/kg) significantly reduced total (cortical and subcortical) corrected infarct volume in all treated groups compared to Alb-treated rats (by 64, 60 and 61%, respectively). Cortical and striatal infarct volumes were also significantly reduced by all doses of DHA-Alb. DHA treatment alone significantly reduced only striatal infarct volume compared to the Alb-treated group (22±4 vs. 52±9, respectively).
Conclusions: The DHA-Alb complex affords high-grade neurobehavioral neuroprotection in focal cerebral ischemia, equaling or exceeding that afforded by native Alb, at considerably moderate doses. It might provide the basis for future therapeutics in patients suffering ischemic stroke.
- © 2012 by American Heart Association, Inc.