Abstract
Objective: Cerebral ischemia initiates lipid peroxidation, uncompensated oxidative stress, and neuronal damage. We investigated the neuroprotective bioactivity of docosanoid (DOC) mediators: Neuroprotectin D1 (NPD1), Resolvin D1 (RvD1), and their combination (NPD1+RvD1) against experimental ischemic stroke. These lipid mediators are biosynthesized “on-demand” in response to stroke onset to resolve neuroinflammation and restore homeostasis. This study investigated the dose-response and therapeutic window in a model of focal cerebral ischemia. Methods: Male SD rats received 2h of middle cerebral artery occlusion (MCAo). Neurological score was evaluated on days 1, 2, 3, and 7, followed by an ex vivo MRI on day 7. In dose-response study, rats were treated with NPD1 (111, 222, and 333μg/kg), RvD1 (111, 222, and 333μg/kg), NPD1 + RvD1 or vehicle (n=4-5 per group). All treatments were administered IV at 3h after the onset of MCAo. In the therapeutic window study, vehicle, NPD1 (222 μg/kg), RvD1 (222 μg/kg), NPD1+RvD1 were administered IV at 3, 4, 5, and 6 h after onset of MCAo. Results: No adverse behavioral side effects were observed after drugs administration. NPD1 (111, 222, and 333μg/kg) treatment alone greatly improved neurological scores (by 32-35%) and RvD1 (111, 222, and 333μg/kg) alone (by 31-35%) vs vehicle group on day 7. The neuroprotective effect was enhanced using the NPD1+ RvD1, which improved total neurological scores on days 1-7 by 25-40% vs vehicle. Ischemic core, penumbra, and total lesion volumes (computed from T2WI) were reduced with NPD1+RvD1 by 69, 70, and 67% vs vehicle. Therapeutic window: treatments with NPD1 and RvD1 alone when administered at 3h improved behavior on day 7 by 35%. Combinatory NPD1+RvD1 treatment improved behavior when administered at 3h (by 56%), 4h (by 23%), 5h (by 26%), and 6 h (by 28%), vs vehicle. Conclusion: We show that NPD1, RvD1 alone provides high-grade neuroprotection against inflammation and elicit neurological recovery in the MCAo model. Combination therapy with NPD1 and RvD1 is more effective than the single therapy when administered up to 6h after focal cerebral ischemia in rats. Thus, we hypothesize that these treatments may potentially be used in treating focal ischemic stroke in the clinical setting.
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