Abstract
Objective: Acute ischemic stroke triggers complex neurovascular, neuroinflammatory, and synaptic alterations. Our study tested the prediction that blocking platelet-activating factor-receptors (PAF-Rs)-induced pro-inflammatory signaling plus administering a docosanoid after middle cerebral artery occlusion (MCAo) would lead to sustained neurological recovery. Thus we used two small molecules: a) LAU-0901, an antagonist of the PAF-R that blocks pro-inflammatory signaling and that has shown promising efficacy in a stroke model; and b) a bioactive derivative of docosahexaenoic acid (DHA), the docosanoid Neuroprotectin D1 (NPD1), which activates cell-survival pathways and possesses potent anti-inflammatory and neuroprotective activity in the brain. Methods: Sprague-Dawley rats were anesthetized with isoflurane/nitrous oxide and received 2h MCAo by intraluminal suture. Neurological status was evaluated on days 1, 3 and 7; a grading scale of 0-12 was employed. Animals were treated with LAU-0901 (i.p. 30mg/kg, 2h after onset of stroke), NPD1 (i.v. 333mg/kg, 3h after onset of stroke) and vehicles (cyclodextrin and saline). There were four groups: LAU-0901+ NPD1; LAU-0901+saline; Cyclodextrin+ NPD1; and cyclodextrin+saline. On day 7, ex vivo MRI of the brains was conducted using 11.7 T MRI. Results: LAU-0901 and NPD1 treatments alone improved behavioral scores compared to vehicle groups by 16-44%. The neuroprotective effect was enhanced using the LAU-0901+NPD1, which resulted in improved behavioral scores up to 54% on day 7. Total lesion volumes, which were computed using T2WI, were significantly reduced by 62% with LAU-0901+NPD1 treatment compared to vehicle-treated groups. Conclusion: We are currently exploring the detailed molecular mechanisms involved in the combination treatment of the PAF-R antagonist, LAU-0901, plus NPD1. The synergistic neuroprotection observed here for the post-ischemic brain provide the basis to explore therapeutic translational avenues for ischemic stroke.
Published Version
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