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 docosahexaenoic acid (DHA) after middle cerebral artery occlusion (MCAo) would lead to sustained neurological recovery. We used two 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) DHA, which activates cell-survival pathways and possesses potent anti-inflammatory and neuroprotective activity in the brain. Methods: Sprague-Dawley rats received 2h MCAo. Behavior was evaluated at 3, 4 and 24h. Treatments: LAU-0901 (i.p. 30mg/kg, 2h after onset of stroke), DHA (i.v. 5mg/kg, 3h after onset of stroke), LAU-0901+DHA and vehicle. On day 1, following lipids were extracted: Prostaglandins (PGE2, PGF2-α, 6-keto-PGF1a), Hydroxyoctadecadienoic acid (HODE), 11-dehydro-thromboxane B2, Thromboxane B2 (TXB2), 12-hydroxyeicosatetraenoic acid (12-HETE). Lipidomic analysis was conducted using LC-ESI-MS/MS in negative ion mode and results were normalized to total sample protein. Results: LAU-0901 and DHA treatments alone improved behavioral scores compared to vehicle groups by 30-35%. The neuroprotective effect was enhanced using the LAU-0901+DHA, which resulted in improved behavioral scores up to 47% on day 1. Expression of 12-HETE (proinflammatory marker) was reduced by DHA, LAU, LAU+DHA (83, 67, 72%, respectively). Conclusion: It is remarkable that there is differential expression of eicosanoid pathways and of other lipid mediators, some of them are proinflammatory, and other are modulators of neuroinflammation in the ipsilateral stroke side. We are currently exploring the detailed molecular mechanisms involved in the combination treatment of the PAF-R antagonist, LAU-0901, plus DHA.
Published Version
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