Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke.
| Autor: | Belayev L; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA., Obenaus A; Department of Pediatrics, School of Medicine, University of California, Irvine, USA., Mukherjee PK; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA., Knott EJ; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA., Khoutorova L; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA., Reid MM; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA., Roque CR; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA.; Department of Morphology and Institute of Biomedicine, School of Medicine, Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Federal University of Ceara, Fortaleza, Brazil., Nguyen L; Department of Pediatrics, School of Medicine, University of California, Irvine, USA., Lee JB; Department of Pediatrics, School of Medicine, University of California, Irvine, USA., Petasis NA; Department of Chemistry, University of Southern California, Los Angeles, CA, USA., Oria RB; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA.; Department of Morphology and Institute of Biomedicine, School of Medicine, Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Federal University of Ceara, Fortaleza, Brazil., Bazan NG; Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Brain circulation [Brain Circ] 2020 Dec 29; Vol. 6 (4), pp. 260-268. Date of Electronic Publication: 2020 Dec 29 (Print Publication: 2020). |
| DOI: | 10.4103/bc.bc_36_20 |
| Abstrakt: | Objective: Acute ischemic stroke triggers complex neurovascular, neuroinflammatory, and synaptic alterations. This study explores whether blocking pro-inflammatory platelet-activating factor receptor (PAF-R) plus selected docosanoids after middle cerebral artery occlusion (MCAo) would lead to neurological recovery. The following small molecules were investigated: (a) LAU-0901, a PAF-R antagonist that blocks pro-inflammatory signaling; and (b) derivatives of docosahexaenoic acid (DHA), neuroprotectin D1 (NPD1), and aspirin-triggered NPD1 (AT-NPD1), which activates cell survival pathways and are exert potent anti-inflammatory activity in the brain. Materials and Methods: Sprague-Dawley rats received 2 h MCAo and LAU-0901 (30 or 60 mg/kg, 2 h after stroke), NPD1, and AT-NPD1 (333 μg/kg), DHA (5 mg/kg), and their combination were administered intravenous at 3 h after stroke. Behavior testing and ex vivo magnetic resonance imaging were conducted on day 3 or 14 to assess lesion characteristics and lipidomic analysis on day 1. Series 1 (LAU-0901 + NPD1, 14d), Series 2 (LAU-0901 + AT-NPD1, 3d), and Series 3 (LAU-0901 + DHA, 1d). Results: All combinatory groups improved behavior compared to NPD1, AT-NPD1, or DHA treatments alone. Total lesion volumes were reduced with LAU-0901 + NPD1 by 62% and LAU-0901 + AT-NPD1 by 90% treatments versus vehicle groups. LAU-0901 and LAU-0901 + DHA increased the production of vasoactive lipid mediators (prostaglandins: PGE Conclusion: Combination therapy with LAU-0901 and selected docosanoids is more effective than the single therapy, affording synergistic neuroprotection, with restored pro-homeostatic lipid mediators and improved neurological recovery. Altogether, our findings support the combinatory therapy as the basis for future therapeutics for ischemic stroke. Competing Interests: There are no conflicts of interest. (Copyright: © 2020 Brain Circulation.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|