Brain Circulation

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 6  |  Issue : 4  |  Page : 260--268

Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke


Ludmila Belayev1, Andre Obenaus2, Pranab K Mukherjee1, Eric J Knott1, Larissa Khoutorova1, Madigan M Reid1, Cassia R Roque3, Lawrence Nguyen2, Jeong Bin Lee2, Nicos A Petasis4, Reinaldo B Oria3, Nicolas G Bazan1 
1 Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, USA
2 Department of Pediatrics, School of Medicine, University of California, Irvine, USA
3 Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans; 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
4 Department of Chemistry, University of Southern California, Los Angeles, CA, USA

Correspondence Address:
Ludmila Belayev
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA, 70112
USA
Nicolas G Bazan
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA, 70112
USA

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: PGE2, PGF2-α, 6-keto-PGF1-α, and PGD2) as well an inflammatory regulating mediator hydroxyoctadecadienoic acid. In contrast, LAU-0901 and LAU-0901 + DHA decreased the production of 12-hydroxyeicosatetraenoic acid, a pro-inflammatory mediator. 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.


How to cite this article:
Belayev L, Obenaus A, Mukherjee PK, Knott EJ, Khoutorova L, Reid MM, Roque CR, Nguyen L, Lee JB, Petasis NA, Oria RB, Bazan NG. Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke.Brain Circ 2020;6:260-268


How to cite this URL:
Belayev L, Obenaus A, Mukherjee PK, Knott EJ, Khoutorova L, Reid MM, Roque CR, Nguyen L, Lee JB, Petasis NA, Oria RB, Bazan NG. Blocking pro-inflammatory platelet-activating factor receptors and activating cell survival pathways: A novel therapeutic strategy in experimental ischemic stroke. Brain Circ [serial online] 2020 [cited 2022 Jul 5 ];6:260-268
Available from: http://www.braincirculation.org/article.asp?issn=2394-8108;year=2020;volume=6;issue=4;spage=260;epage=268;aulast=Belayev;type=0