Effect of Experimental Ischemic Stroke and PGE₂ EP1 Selective Antagonism in Alzheimer’s Disease Mouse Models

Article type: Research Article

Authors: Mendes, Fúlvio R.^{a; b; 2} | Leclerc, Jenna L.^{a; c; 1; 2} | Liu, Lei^a | Kamat, Pradip K.^a | Naziripour, Arash^a | Hernandez, Damian^a | Li, Chris^a | Ahmad, Abdullah S.^a | Doré, Sylvain^{a; c; *}

Affiliations: [a] Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA | [b] Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, São Bernardo do Campo, Brazil | [c] Department of Neuroscience, Neurology, Psychiatry, and Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA

Correspondence: [] Correspondence to: Sylvain Doré, 1275 Center Drive, Gainesville, FL 32610, USA. Tel.: +1 352 273 9663; E-mail: [email protected].

Note: [1] Current affiliation: Oregon Health & Science University, Department of Anesthesiology and Perioperative Medicine, Portland, OR, USA.

Note: [2] These authors contributed equally to this work.

Abstract: Background:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer’s disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. Objective:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. Methods:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. Results:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented with characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. Conclusion:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits in anatomical outcomes after stroke, mainly in APP/PS1 mice.

Keywords: Alzheimer’s disease, amyloid-β, EP1 receptor, ischemia, permanent middle cerebral artery occlusion, prostaglandin E₂, transgenic mice

DOI: 10.3233/JAD-191069

Journal: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 173-187, 2020