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Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 8;97:109793. doi: 10.1016/j.pnpbp.2019.109793. Epub 2019 Oct 24.

Neuroprotective effect of PPAR alpha and gamma agonists in a mouse model of amyloidogenesis through modulation of the Wnt/beta catenin pathway via targeting alpha- and beta-secretases.

Author information

1
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr University for Science and Technology, Cairo, Egypt.
2
Department of Narcotics, Ergogenic Aids and Poisons, Medical Research Division, National Research Centre, Giza, Egypt.
3
Department of Narcotics, Ergogenic Aids and Poisons, Medical Research Division, National Research Centre, Giza, Egypt; Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia.
4
Department of Medical Physiology, Medical Research Division, National Research Centre, Egypt.
5
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: nesrine.salah@pharma.cu.edu.eg.

Abstract

The present study was conducted to evaluate the efficacy of fenofibrate and pioglitazone in a mouse model of amyloidogenesis induced by amyloidβ (βA) peptide. Mice were injected intracerebroventricularly with βA1-40 (400 pmol/mouse) once, followed by treatment with fenofibrate (300 mg/kg), pioglitazone (30 mg/kg),or both. After 21 days of daily treatment, memory impairment and cognitive function were evaluated by Morris water maze (MWM), Y-maze and object recognition tests. On the 22nd day, mice were sacrificed, and their hippocampi were dissected to determine the levels of α- and β-secretase, peroxisome proliferator-activated receptor (PPARα and β), Wnt and β-catenin. Significant memory impairment and cognitive dysfunction were observed in the mouse model group. This finding was associated with a significant increase in α- and β-secretase levels and a significant decrease in Wnt, β-catenin, and PPARα and β levels. Neuronal damage was also evident after histopathological examination. Treatment with fenofibrate, pioglitazone and their combination resulted in a significant improvement in the behavioural and neurochemical changes induced by βA injection. The present findings indicate that the combined administration of fenofibrate and pioglitazone was more effective than monotherapy in ameliorating the behavioural, neurochemical and histopathological changes in amyloidogenesis model mice and provide a promising therapeutic approach in the management of Alzheimer's disease complicated by diabetes and hypercholesterolemia.

KEYWORDS:

Amyloidogenesis; Fenofibrate; Pioglitazone; Secretases; Wnt; β-catenin

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