Anti-Alzheimer Activity of Combinations of Cocoa with Vinpocetine or Other Nutraceuticals in Rat Model: Modulation of Wnt3/β-Catenin/GSK-3β/Nrf2/HO-1 and PERK/CHOP/Bcl-2 Pathways

Author:

Abu-Elfotuh Karema1,Tolba Amina M. A.2,Hussein Furqan H.3,Hamdan Ahmed M. E.4ORCID,Rabeh Mohamed A.5,Alshahri Saad A.5ORCID,Ali Azza A.6,Mosaad Sarah M.7,Mahmoud Nihal A.8ORCID,Elsaeed Magdy Y.9,Abdelglil Ranya M.10,El-Awady Rehab R.11,Galal Eman Reda M.11ORCID,Kamal Mona M.6,Elsisi Ahmed M. M.1213ORCID,Darwish Alshaymaa14,Gowifel Ayah M. H.15ORCID,Mahran Yasmen F.16ORCID

Affiliation:

1. Clinical Pharmacy Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt

2. Anatomy Department, Faculty of Medicine, Girls Branch, Al-Azhar University, Cairo 11651, Egypt

3. College of Dentistry, University of Alkafeel, Najaf 54001, Iraq

4. Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia

5. Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62521, Saudi Arabia

6. Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt

7. Research Unit, Egypt Healthcare Authority, Ismailia Branch, Ismailia 41522, Egypt

8. Physiology Department, Faculty of Medicine (Girls), Al-Azhar University, Cairo 11651, Egypt

9. Physiology Department, Faculty of Medicine (Boys), Al-Azhar University, Demietta 34517, Egypt

10. Department of Anatomy and Embryology, Faculty of Medicine (Girls), Al-Azhar University, Cairo 11651, Egypt

11. Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt

12. Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11651, Egypt

13. Biochemistry Department, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef 62521, Egypt

14. Biochemistry Department, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt

15. Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt

16. Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt

Abstract

Alzheimer’s disease (AD) is a devastating illness with limited therapeutic interventions. The aim of this study is to investigate the pathophysiological mechanisms underlying AD and explore the potential neuroprotective effects of cocoa, either alone or in combination with other nutraceuticals, in an animal model of aluminum-induced AD. Rats were divided into nine groups: control, aluminum chloride (AlCl3) alone, AlCl3 with cocoa alone, AlCl3 with vinpocetine (VIN), AlCl3 with epigallocatechin-3-gallate (EGCG), AlCl3 with coenzyme Q10 (CoQ10), AlCl3 with wheatgrass (WG), AlCl3 with vitamin (Vit) B complex, and AlCl3 with a combination of Vit C, Vit E, and selenium (Se). The animals were treated for five weeks, and we assessed behavioral, histopathological, and biochemical changes, focusing on oxidative stress, inflammation, Wnt/GSK-3β/β-catenin signaling, ER stress, autophagy, and apoptosis. AlCl3 administration induced oxidative stress, as evidenced by elevated levels of malondialdehyde (MDA) and downregulation of cellular antioxidants (Nrf2, HO-1, SOD, and TAC). AlCl3 also upregulated inflammatory biomarkers (TNF-α and IL-1β) and GSK-3β, leading to increased tau phosphorylation, decreased brain-derived neurotrophic factor (BDNF) expression, and downregulation of the Wnt/β-catenin pathway. Furthermore, AlCl3 intensified C/EBP, p-PERK, GRP-78, and CHOP, indicating sustained ER stress, and decreased Beclin-1 and anti-apoptotic B-cell lymphoma 2 (Bcl-2) expressions. These alterations contributed to the observed behavioral and histological changes in the AlCl3-induced AD model. Administration of cocoa, either alone or in combination with other nutraceuticals, particularly VIN or EGCG, demonstrated remarkable amelioration of all assessed parameters. The combination of cocoa with nutraceuticals attenuated the AD-mediated deterioration by modulating interrelated pathophysiological pathways, including inflammation, antioxidant responses, GSK-3β-Wnt/β-catenin signaling, ER stress, and apoptosis. These findings provide insights into the intricate pathogenesis of AD and highlight the neuroprotective effects of nutraceuticals through multiple signaling pathways.

Funder

King Khalid University

Publisher

MDPI AG

Subject

Pharmaceutical Science

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