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

Karema Abu-Elfotuh; Amina M A Tolba; Furqan H Hussein; Ahmed M E Hamdan; Mohamed A Rabeh; Saad A Alshahri; Azza A Ali; Sarah M Mosaad; Nihal A Mahmoud; Magdy Y Elsaeed; Ranya M Abdelglil; Rehab R El-Awady; Eman Reda M Galal; Mona M Kamal; Ahmed M M Elsisi; Alshaymaa Darwish; Ayah M H Gowifel; Yasmen F Mahran

doi:10.3390/pharmaceutics15082063

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

Pharmaceutics. 2023 Jul 31;15(8):2063. doi: 10.3390/pharmaceutics15082063.

Authors

Karema Abu-Elfotuh¹, Amina M A Tolba², Furqan H Hussein³, Ahmed M E Hamdan⁴, Mohamed A Rabeh⁵, Saad A Alshahri⁵, Azza A Ali⁶, Sarah M Mosaad⁷, Nihal A Mahmoud⁸, Magdy Y Elsaeed⁹, Ranya M Abdelglil¹⁰, Rehab R El-Awady¹¹, Eman Reda M Galal¹¹, Mona M Kamal⁶, Ahmed M M Elsisi^{12

13}, Alshaymaa Darwish¹⁴, Ayah M H Gowifel¹⁵, Yasmen F Mahran¹⁶

Affiliations

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.

Keywords: Alzheimer’s disease; GSK-3β-Wnt/β-catenin; PERK/CHOP/Bcl-2; cocoa; oxidative stress; vinpocetine.

Grants and funding

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid Uni-versity for funding this work through small group Research Project under grant number RGP1/165/44./Deanship of Scientific Research at King Khalid University