Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer's Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model

Ahmed Mohsen Elsaid Hamdan; Fatimah Hussain J Alharthi; Ahmed Hadi Alanazi; Soad Z El-Emam; Sameh S Zaghlool; Kamel Metwally; Sana Abdulaziz Albalawi; Yahia S Abdu; Reda El-Sayed Mansour; Hoda A Salem; Zakaria Y Abd Elmageed; Karema Abu-Elfotuh

doi:10.3390/ph15081008

Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer's Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model

Pharmaceuticals (Basel). 2022 Aug 17;15(8):1008. doi: 10.3390/ph15081008.

Affiliations

¹ Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
² Graduate Pharmacist, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
³ Pharmacist in IV Room, King Fahad Specialist Hospital, Dammam 32253, Saudi Arabia.
⁴ Pharmacology and Toxicology Department, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt.
⁵ Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Mokattam, Cairo 11571, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁷ Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
⁸ Faculty of Medicine, Ain Shams University, Giza 11591, Egypt.
⁹ Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt.
¹⁰ Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
¹¹ Department of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana at Monroe, Monroe, LA 71203, USA.
¹² Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. Additionally, Nrf2/HO-1, APOE4/LRP1, Wnt3/β-catenin, and TLR4/NLRP3 are the main signaling pathways involved in AD pathogenesis. Several phytochemicals are promising options in delaying AD evolution.

Objectives: This study aimed at studying the neuroprotective effects of some phytochemicals as morin (MOR), thymol (TML), and thymoquinone (TMQ) on physical and mental activities (PhM) in Al chloride (AlCl₃)-induced AD rat model. Another objective was to determine the specificity of phytochemicals to AD signaling pathways using molecular docking.

Methods: Eighty male Dawley rats were divided into eight groups. Each group received: saline (control group), AlCl₃, (ALAD), PhM, either alone or with a combination of MOR, TML, and/or TMQ for five weeks. Animals were then subjected to behavioral evaluation. Brain tissues were used for histopathological and biochemical analyses to determine the extent of neurodegeneration. The effect of phytochemicals on AlCl₃-induced oxidative stress and the main signaling pathways involved in AD progression were also investigated.

Results: AlCl₃ caused a decline in spatial learning and memory, as well as histopathological changes in the brains of rats. Phytochemicals combined with PhM restored antioxidant activities, increased HO-1 and Nrf2 levels, blocked inflammasome activation, apoptosis, TLR4 expression, amyloide-β generation, and tau hyperphophorylation. They also brought ApoE4 and LRP1 levels back to normal and regulated Wnt3/β-catenin/GSK3β signaling pathway.

Conclusions: The use of phytochemicals with PhM is a promising strategy for reducing AD by modulating Nrf2/HO-1, TLR4/NLRP3, APOE4/LRP1, and Wnt3/β-catenin/GSK-3β signaling pathways.

Keywords: NLRP3; amyloid beta; inflammasome; molecular docking; neurodegeneration; oxidative stress; phytochemicals; tau.

Grants and funding

00085-1442-S/Deanship of scientific research, University of Tabuk, Tabuk, Saudi Arabia