The protective effects of sesamol and/or the probiotic, Lactobacillus rhamnosus, against aluminum chloride-induced neurotoxicity and hepatotoxicity in rats: Modulation of Wnt/β-catenin/GSK-3β, JAK-2/STAT-3, PPAR-γ, inflammatory, and apoptotic pathways

Karema Abu-Elfotuh; Heba Mohammed Refat M Selim; Omnia Karem M Riad; Ahmed M E Hamdan; Soha Osama Hassanin; Asmaa F Sharif; Nouran Magdy Moustafa; Ayah M H Gowifel; Marwa Y A Mohamed; Ahmed M Atwa; Sameh S Zaghlool; Mahmoud Nour El-Din

doi:10.3389/fphar.2023.1208252

The protective effects of sesamol and/or the probiotic, Lactobacillus rhamnosus, against aluminum chloride-induced neurotoxicity and hepatotoxicity in rats: Modulation of Wnt/β-catenin/GSK-3β, JAK-2/STAT-3, PPAR-γ, inflammatory, and apoptotic pathways

Front Pharmacol. 2023 Aug 2:14:1208252. doi: 10.3389/fphar.2023.1208252. eCollection 2023.

Authors

Affiliations

¹ Clinical Pharmacy Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
² Pharmaceutical Sciences Department, Faculty of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
³ Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁴ Pharmacy Practice Department, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.
⁵ Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, Egypt.
⁶ Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
⁷ Clinical Medical Sciences Department, College of Medicine, Dar Al Uloom University, Riyadh, Saudi Arabia.
⁸ Basic Medical Science Department, College of Medicine, Dar Al Uloom University, Riyadh, Saudi Arabia.
⁹ Medical Microbiology and Immunology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
¹⁰ Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, Egypt.
¹¹ Biology Department, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.
¹² Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt.
¹³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City (USC), Menoufia, Egypt.

Abstract

Introduction: Aluminium (Al) is accumulated in the brain causing neurotoxicity and neurodegenerative disease like Alzheimer's disease (AD), multiple sclerosis, autism and epilepsy. Hence, attenuation of Al-induced neurotoxicity has become a "hot topic" in looking for an intervention that slow down the progression of neurodegenerative diseases. Objective: Our study aims to introduce a new strategy for hampering aluminum chloride (AlCl3)-induced neurotoxicity using a combination of sesamol with the probiotic bacteria; Lactobacillus rhamnosus (L. rhamnosus) and also to test their possible ameliorative effects on AlCl₃-induced hepatotoxicity. Methods: Sprague-Dawley male rats were randomly divided into five groups (n = 10/group) which are control, AlCl₃, AlCl₃ + Sesamol, AlCl₃ + L. rhamnosus and AlCl₃ + Sesamol + L. rhamnosus. We surveilled the behavioral, biochemical, and histopathological alterations centrally in the brain and peripherally in liver. Results: This work revealed that the combined therapy of sesamol and L. rhamnosus produced marked reduction in brain amyloid-β, p-tau, GSK-3β, inflammatory and apoptotic biomarkers, along with marked elevation in brain free β-catenin and Wnt3a, compared to AlCl₃-intoxicated rats. Also, the combined therapy exerted pronounced reduction in hepatic expressions of JAK-2/STAT-3, inflammatory (TNF-α, IL-6, NF-κB), fibrotic (MMP-2, TIMP-1, α-SMA) and apoptotic markers, (caspase-3), together with marked elevation in hepatic PPAR-γ expression, compared to AlCl₃ -intoxicated rats. Behavioral and histopathological assessments substantiated the efficiency of this combined regimen in halting the effect of neurotoxicity. Discussion: Probiotics can be used as an add-on therapy with sesamol ameliorate AlCl₃ -mediated neurotoxicity and hepatotoxicity.

Keywords: AlCl3; JAK-2/STAT-3; Lactobacillus rhamnosus; PPAR-γ; Wnt/β-catenin/GSK-3β; neurotoxicity; probiotic; sesamol.