Neuroprotective effect of naringin against cerebellar changes in Alzheimer's disease through modulation of autophagy, oxidative stress and tau expression: An experimental study

Hend M Hassan; Mohamed R Elnagar; Eman Abdelrazik; Mohamed R Mahdi; Eman Hamza; Eman M Elattar; Eman Mohamed ElNashar; Mansour Abdullah Alghamdi; Zainah Al-Qahtani; Khulood Mohammed Al-Khater; Rashid A Aldahhan; Mamdouh ELdesoqui

doi:10.3389/fnana.2022.1012422

Neuroprotective effect of naringin against cerebellar changes in Alzheimer's disease through modulation of autophagy, oxidative stress and tau expression: An experimental study

Front Neuroanat. 2022 Oct 14:16:1012422. doi: 10.3389/fnana.2022.1012422. eCollection 2022.

Authors

Hend M Hassan¹, Mohamed R Elnagar^{2

3}, Eman Abdelrazik⁴, Mohamed R Mahdi¹, Eman Hamza^{5

6}, Eman M Elattar⁷, Eman Mohamed ElNashar^{8

9}, Mansour Abdullah Alghamdi^{8

10}, Zainah Al-Qahtani¹¹, Khulood Mohammed Al-Khater¹², Rashid A Aldahhan¹², Mamdouh ELdesoqui^{1

13}

Affiliations

¹ Department of Human Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
² Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
³ Department of Pharmacology, College of Pharmacy, The Islamic University, Najaf, Iraq.
⁴ Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
⁵ Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
⁶ Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Horus University, Damietta, Egypt.
⁷ Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
⁸ Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia.
⁹ Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Banha, Egypt.
¹⁰ Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha, Saudi Arabia.
¹¹ Neurology Section, Department of Internal Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia.
¹² Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
¹³ Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual cognitive decline. Strong antioxidants that inhibit free radicals, such as polyphenols, reduce the likelihood of developing oxidative stress-related degenerative diseases such as AD. Naringin, a flavonoid found in citrus fruit shown to be neuroprotective, reduce oxidative damage and minimize histopathological changes caused by ischemic reperfusion, enhance the long-term memory in AD animal models. This work aimed to comprehend the role of naringin in the defense of the cerebellum against aluminum chloride (AlCl₃)-induced AD in rats by investigating the behavioral, neurochemical, immunohistochemical, and molecular mechanisms that underpin its possible neuroprotective effects. Twenty-four adult albino rats were divided into four groups (n = 6/group): (i) Control (C) received saline per oral (p.o.), (ii) Naringin(N)-received naringin (100 mg/kg/d) p.o, (iii) AlCl₃-recived AlCl₃ (100 mg/kg/d) p.o and (iv) AlCl₃ + Naringin (AlCl₃ + N) received both AlCl₃ and naringin p.o for 21 days. Behavioral tests showed an increase in the time to reach the platform in Morris water maze, indicating memory impairment in the AlCl₃-treated group, but co-administration of naringin showed significant improvement. The Rotarod test demonstrated a decrease in muscle coordination in the AlCl₃-treated group, while it was improved in the AlCl₃ + N group. Neurochemical analysis of the hippocampus and cerebellum revealed that AlCl₃ significantly increased lipid peroxidation and oxidative stress and decreased levels of reduced glutathione. Administration of naringin ameliorated these neurochemical changes via its antioxidant properties. Cerebellar immunohistochemical expression for microtubule assembly (tau protein) and oxidative stress (iNOS) increased in A1C1₃-treated group. On the other hand, the expression of the autophagic marker (LC3) in the cerebellum showed a marked decline in AlCl₃-treated group. Western blot analysis confirmed the cerebellar immunohistochemical findings. Collectively, these findings suggested that naringin could contribute to the combat of oxidative and autophagic stress in the cerebellum of AlCl₃-induced AD.

Keywords: Alzheimer’s disease; aluminum chloride; autophagy; cerebellum; naringin; oxidative stress.