학술논문
Retinoprotective effect of donepezil in diabetic mice involves mitigation of excitotoxicity and activation of PI3K/mTOR/BCl 2 pathway.
Document Type
Academic Journal
Author
Zaitone SA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, 71491 Tabuk, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt. Electronic address: szaitone@ut.edu.sa.; Alshaman R; Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, 71491 Tabuk, Saudi Arabia.; Alattar A; Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, 71491 Tabuk, Saudi Arabia.; Elsherbiny NM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, 71491 Tabuk, Saudi Arabia; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.; Abogresha NM; Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.; El-Kherbetawy MK; Pathology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.; Elaskary AA; Ophthalmology Department, Al-Azher Asyut Faculty of Medicine for Men, Asyut, Egypt.; Hashish AA; Clinical Pathology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.; Rashed LA; Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.; Ahmed E; Clinical Pharmacology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
Source
Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0375521 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0631 (Electronic) Linking ISSN: 00243205 NLM ISO Abbreviation: Life Sci Subsets: MEDLINE
Subject
Language
English
Abstract
Donepezil (DNPZ) has shown neuroprotective effect in many disorders. The current study tested the putative retinoprotection provided by donepezil in mouse diabetic retinopathy. Swiss albino mice were allocated to, 1] saline control, 2] diabetic, 3&4] diabetic+DNPZ (1 or 4 mg/kg). After induction of diabetes, mice were maintained for 8 weeks then DNPZ therapy was launched for 28 days. Retinas were isolated and used for histopathology and immunohistochemistry for caspase 3 and the anti-apoptotic protein, B-cell lymphoma 2 (BCl2). Retinas were examined for glutamate, acetylcholine and oxidation markers. Western blot analysis measured inflammatory cytokines, N-methyl-d-aspartate receptors (NMDARs), phosphorylated and total phosphatidylinositol-3 kinase and mTOR, BCl2 and cleaved caspase 3. Significant histopathological changes and decreased thickness were found in diabetic retinas (125.52 ± 2.85 vs. 157.15 ± 7.55 in the saline group). In addition, retinal glutamate (2.39-fold), inflammatory cytokines and NMDARs proteins (4.9-fold) were higher in the diabetic retinas. Western blot analysis revealed low ratio of phosphorylated/total PI3K (0.21 ± 0.043 vs. 1 ± 0.005) and mTOR (0.18 ± 0.04 vs. 1 ± 0.005), low BCl2 (0.28 ± 0.06 vs. 1 ± 0.005) and upregulated cleaved caspase 3 (5.18 ± 1.27 vs. 1 ± 0.05 in the saline group) versus the saline control. DNPZ ameliorated the histopathologic manifestations and to prevent the decrease in retinal thickness. DNPZ (4 mg/kg) improved phosphorylation of PI3K (0.76 ± 0.12 vs. 0.21 ± 0.04) and mTOR (0.59 ± 0.09 vs. 0.18 ± 0.04) and increased BCl2 (0.75 ± 0.08 vs. 0.28 ± 0.06) versus the diabetic control group. This study explained the retinoprotective effect of DNPZ in mouse diabetic retinopathy and highlighted that mitigation of excitotoxicity, improving phosphorylation of PI3K/mTOR and increasing BCl2 contribute to this effect.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
(Copyright © 2020 Elsevier Inc. All rights reserved.)