دورية أكاديمية

Retinoprotective effect of donepezil in diabetic mice involves mitigation of excitotoxicity and activation of PI3K/mTOR/BCl 2 pathway.

التفاصيل البيبلوغرافية
العنوان: Retinoprotective effect of donepezil in diabetic mice involves mitigation of excitotoxicity and activation of PI3K/mTOR/BCl 2 pathway.
المؤلفون: 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.
المصدر: Life sciences [Life Sci] 2020 Dec 01; Vol. 262, pp. 118467. Date of Electronic Publication: 2020 Sep 19.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: 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
أسماء مطبوعة: Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.
مواضيع طبية MeSH: Cholinesterase Inhibitors/*pharmacology , Diabetes Mellitus, Experimental/*drug therapy , Diabetic Retinopathy/*prevention & control , Donepezil/*pharmacology, Animals ; Diabetes Mellitus, Experimental/complications ; Male ; Mice ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; TOR Serine-Threonine Kinases/metabolism
مستخلص: 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.)
فهرسة مساهمة: Keywords: Apoptosis; Diabetic retinopathy; Donepezil; Glutamate; Mouse; PI3K/mTOR/BCl2
المشرفين على المادة: 0 (Cholinesterase Inhibitors)
0 (Proto-Oncogene Proteins c-bcl-2)
114100-40-2 (Bcl2 protein, mouse)
8SSC91326P (Donepezil)
EC 2.7.1.1 (mTOR protein, mouse)
EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
تواريخ الأحداث: Date Created: 20200922 Date Completed: 20201204 Latest Revision: 20211204
رمز التحديث: 20231215
DOI: 10.1016/j.lfs.2020.118467
PMID: 32961236
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-0631
DOI:10.1016/j.lfs.2020.118467