Carbamazepine Alleviates Retinal and Optic Nerve Neural Degeneration in Diabetic Mice via Nerve Growth Factor-Induced PI3K/Akt/mTOR Activation

Nehal M Elsherbiny; Yousra Abdel-Mottaleb; Amany Y Elkazaz; Hoda Atef; Rehab M Lashine; Amal M Youssef; Wessam Ezzat; Sabah H El-Ghaiesh; Rabie E Elshaer; Mohamed El-Shafey; Sawsan A Zaitone

doi:10.3389/fnins.2019.01089

Carbamazepine Alleviates Retinal and Optic Nerve Neural Degeneration in Diabetic Mice via Nerve Growth Factor-Induced PI3K/Akt/mTOR Activation

Front Neurosci. 2019 Nov 1:13:1089. doi: 10.3389/fnins.2019.01089. eCollection 2019.

Authors

Nehal M Elsherbiny^{1

2}, Yousra Abdel-Mottaleb³, Amany Y Elkazaz^{4

5}, Hoda Atef⁶, Rehab M Lashine⁷, Amal M Youssef^{8

9}, Wessam Ezzat¹⁰, Sabah H El-Ghaiesh^{11

12}, Rabie E Elshaer¹³, Mohamed El-Shafey^{14

15}, Sawsan A Zaitone^{16

17}

Affiliations

¹ Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.
³ Department of Pharmacology and Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt.
⁴ Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
⁵ Biochemistry and Molecular Biology Department, Faculty of Medicine, Portsaid University, Port Said, Egypt.
⁶ Department of Histology and Cytology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
⁷ Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
⁸ Department of Physiology, Faculty of Medicine, Taibah University, Medina, Saudi Arabia.
⁹ Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
¹⁰ Department of Physiology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
¹¹ Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt.
¹² Department of Pharmacology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia.
¹³ Pathology Department, Faculty of Medicine (Boys), Al-Azhar University, Cairo, Egypt.
¹⁴ Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
¹⁵ Physiological Sciences Department, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia.
¹⁶ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
¹⁷ Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.

Abstract

Aim: Diabetic retinopathy causes loss of vision in adults at working-age. Few therapeutic options are available for treatment of diabetic retinopathy. Carbamazepine (CARB), a widely used antiepileptic drug, was recently accounted for its neuroprotective effect. Nerve growth factor (NGF) activates various cascades among which, PI3K/Akt/mTOR pathway has a vital action in NGF-mediated neuronal differentiation and survival. This study evaluated the effect of CARB in the treatment of diabetic retina and unveiled some of the underlying molecular mechanisms. Main Methods: Alloxan diabetes model was induced in 36 albino well-acclimatized mice. After establishment of the diabetic model in 9 weeks, mice were assigned to treatment groups: (1) saline, (2) alloxan-diabetic, (3 and 4) alloxan+CARB (25 or 50 mg per kg p.o) for 4 weeks. After completion of the therapeutic period, mice were sacrificed and eyeballs were enucleated. Retinal levels of NGF and PI3K/Akt were assessed using real-time polymerase chain reaction. Further, total and phosphorylated TrKA, PI3K, Akt, mTOR as well as Caspase-3 were measured by Western blot analysis. Key Findings: Histopathological examination demonstrated that CARB attenuated vacuolization and restored normal thickness and organization of retinal cell layers. In addition, CARB increased pTrKA/TrKA ratio and ameliorated diabetes-induced reduction of NGF mRNA and immunostaining in retina. Additionally, it augmented the mRNA expression of PI3K and Akt, as well as the protein level of the phosphorylated PI3/Akt/mTOR. Significance: Results highlighted, for the first time, the neuronal protective effect for CARB in diabetic retina, which is mediated, at least in part, by activation of the NGF/PI3K/Akt/mTOR pathway.

Keywords: NGF; PI3K/Akt/mTOR pathway; apoptosis; carbamazepine; mouse diabetic retinopathy; neuroprotection.