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.
Highlights
The increased prevalence of diabetes is gaining a great concern worldwide
Since retinal NGF was reported to promote neuronal survival in diabetic retinopathy and since CARB was documented as a neuroprotective agent in many neurologic disorders, this study explored the possible retinal protective action of CARB in diabetic mice
There was no significant difference between the mice groups that received CARB vs. the alloxan control group
Summary
The increased prevalence of diabetes is gaining a great concern worldwide. The International Diabetes Federation expected that the global number of diabetic patients will rise from 285 million diabetic patients in 2010 to 552 million by 2030 (Zochodne and Malik, 2014). Epidemiological studies have shown that more than one-third of diabetic patients worldwide suffer from diabetic retinopathy and approximately 1 in 10 suffer from high levels of diabetic retinopathy that threaten the vision (Yau et al, 2012). The main treatment options are laser photocoagulation, ocular surgery and anti-vascular endothelial growth factor (antiVEGF) for vision-threatening diabetic retinopathy (Wong and Sabanayagam, 2019). Some studies have been conducted on the use of statins and fibrates as a supplementary treatment option to delay the progress of the disease (Shi et al, 2018). Substantial progress has been made to reduce blindness due to diabetic retinopathy in high-income countries, such as orchestrated efforts directed toward public health education leading to early detection and the availability of effective therapeutic options (Wong and Sabanayagam, 2019). The search for newer, less invasive, as well as inexpensive treatment options is imperative
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