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

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.

Effects of Topical Application of CHF6467, a Mutated Form of Human Nerve Growth Factor, on Skin Wound Healing in Diabetic Mice

“…Akt and mTOR are considered survival and cellular growth in response to lesions. NGF, via trkA, activates PI3K/Akt and ERK/MAPK signaling pathways and the downstream mTOR, and this pathway mediates several NGF effects, such as endothelial cell invasion and cord formation during development (Park et al 2007), angiogenesis in subchondral bone (Yu et al 2019), and neuroprotection (Elsherbiny et al 2019).…”

TSC1 as a Novel Gene for Sleep-Related Hypermotor Epilepsy: A Child with a Mild Phenotype of Tuberous Sclerosis

“…It has recently been demonstrated that carbamazepine activates NGF/PI3K/Akt/mTOR signaling in mice models of diabetic retinopathy. 9 This effect was never tested in any model of epileptogenesis, but it may result in a positive modulation of residual activity of the TSC and GATOR1 complexes in tuberous sclerosis and GATORopathies, with subsequent benefits on seizure control.…”

Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis

“…In the sixth day after the injection of alloxan, the fasting blood glucose (FBG) was measured using a One Touch Ultra Mini glucometer (USA) by applying a droplet of blood taken from the tail veins. The mice that had an FBG level greater than 200 mg/dL were counted as diabetic [ 46 ].…”