Metformin treatment confers protection of the optic nerve following photoreceptor degeneration

Abstract

Acquired or inherited or photoreceptor loss causes retinal ganglion cell loss and ultimately axonal transport alteration. Thus, therapies should be applied early during photoreceptors degeneration before the remodeling process reaches the inner retina. This study aimed to evaluate the protective effect of metformin on the rat optic nerve following photoreceptors loss induced by N-Ethyl- N -nitrosourea (ENU). Eighteen adults male Wistar rats were divided into two groups. Group I: normal vehicle control (n=6). Group II: ENU-induced photoreceptors degeneration (n=12) received a single intraperitoneal injection of ENU at a dose of 600 mg/kg. Rats in group II were equally divided into two subgroups: IIa: photoreceptor degeneration induced group and IIb: metformin treated group (200 mg/kg) for 7 days. Specimens from the optic nerve were processed for light and electron microscopy. In ENU treated group, the optic nerve revealed reduction in the diameter of the optic nerve fibers and thinning of myelin sheath with morphological changes in the glia (astrocytes, oligodendrocytes, and microglia). Caspase-3 (apoptotic marker), iNOS (oxidative stress marker) and CD68 (macrophage marker) expression increased. In metformin-treated group, the diameter of optic nerve fibers and myelin sheath thickness increased with improvement of the deterioration in the glia. Caspase-3, iNOS and CD68 expression decreased. Metformin ameliorates the histological changes of the rat optic nerve following photoreceptors loss induced by ENU.

The role of hesperidin in ameliorating retinal changes in rats with experimentally induced type 1 diabetes mellitus and the active role of vascular endothelial growth factor and glial fibrillary acidic protein

“…In contrast, nitric oxide synthase‐2 (NOS‐2) was suggested to be the result of cell death by increasing oxidative stress via caspase activation and mitochondrial dysfunction [ 48 ].…”

Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape

“…Photoreceptor cells convey visual information to RGC neurons whose myelinated axons form the optic nerve responsible for engaging visual cortex processing (Etxeberria et al, 2016 ; Kim et al, 2021 ). By using the DNA alkylating agent N-ethyl- N- nitrosourea (ENU) to induce retinal photoreceptor degeneration in rats, Eltony et al ( 2021 ) assessed whether metformin was neuroprotective. Daily ENU treated retina developed pronounced photoreceptor degeneration with vacuolations and loss of nuclei, followed by RGC death and a reduction in myelinated axons.…”

“…Additionally, the diameter of the optic nerve fiber and the thickness of its myelin sheath increased significantly by >two-fold when compared to the ENU+ only group, although the metformin+ENU group did not match the levels seen in the untreated controls. Metformin also led to significant reductions in inducible nitric oxide synthase (iNOS), a proinflammatory agent induced by microglia, and the apoptotic marker caspase-3, whose activity is modulated by AMPK (Villanueva-Paz et al, 2016 ; Eltony et al, 2021 ). However experiments to measure OL dynamics or its metabolism were not conducted, thus leaving open the question of whether changes in myelin were due to alterations in OL metabolism and possibly myelin repair (Eltony et al, 2021 ).…”

“…Metformin also led to significant reductions in inducible nitric oxide synthase (iNOS), a proinflammatory agent induced by microglia, and the apoptotic marker caspase-3, whose activity is modulated by AMPK (Villanueva-Paz et al, 2016 ; Eltony et al, 2021 ). However experiments to measure OL dynamics or its metabolism were not conducted, thus leaving open the question of whether changes in myelin were due to alterations in OL metabolism and possibly myelin repair (Eltony et al, 2021 ).…”