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Oksana Kutsyr, Blanca Arango-Gonzalez, Laura Fernandez-Sanchez, Victoria Maneu, Pedro Lax, Antonio F Ambrosio, Marius Ueffing, Nicolas Cuenca; Dipeptidyl deptidase-IV inhibition by sitagliptin slows down retinal neurodegeneration in rd10 mice retinas.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4879. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) is an inherited retinal degenerative disease characterized by a progressive loss of structure and function of photoreceptors and retinal pigmented epithelium. The disease courses with oxidative stress, inflammation and apoptosis processes. Sitagliptin is a dipeptidyl peptidase-IV inhibitor that has demonstrated neuroprotective effects in mouse models of diabetes. This work aimed to evaluate the possible neuroprotective effect of sitagliptin in RP.
Rd10 mice were used as a model of RP. The animals were treated orally with sitagliptin (10 mg/Kg/day) or vehicle (PBS). Electroretinography (ERG), optomotor test and vertical retinal cryostat sections stained with hematoxylin or immunohistochemistry were used to evaluate the function and morphology of the retina. Secondly, retinal organotypic cultures treated with 0.1 μM of sitagliptin were performed to determine the effect and the action pathways of sitagliptin directly on the retina, discarding systemic influences. These retinas were analyzed to measure the percentage of TUNEL-positive cells and quantify changes in cytochrome c, CREB, pCREB, and CHOP, proteins involved in sitagliptin action pathway, using western blot.
Sitagliptin administration improved retinal function in rd10 mice, displaying significantly higher amplitudes in a- and b-waves (p<0.001 both), as well as higher visual acuity (p<0.001). These functional findings correlated with a raised number of photoreceptor rows found in sitagliptin treated animals (p<0.05 in all measured points). Better-preserved photoreceptor outer and inner segments as well as well-defined axon terminals were observed in treated animals. Furthermore, presynaptic and postsynaptic elements, and synaptic contacts between photoreceptors and bipolar or horizontal cells were preserved. On the other hand, retinal organotypic cultures treated with sitagliptin showed 35% less TUNEL-positive cells (p<0.01) and western blot analysis revealed less cytochrome c and higher CREB and pCREB expression.
Sitagliptin treatment delayed retinal degeneration either by systemic administration or by local retinal treatment ameliorating function loss and photoreceptor cell survival, and preserving the cell morphology and the connectivity between the cells in the retina.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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