SITAGLIPTIN

The underlying molecular mechanisms involved in retinal ganglion cell (RGC) apoptosis in glaucoma remain to be fully elucidated, but inflammation plays an important role. 

Studies have shown neuroprotective properties with Glucagon-Like Peptide (GLP-1) and GLP-1 receptor agonists (GLP-1RA).

GLP-1/GLP-1R are produced by the human retina and mRNA levels and protein content of GLP-1 were significantly lower in retinas from subjects with diabetes in comparison with normal individuals.

GLP-1 levels in the retina can be increased by two mechanisms. One, by topical administration of GLP-1, so that the agent reaches the retina. And two, by reducing the degradation of GLP-1. 

Degradation of GLP-1 occurs by catalytic activity of the enzyme dipeptidyl peptidase IV (DPP-IV). This enzyme is found in higher concentration in diabetic retinas.

Sitagliptin an inhibitor of DPP-IV, reduces the degradation of GLP-1 and thereby, increases its levels in the retina.

The main function of mature oligodendrocytes in the central nervous system is to generate myelin sheaths, which accelerate the conduction of nerve impulses and provide metabolic support for neuronal axons. In a dexamethasone induced glaucoma model, researchers found a significant loss of positive Oligo-2 cells compared to untreated controls (p < 0.05). However, Sitagliptin treatment prevented RGC and oligodendrocyte (OL) loss in the retina and optic nerve head (ONH).

In glaucomatous retina, three types of glial cells, astrocytes, microglia, and Müller cells, can become activated. Microglia and macroglia are the cell types involved in inflammatory responses within the retina. Under pathological conditions, these glial cells become reactive, lose their homeostatic functions of trophic and metabolic support, and gain neurotoxic properties that trigger inflammatory-mediated neurodegeneration. Sitagliptin is neuroprotective by reducing astroglial activation in the ONH and the retina. It also reduces microglial activation in the ONH.

Gamma-synuclein can be considered a member of the Bcl-2 apoptosis family, and its overexpression and accumulation in glaucomatous eyes has a role in the pathogenesis of glaucomatous neurodegeneration by facilitating the disintegration of neurofilament networks such as Neurofilament heavy subunit (NFH) by activating astrocyte phagocytosis in the ONH and inhibiting optic nerve regeneration. The loss and dephosphorylation of neurofilament deprives metabolic routes of essential substrates for axonal energetics, thereby increasing the susceptibility of axons to injury. 

The authors found that topical administration of sitagliptin inhibits the overexpression of both macro and microglial activation that occurs in the neuroretina and in the ONH. In glaucoma there is significant loss of NFH, which is prevented by topical administration of sitagliptin.

REFERENCE:

Bogdanov P, Duarri A, Sabater D, Canz MJ, Isla-Magrané H, Ramos H, Deàs-Just A, Simó R, Hernández C. Topical Administration of Sitagliptin Prevents Retinal Neurodegeneration in a Model of Glaucoma Induced by Dexamethasone. Int J Mol Sci. 2025 Dec 20;27(1):48. doi: 10.3390/ijms27010048. PMID: 41515932; PMCID: PMC12785737.