Abstract
Optic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.
Highlights
Background radioactivityThe following samples underwent radioactivity assay: dosing solution, the solvent used for dilution; column recovery of solution, HPLC mobile phase; biological samples, samples from untreated animals, and blood from an untreated animal.Radioactivity concentration was calculated using the data processing system (ADMEDAMS Ver.2.02)
In order to test the efficacy of pridopidine for treating retinal ganglion cell (RGC) degeneration and ultimate death, the well-established Morrison model for glaucoma was utilized
Hypertonic saline injection (HSI) was performed on day 0 and day 7 into the episcleral veins of the right eye of pigmented Brown Norway rats in order to create a sustained increase of intraocular pressure (IOP)
Summary
Background radioactivityThe following samples underwent radioactivity assay: dosing solution, the solvent used for dilution; column recovery of solution, HPLC mobile phase; biological samples, samples from untreated animals, and blood from an untreated animal (to represent untreat tissues).Radioactivity concentration was calculated using the data processing system (ADMEDAMS Ver.2.02). Results Pridopidine protects retinal ganglion cells in the rat Morrison model of glaucoma.
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