Abstract
Thy-1 is a cell surface protein that is expressed during the differentiation of retinal ganglion cells (RGCs). Optic nerve injury induces progressive loss in the number of RGCs expressing Thy-1. The rate of this loss is fastest during the first week after optic nerve injury and slower in subsequent weeks. This study was undertaken to determine whether oral treatment with a water-soluble N-hydroxy-2,2,6,6-tetramethylpiperidine derivative (OT-440) protects against loss of Thy-1 promoter activation following optic nerve crush and whether this effect targets the earlier quick phase or the later slow phase. The retina of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) was imaged using a blue-light confocal scanning laser ophthalmoscope (bCSLO). These mice then received oral OT-440 prepared in cream cheese or dissolved in water, or plain vehicle, for two weeks and were imaged again prior to unilateral optic nerve crush. Treatments and weekly imaging continued for four more weeks. Fluorescent neurons were counted in the same defined retinal areas imaged at each time point in a masked fashion. When the counts at each time point were directly compared, the numbers of fluorescent cells at each time point were greater in the animals that received OT-440 in cream cheese by 8%, 27%, 52% and 60% than in corresponding control animals at 1, 2, 3 and 4 weeks after optic nerve crush. Similar results were obtained when the vehicle was water. Rate analysis indicated the protective effect of OT-440 was greatest during the first two weeks and was maintained in the second two weeks after crush for both the cream cheese vehicle study and water vehicle study. Because most of the fluorescent cells detected by bCSLO are RGCs, these findings suggest that oral OT-440 can either protect against or delay early degenerative responses occurring in RGCs following optic nerve injury.
Highlights
Loss of retinal ganglion cells (RGCs) is a well-known consequence of optic nerve damage that occurs in a number of diseases including glaucoma, ischemic optic neuropathy and compressive optic neuropathy [1,2,3]
Modification of Tempol-H to facilitate oral absorbtion yielded the derivative 4–(4(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yloxy)-1,2,5-thiadiazol3-yl) morpholine hydrochloride (OT-440). It is unknown whether oral administration of OT-440 can reduce or slow the loss of Thy1 expression in RGCs that occurs following optic nerve injury
Among retinas from different animals, the count variations could be up to 2-fold. In view of these results, it seemed appropriate to investigate the differences between the baseline counts of a defined retinal area from an experimental eye and counts of the same retinal area of that eye collected at different time points after optic nerve crush
Summary
Loss of retinal ganglion cells (RGCs) is a well-known consequence of optic nerve damage that occurs in a number of diseases including glaucoma, ischemic optic neuropathy and compressive optic neuropathy [1,2,3]. Elevating RGC expression of the antioxidant enzyme Cu -Zn-superoxide dismutase reduces RGC loss following optic nerve crush [9]. Both the nitroxide Tempol (4hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) and its hydroxylamine form Tempol-H (1,4-dihydroxy-2,2,6,6-tetramethylpiperidine) are superoxide dismutase mimetics [10]. Intraperitoneal (IP) administration of Tempol or more potent Tempol-acyl derivatives can protect against loss of RGCs following partial optic nerve crush [8,11]. Modification of Tempol-H to facilitate oral absorbtion yielded the derivative 4–(4(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yloxy)-1,2,5-thiadiazol3-yl) morpholine hydrochloride (OT-440). It is unknown whether oral administration of OT-440 can reduce or slow the loss of Thy expression in RGCs that occurs following optic nerve injury
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