Abstract
Purpose :
Glaucoma is the second leading cause of blindness in the world. Presently, no effective treatment exists for glaucoma-induced degeneration of retinal ganglion cells and their axons. One possible neuroprotective target is sigma-1 receptor (S1R). S1R is a multifunctional molecular chaperone found in neurons and glia at the mitochondrial-endoplasmic reticulum interface. S1R mediates Ca2+ signaling, the antioxidant stress response, ER stress, and neurotrophin expression, all of which are critical to RGC health and survival. S1R ligands are potential therapeutic targets in other neurodegenerative conditions; however, effects of S1R activation in glaucoma have not been investigated.
Methods :
Intraocular injection of microbeads was used to induce ocular hypertension in Sprague-Dawley rat retired breeders. Tonometer (TonoLab) measurement of ocular pressure was performed on conscious rats, 2-3 times per week for the duration of the experiment. Sprague-Dawley rats were treated with the SR1 specific agonist (+)-pentazocine (PTZ). PTZ was administered (0.5 mg/kg, 3 times per week) by intraperitoneal injection starting 1 week before through 5 weeks after onset of ocular hypertension. Contralateral eyes as well as non-injected eyes served as controls. After 5 weeks of ocular hypertension optic nerves were harvested and processed for electron microscopy (EM). Axon numbers were calculated based on axon counts from 1000x EM images covering at least 10% of the optic nerve cross sectional area. Eyes were frozen in OCT then sectioned for immunohistochemical analysis.
Results :
Although animal numbers used in this study were small, the results were promising. After 5 weeks of elevated ocular hypertension axon numbers were significantly reduced by 30% compared to contralateral control eyes (n=3, * P< 0.05). Treatment with PTZ protected axons from ocular hypertension, preserving axon numbers to levels comparable to contralateral controls.
Conclusions :
Our results indicate that S1R activation is a promising strategy for providing neuroprotection in glaucoma. Further studies to elucidate the mechanisms by which S1R prevents axon loss in glaucoma will contribute to developing a cure for this blinding disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.