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S. R. Alcala, L. K. McLoon; Intranasal Administration of CNTF and Erythropoietin Activate the JAK/STAT Survival Pathway in Rat Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3184.
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Ciliary neurotrophic factor (CNTF) and erythropoietin (EPO) each have been shown to increase retinal ganglion cell (RGC) survival in vitro and after intravitreal injections in vivo. Both CNTF and EPO activate multiple signaling pathways, including the JAK-STAT and PI3K/Akt survival pathways. We have previously shown that intranasal administration of radiolabeled EPO and CNTF yield nanogram levels of each drug in the retina and optic nerve. In the present study, we examined whether intranasal administration of CNTF and EPO activates the JAK/STAT survival pathway in the rat retina. The aim is to demonstrate that the intranasal delivery method may serve as a novel, noninvasive treatment method for ischemic optic neuropathy, traumatic injury to the optic nerve, or other injury that would normally result in RGC death and permanent vision loss.
Male Long-Evans rats were anesthetized and placed in a supine position. A dose of 70 or 90 µg of CNTF or EPO (in saline) was administered intranasally over an 18 minute period. Animals surviving for a total of 48 hours received two 70 or 90 µg doses of CNTF or EPO. Intranasal saline administration served as the negative control. Animals were sacrificed following a 25 minute, 1 hour, 24 hour and 48 hour survival period, and retinas were collected and flash frozen in liquid nitrogen. Whole cell lysates were prepared, protein concentrations determined, and aliquots resolved by SDS-PAGE. The separated proteins were transferred onto nitrocellulose membranes for western blot analysis, and were immunoprobed for phosphorylated Stat3 (pStat3) and phosphorylated bad (pbad). α-tubulin was used as a loading control. Densitometric analysis allowed semi-quantitation of molecular changes in pStat3 and pbad.
Following a 25 minute survival period, pStat3 levels increased after intranasal delivery of either EPO or CNTF in treated groups compared to saline controls. This indicates that intranasal administration of these compounds rapidly reaches the retina and elicits a functional response. Both 24 and 48 hours after intranasal administration of EPO or CNTF, pbad levels increased in both the treated groups compared to saline controls.
These results demonstrate that intranasal delivery of CNTF and EPO activate prosurvival pathways within the retina and suggest the viability and efficacy of using this delivery system to target neuroprotective drugs to injured optic nerve and retina.
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