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A. E. Semmer, S. R. Alcala-Barraza, M. S. Lee, L. K. McLoon; Intranasal Delivery of Brain Derived Neurotrophic Factor Results in Activation of Retinal Pro-Survival Pathways. Invest. Ophthalmol. Vis. Sci. 2009;50(13):92.
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Ischemic and traumatic optic neuropathy result in significant vision loss. Appropriate drug therapy administered at the right time could potentially activate retinal pro-survival pathways after these types of injury and prevent retinal ganglion cell death. Recent studies suggest that drugs delivered intranasally reach the retina and optic nerve in potentially therapeutic levels. We tested whether intranasal delivery of brain derived neurotrophic factor (BDNF) results in activation of pro-survival pathways in adult rat retinas.
One group of rats underwent partial crush injury to one optic nerve. A second group of uninjured rats was given 70 µg of 70µg/µl intranasal BDNF in 7 µl drops over a 20 minute period. At various post-injury and post-treatment time intervals, retinas were analyzed for up-regulation of pSTAT3, a molecule known to be activated in the JAK-STAT pro-survival pathway. Retinas were homogenized, and proteins were separated by electrophoresis. Western blot analysis and densitometry were used to quantify relative pSTAT3 expression.
After crush injury, there is a transient increase in pSTAT3 expression. A statistically significant four-fold increase in pSTAT3 was seen at peak expression 48 hours after injury. A single intranasal BDNF administration resulted in a transient pSTAT3 increase to over 1.5 times the expression seen in control retinas.
Previous studies demonstrate a window of opportunity after optic nerve injury when it is possible to prevent or delay ganglion cell death. It appears that retinal ganglion cells have a limited ability to activate cell survival pathways after optic nerve crush injury. The duration of pro-survival protein expression may be extended by treating these injuries with intranasal neuroprotective factors. Not only do large proteins like BDNF reach the retina and optic nerve after intranasal administration, they also increase expression of pro-survival pathways by increasing expression of molecules like pSTAT3. Future studies will work to define dosage and duration of treatment needed to maximize expression of pro-survival molecules, with the ultimate goal of rescuing vision after optic nerve injury through the prevention of ganglion cell death.
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