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A. A. McDonald, S. R. Alcala-Barraza, M. S. Lee, L. K. McLoon; Intranasal Delivery of Ciliary Neurotrophic Factor Results in Activation of Pro-Survival Pathways Following Crush Injury in Rats. Invest. Ophthalmol. Vis. Sci. 2010;51(13):644.
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Traumatic optic neuropathy (TON) and ischemic optic neuropathy (ION) are injuries to the optic nerve that lead to the death of axons of the optic nerve and their originating retinal ganglion cells. This death results in permanent vision loss, and currently there is no clinically available treatment. Providing neuroprotective factors may prevent this neuronal death by activation of pro-survival and/or anti-apoptotic pathways. In this study we assessed the effect of intranasal (IN) delivery of ciliary neurotrophic factor (CNTF) on the activation of the pStat3 and pAkt pathways.
Anesthetized adult rats were subjected to a unilateral controlled optic nerve crush (ONC) by applying a self-closing forceps to the nerve for 10 seconds. The crush-injured rats then received either a single IN administration of 70µg recombinant human CNTF 24 hours post-injury, or a series of two treatments 24 and 48 hours post-crush. After an additional 24 or 48 hours, animals were euthanized, and the retinas removed and assayed for activation of pro-survival pathways. Activation was assessed by quantification of pStat3 and pAkt levels as measured in Western blots and by immunofluorescent staining.
IN application of CNTF resulted in what we believe to be therapeutic levels in the retina and other visual system structures following delivery. This method also resulted in activation of pro-survival/anti-apoptotic pathways in the retina following a crush injury. pAkt activation was doubled in treated animals 72 hours post-crush and tripled in those animals sacrificed 96 hours post-crush as compared to untreated and crush-only retinas.
Previous treatments for ION and TON have been unsuccessful, and these injuries often result in permanent loss of visual function in these patients. Our data suggests that intranasal delivery of CNTF may result in increased retinal ganglion survival and/or decreased apoptosis following traumatic or ischemic injury to the optic nerve. A non-invasive procedure, IN delivery of neuroprotective factors appears to be a promising method for treatment of these vision-threatening injuries.
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