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S.R. Alcala, N. Danylkova, J. Hoekman, L. Hanson, W. Frey, L.K. McLoon; Intranasal Delivery of Insulin–Like Growth Factor–1 Distributes to the Optic Nerve and Retina in the Rat . Invest. Ophthalmol. Vis. Sci. 2006;47(13):728.
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IGF–1 is an endogenous growth factor that regulates survival and development in the central nervous system and can be neuroprotective after retinal and optic nerve injury. IGF–1 acts by initiating intracellular signaling cascades that lead to expression of prosurvival proteins or downregulation of proapoptotic proteins, thereby signaling cell proliferation and neuronal survival. Delivery of therapeutic doses of IGF–1 to the CNS, however, is circumvented by the blood brain barrier (BBB). Recent studies have determined that intranasal delivery of IGF–1 bypasses the BBB and diffusely distributes to the brain parenchyma. In this study, we examined if intranasal delivery of IGF–1 allows for distribution of therapeutic concentrations to the retina and optic nerve.
Rats were anesthetized and placed in a supine position for the duration of the procedure. Seventy µg of [125I]–IGF–1 (in 70 µl of saline) was administered to 10 male Sprague–Dawley rats by pipette in 7 µl drops, alternating between each naris every 2 minutes, over a total of 18 minutes. Animals were perfused following a 25 minute (n=6) or 1 hour (n=4) survival period. All ocular tissues were carefully dissected. Serial 1 mm coronal sections of fixed brain were prepared, and discrete brain areas were microdissected. Each sample was weighed prior to gamma counting. Tissue concentrations of [125I]–IGF–1 were determined in the cornea, lens, sclera, and retina as well as the tissues associated with the visual pathway, the anterior optic nerve, optic chiasm, posterior optic nerve, superior colliculus and occipital cortex.
Radiolabeled concentrations of IGF–1 were measured following a 25 minute and 1 hour period. Following 25 minutes, IGF–1 was detected in cornea (1.51±0.41 nM), lens (0.27±0.04 nM), retina (1.16±0.19 nM), and sclera (1.98±0.5 nM) as well as anterior optic nerve (2.91±0.41 nM), optic chiasm (5.76±2.45 nM) and posterior optic nerve (4.27±1.09 nM). During the 1 hour period, concentrations in the cornea (3.49±0.65 nM), lens (0.63±0.12 nM), retina (2.07±0.22 nM), and sclera (2.56±0.24 nM) increased, while concentrations in anterior optic nerve (3.52±0.88 nM), optic chiasm (2.10±0.65 nM) and posterior optic nerve (3.07±1.07 nM) decreased slightly.
These findings demonstrate that the intranasal delivery method allows for rapid distribution of therapeutic doses of IGF–1 to the retina and optic nerve with minimal systemic exposure. Investigations into the potential therapeutic applications of this delivery method are currently under investigation.
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