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Y. Shinohara, M. Nakatani, M. Hirabayashi, H. Mori, N. Asai, S. Nishimura, Y. Hibi, A. Nitta; Peribulbar Leu-Ile Delivery Using Thermo-Reversible Hydrogel Promotes Retinal Ganglion Cell Survival After Optic Nerve Injury by Inducing BDNF and GDNF Production. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2461.
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Leucine-isoleucine (Leu-Ile), a neuroprotective dipeptide, appears to induce the production of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) both in vitro and in vivo. The purpose of this study was to investigate whether peribulbar injection of Leu-Ile using an in situ gelling system promotes BDNF and GDNF production and prevents neurodegeneration of retinal ganglion cells (RGCs) in rat model of optic nerve (ON) injury.
Thermo-reversible hydrogels were prepared from 20% poloxamer 407 and 0.2% alginate. To estimate penetration of Leu-Ile into the eye, hydrogels loaded with FITC-conjugated Leu-Ile (FITC-Leu-Ile) were injected subconjunctivally in normal rats. Fluorescence intensities in posterior segments were measured at 2, 6 and 24 hours after injection. The hydrogels loaded with Leu-Ile were injected at 30 minutes after ON injury as well as in normal rats. BDNF and GDNF contents in the retina were measured by an enzyme immunoassay at 6, 24 and 72 hours after injection. RGC densities were determined by retrograde labeling of FluoroGold to the superior colliculus at 14 days after ON injury. Immunohistochemistry was conducted to elucidate expression of ED-1 (a marker for macrophage/microglia) in the ON.
At 2 hours after injection of the FITC-Leu-Ile hydrogel, fluorescence intensity in the retina was 3.9-fold higher than the saline control. Treatment with hydrogels loaded with 0.02, 0.2 or 2% Leu-Ile in normal rats significantly increased the level of BDNF and GDNF in the retina compared to those of saline- or hydrogel-treated rats. Induction of BDNF and GDNF production by Leu-Ile was also observed in the ON-injured rats. At 14 days after ON injury, the RGC densities in the retina were significantly higher in the 0.2 and 2% Leu-Ile-treated rats than in the saline- or hydrogel-treated rats. The number of ED-1 positive cells, which increased in the injured ON, was reduced by the Leu-Ile treatment.
These results suggest that Leu-Ile, released from hydrogels onto the sclera, induce BDNF and GDNF production, which may eventually facilitate the RGC survival after ON injury.
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