title: Periocular injection of in situ hydrogels containing Leu-Ile, an inducer for neurotrophic factors, promotes retinal ganglion cell survival after optic nerve injury.
abstract: Intraocular administration of neurotrophic factors has been shown to delay irreversible degeneration of retinal ganglion cells (RGCs). It would be beneficial for the treatment of optic nerve (ON) injury if such neurotrophic factors could be delivered in a less-invasive manner. The dipeptide leucine-isoleucine (Leu-Ile) appears to induce the production of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in the brain. We therefore administered Leu-Ile via periocular depot injection in rats and investigated the dipeptide's ability to induce BDNF and GDNF in the retina and to delay RGC loss in an ON injury model. Poloxamer-alginate hydrogels containing Leu-Ile were injected into the subconjunctival space of intact or ON-injured rats. BDNF and GDNF levels in the retina were determined by an enzyme immunoassay. Survival of RGCs was assessed in retinal flatmounts. Activation of extracellular signal-regulated kinases (ERK) and cAMP response element binding protein (CREB) in the retina was examined by Western blotting. At 2 h after injection of fluorescein isothiocyanate-conjugated Leu-Ile, the fluorescence intensities in the retina were 4.3-fold higher than those in the saline control. Treatment with Leu-Ile significantly increased the retinal levels of BDNF at 6 h and GDNF at 6-72 h after injection. Treatment with Leu-Ile significantly increased RGC survival to 14 days after ON injury and enhanced the activation of ERK at 72 h and CREB at 48 h after injection in the ON-injured retina. These results suggest that periocular delivery of Leu-Ile induces BDNF and GDNF production in the retina, which may eventually enhance RGC survival after ON injury.
authors: Bioengineering Institute, Research & Development Division, Nidek Co., Ltd., 13-2 Hama-cho, Gamagori, Aichi 443-0036, Japan. masayoshi_nakatani@nidek.co.jp
authors: Masayoshi
authors: M
authors: Nakatani
authors: Yuko
authors: Y
authors: Shinohara
authors: Miki
authors: M
authors: Takii
authors: Hisato
authors: H
authors: Mori
authors: Nobuharu
authors: N
authors: Asai
authors: Shigeru
authors: S
authors: Nishimura
authors: Yoko
authors: Y
authors: Furukawa-Hibi
authors: Yoshiaki
authors: Y
authors: Miyamoto
authors: Atsumi
authors: A
authors: Nitta
mesh_terms: D000464:Alginates / Q000737:chemistry*; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003692:Delayed-Action Preparations; D004151:Dipeptides / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D020100:Hydrogels; D007124:Immunoenzyme Techniques; D056965:Injections, Intraocular; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020442:Poloxamer / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000464:Alginates; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D003692:Delayed-Action Preparations; D004151:Dipeptides; D004337:Drug Carriers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006603:Hexuronic Acids; D020100:Hydrogels; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C492946:leucyl-isoleucyl; D020442:Poloxamer; D020723:Glucuronic Acid; D048049:Extracellular Signal-Regulated MAP Kinases