title: Eye drop delivery of pigment epithelium-derived factor-34 promotes retinal ganglion cell neuroprotection and axon regeneration.
abstract: Axotomised retinal ganglion cells (RGCs) die rapidly by apoptosis and fail to regenerate because of the limited availability of neurotrophic factors and a lack of axogenic stimuli. However, we have recently showed that pigment epithelium-derived factor (PEDF) promotes RGC survival and axon regeneration after optic nerve crush injury. PEDF has multiple fragments of the native peptide that are neuroprotective, anti-angiogenic and anti-inflammatory. Here we investigated the neuroprotective and axogenic properties of a fragment of PEDF, PEDF-34, in retinal neurons in vitro and when delivered by intravitreal injection and eye drops in vivo. We found that PEDF-34 was 43% more neuroprotective and 52% more neuritogenic than PEDF-44 in vitro. Moreover, in vivo, intravitreal delivery of 1.88nM PEDF-34 was 71% RGC neuroprotective at 21days after optic nerve crush compared to intact controls, whilst daily eye drops containing 1.88nM PEDF-34 promoted 87% RGC survival. After topical eye drop delivery, PEDF-34 was detected in the vitreous body within 30min and attained physiologically relevant concentrations in the retina by 4h peaking at 1.4±0.05nM by 14days. In eye drop- compared to intravitreal-treated PEDF-34 animals, 55% more RGC axons regenerated 250μm beyond the optic nerve lesion. We conclude that daily topical eye drop application of PEDF-34 is superior to weekly intravitreal injections in promoting RGC survival and axon regeneration through both direct effects on retinal neurons and indirect effects on other retinal cells.
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Vasanthy
authors.initials: V
authors.lastname: Vigneswara
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Esmaeili
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Deer
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Berry
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Logan
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK. Electronic address: z.ahmed.1@bham.ac.uk.
authors.forename: Zubair
authors.initials: Z
authors.lastname: Ahmed
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D066298:In Vitro Techniques; D058449:Intravitreal Injections; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009883:Ophthalmic Solutions / Q000627:therapeutic use; D020221:Optic Nerve Injuries / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D015843:Serpins / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D019922:GAP-43 Protein; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D009883:Ophthalmic Solutions; D015843:Serpins; D014404:Tubulin; D000099174:Pigment Epithelium-Derived Factor; C488416:Tubb3 protein, rat
keywords: Axon regeneration; Neurite outgrowth; Neuroprotection; PEDF eye drops; Retinal ganglion cells