title: A PEDF N-terminal peptide protects the retina from ischemic injury when delivered in PLGA nanospheres.
abstract: The neuroprotective effects of small pigment epithelium-derived factor (PEDF) peptides injected intravitreally as free peptides or delivered in poly(lactide-co-glycolide) (PLGA) nanospheres, were tested in retinal ischemic injury. We induced transient ischemia in C57BL/6 mice by elevating the intraocular pressure to the equivalent of 120 mmHg for 60 min, then injected these eyes with one of the following: PBS, full-length native PEDF, N-terminal peptides-PEDF(136-155) and PEDF(82-121), blank PLGA nanospheres or PLGA loaded with PEDF(82-121) (PLGA-PEDF(82-121)). Morphometric analysis and TUNEL assays were used to determine the extent of retinal damage. Transient ischemia caused a rapid reduction in the number of viable cells in the retinal ganglion cell (RGC) layer over 48h as compared to non-ischemic retinas. About 76% surviving cells in the RGC layer were observed in the full-length PEDF protein treated group, whereas only 32% of cells survived in the PBS group. Thus, PEDF prevented approximately 44% of the cell death in the RGC layer resulting from transient ischemia. PEDF(82-121) peptide was as effective as full-length PEDF when injected as either a free peptide or delivered in PLGA nanospheres. PLGA-PEDF(82-121) showed longer-term protection of the RGC layer with no noticeable side effects at 7days. PEDF and PEDF(82-121) lessened damage to the IPL as measured by layer thickness. PEDF and PEDF(82-121) also delayed retinal responses to ischemic injury as measured by GFAP immunolabeling in Müller cells. PEDF(82-121) is an effective neuroprotective peptide in retinal ischemia. PLGA-PEDF(82-121) offers greater protection to the retina suggesting that this peptide and the method of delivering therapeutically active drugs have potential clinical advantages for longer-term treatments of retinal diseases.
authors.affiliation: Department of Ophthalmology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Veronique V
authors.initials: VV
authors.lastname: Tran
authors.forename: Yueyue
authors.initials: Y
authors.lastname: Hu
authors.forename: W
authors.initials: W
authors.lastname: Mark Saltzman
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Barnstable
authors.forename: Joyce
authors.initials: J
authors.lastname: Tombran-Tink
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005136:Eye Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D019344:Lactic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043942:Nanotubes; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000473:pathology; D012171:Retinal Vessels; D015843:Serpins / Q000008:administration & dosage* / Q000627:therapeutic use; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D003692:Delayed-Action Preparations; D005136:Eye Proteins; D019344:Lactic Acid; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor