A PEDF N-terminal peptide protects the retina from ischemic injury when delivered in PLGA nanospheres

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-PEDF136-155 and PEDF82-121, blank PLGA nanospheres or PLGA loaded with PEDF82-121 (PLGA-PEDF82-121). 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 48 h 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. PEDF82-121 peptide was as effective as full-length PEDF when injected as either a free peptide or delivered in PLGA nanospheres. PLGA-PEDF82-121 showed longer-term protection of the RGC layer with no noticeable side effects at 7 days. PEDF and PEDF82-121 lessened damage to the IPL as measured by layer thickness. PEDF and PEDF82-121 also delayed retinal responses to ischemic injury as measured by GFAP immunolabeling in Muller cells. PEDF82-121 is an effective neuroprotective peptide in retinal ischemia. PLGA-PEDF82-121 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. (c) 2006 Elsevier Ltd. All rights reserved.