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Li Guo, Ben Davis, Nivedita Ravindran, Joana Galvao, Neel Kapoor, Nasrin Haamedi, M Francesca Cordeiro; Topical rh-NGF is neuroprotective to retinal ganglion cells by targeting secondary degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6131.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuropathy, including glaucoma is a major cause of irreversible blindness worldwide, and no effective treatment is currently available. Secondary degeneration is believed to be the major contributor to retinal ganglion cell (RGC) death, the endpoint of optic neuropathy. Nerve growth factor (NGF) has been increasingly recognised to be neuroprotective to RGCs in both animal models and clinical trials. The aim of this study was to determine whether the protective effects of NGF was associated with inhibiting secondary degeneration, which has never been studied before.
Dark Agouti (DA) rats under general anaesthesia, had the left optic nerve partially and superiorly transected (pONT). Recombinant human NGF (rh-NGF) was topically applied to the eye with three concentrations (60, 180 and 540 µg/ml, n=10), twice a day for three weeks. pONT only without NGF was served as control. Animals were imaged for RGC apoptosis with DARC (Detection of Apoptotic Retinal Cell) at baseline and 3 weeks, before sacrificed for histological assessment of RGC survival in retinal wholemounts by Brn-3a staining and algorithm counts. The optic nerves were stained and examined for axonal counts (anti-neurofilament) and astrocyte activation (anti-GFAP).
Topical rh-NGF significantly reduced pONT-induced damage in the retinal wholemounts, by prevention of RGC loss and preservation of nearest neighbour distances (NND) and regularity (IR) of RGCs (p<0.01 to p<0.001). The protective effects were significantly more notable in the inferior retina, where RGCs escaped initial injury but were vulnerable to secondary degeneration, than the superior retina. DARC imaging showed that topical NGF significantly reduced RGC apoptosis in vivo (p<0.05). NGF treatments also promoted RGC axonal survival (p<0.05) and reduced astrocyte activation (p<0.01), caused by pONT.
Topical rh-NGF is neuroprotective to RGCs and their axons following optic nerve injury. The protective effects of NGF are associated with targeting secondary degeneration, with implications for translating the therapy to clinic. pONT represents a reliable and reproducible model for studying secondary degeneration. DARC imaging is a useful tool for assessment of drug efficacy.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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