Yoko Ishii1, Jacky M K Kwong, Joseph Caprioli. 1. Department of Ophthalmology, Jules Stein Eye Institute, University of California Los Angeles School of Medicine, Los Angeles, California 90095-7000, USA.
Abstract
PURPOSE: To study the effects of geranylgeranylacetone (GGA) on the expression of inducible (HSP72) and constitutive (HSC70) heat shock proteins (HSPs) on retinal ganglion cells (RGCs) in a rat model of glaucoma. METHODS: Adult Wistar rats were given intraperitoneal injections of GGA at 200 mg/kg daily. Western blot analysis and immunohistochemical staining for HSP72 and HSC70 were performed after 1, 3, and 7 days of treatment with GGA. After 7 days of GGA pretreatment, intraocular pressure (IOP) was elevated unilaterally by repeated trabecular argon laser photocoagulation 5 days after intracameral injection of india ink. After the first laser photocoagulation, GGA was administered twice a week. RGC survival was evaluated after 5 weeks of elevated IOP. Immunohistochemistry and TdT-mediated biotin-dUTP nick end labeling (TUNEL) were performed after 1 week of elevated IOP. Quercetin, an inhibitor of HSP expression, was also administered to a separate group. RESULTS: There was increased expression of HSP72 in RGCs at 3 and 7 days after administration of GGA, but HSC70 was unchanged. After 5 weeks of elevated IOP, there was a 27% +/- 6% loss of RGCs. The administration of GGA significantly reduced the loss of RGCs, lessened optic nerve damage, decreased the number of TUNEL-positive cells in the RGC layer, and increased HSP72. Quercetin abolished these protective effects. CONCLUSIONS: These results demonstrate that systemic administration of GGA protects RGCs from glaucomatous damage in a rat model and suggest a novel pathway for neuroprotection in patients with glaucoma.
PURPOSE: To study the effects of geranylgeranylacetone (GGA) on the expression of inducible (HSP72) and constitutive (HSC70) heat shock proteins (HSPs) on retinal ganglion cells (RGCs) in a rat model of glaucoma. METHODS: Adult Wistar rats were given intraperitoneal injections of GGA at 200 mg/kg daily. Western blot analysis and immunohistochemical staining for HSP72 and HSC70 were performed after 1, 3, and 7 days of treatment with GGA. After 7 days of GGA pretreatment, intraocular pressure (IOP) was elevated unilaterally by repeated trabecular argon laser photocoagulation 5 days after intracameral injection of india ink. After the first laser photocoagulation, GGA was administered twice a week. RGC survival was evaluated after 5 weeks of elevated IOP. Immunohistochemistry and TdT-mediated biotin-dUTP nick end labeling (TUNEL) were performed after 1 week of elevated IOP. Quercetin, an inhibitor of HSP expression, was also administered to a separate group. RESULTS: There was increased expression of HSP72 in RGCs at 3 and 7 days after administration of GGA, but HSC70 was unchanged. After 5 weeks of elevated IOP, there was a 27% +/- 6% loss of RGCs. The administration of GGA significantly reduced the loss of RGCs, lessened optic nerve damage, decreased the number of TUNEL-positive cells in the RGC layer, and increased HSP72. Quercetin abolished these protective effects. CONCLUSIONS: These results demonstrate that systemic administration of GGA protects RGCs from glaucomatous damage in a rat model and suggest a novel pathway for neuroprotection in patients with glaucoma.
Authors: Liyo Kao; Lisa M Kurtz; Xuesi Shao; Marios C Papadopoulos; Li Liu; Dean Bok; Steven Nusinowitz; Bryan Chen; Salvatore L Stella; Mark Andre; Josh Weinreb; Serena S Luong; Natik Piri; Jacky M K Kwong; Debra Newman; Ira Kurtz Journal: J Biol Chem Date: 2011-06-24 Impact factor: 5.157