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Y Ishii, JM K Kwong, J Caprioli; Retinal Ganglion Cell Protection with Geranylgeranylacetone, a Heat Shock Protein Inducer, in a Rat Glaucoma Model . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2195.
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Purpose: To study the expression of heat shock protein (HSP) 70 family members in retinal ganglion cells (RGCs) after systemic administration of geranylgeranylacetone (GGA), a HSP inducer, and to evaluate the effects of GGA against the loss of RGCs and axonal damage in a rat glaucoma model. Methods: Adult Male Wistar rats (250-300 g) were given intraperitoneal (IP) injections of GGA 200mg/kg daily. At 1, 3 or 7 days, animals were euthanized and RGCs were isolated for western blot analyses of constitutive (HSC70), inducible (HSP72), mitochondrial (GRP75) and endoplasmic reticulum (GRP78) form. After pretreatment of GGA for 7 days, repeated argon laser photocoagulation (200 spots, 200 mm, 180 mW, 0.2 sec) was given to the trabecular meshwork of the right eye at 5 days after intracameral injection of India ink while the contralateral eye served as control. Intraocular pressure (IOP) was measured with the Tonopen XL. After photocoagulation, GGA was given twice a week for 5 weeks (long-term) while control rats received IP injections of saline. At 5 weeks after photocoagulation, the number of RGCs retrogradely labeled with DTMR (n=33) or stained with cresyl violet (n=54) was counted. The axonal damage in the optic nerve at 1mm posterior to the eyeball (n=54) was examined under light microscopy and graded. Results: Induction of HSP72, GRP75 and GRP78 was noted in the enriched RGC fractions at 3 and 7 days after GGA administration whereas no remarkable change in HSC70 was detected. Significant elevation of IOP (74%), reduction on averaged number of DTMR labeled (26%) and cresyl violet stained (26%) RGCs, and optic nerve damage (P<0.012) was noted at 5 weeks after photocoagulation. After long-term administration of GGA, there was no significant loss of weight or reduction of IOP. Both retrograde labeling and cresyl violet staining showed a significant preservation of RGCs in GGA-treated retina while there was a tendency to protect the axons of optic nerve. Conclusion: Systemic administration of GGA induced the expression of HSP72, GRP75 and GRP78. Pretreatment and long-term administration of GGA protected the RGCs and axons against glaucomatous damage in rats. GGA may be useful to the patients with glaucoma. Supported by RPB and Glaucoma Research Foundation None
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