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S. Park, J. D. Lindsey, R. N. Weinreb, W.-K. Ju; A Selective Inhibitor of Drp1, Mdivi-1, Increases Retinal Ganglion Cell Survival in Acute Ischemic Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3189.
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© ARVO (1962-2015); The Authors (2016-present)
To determine whether acute intraocular pressure (IOP) elevation alters dynamin-related protein 1 (Drp1) as well as whether a selective inhibitor of Drp1, mdivi-1, can block apoptotic cell death and subsequently increase retinal ganglion cell (RGC) survival in ischemic mouse retina.
C57BL/6 mice received injections of mdivi-1 (50 mg/kg) or vehicle and then transient retinal ischemia was induced by acute IOP elevation. RGC survival was measured after FluoroGold labeling. Drp1, optic atrophy type 1 (OPA1) and glial fibrillary acidic protein (GFAP) protein expression and distribution were assessed at 12 hours after ischemia by Western blot and immunohistochemistry. Apoptotic cell death was assessed by TUNEL staining.
Drp1, OPA1 and GFAP protein expression were significantly increased in the early neurodegenerative events (within 12 hours) of ischemic mouse retina. Mdivi-1 treatment blocked apoptotic cell death in ischemic retina, and significantly increased RGC survival at 2 weeks after ischemia. Further, mdivi-1 treatment did not change Drp1 protein expression but significantly decreased OPA1 and GFAP protein expression. Both isoforms of OPA1 protein (80- and 90-kDa) were significantly decreased in mdivi-1-treated ischemic retina.
These findings suggest that altered Drp1 and OPA1 activity following acute IOP elevation may be an important component of a biochemical cascade leading to RGC death in ischemic retina. Thus, these results support further studies to determine whether pharmacological inhibition of Drp1 by mdivi-1 may provide a novel mechanism to protect RGCs against pressure-related ischemic damage in glaucoma.
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