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R.S. Mali, M. Cheng, S.K. Chintala; Matrix Metalloproteinase–9 Promotes Depolarization–Mediated Retinal Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5312.
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Purpose: Membrane depolarization and subsequent synaptic release of L–glutamate has been implicated in ischemic retinal damage. Yet, the mechanisms involved in ischemic retinal damage are poorly understood. The purpose of this study is to investigate the role of matrix metalloproteinase–9 (MMP–9) in depolarization–induced retinal degeneration. Methods: Retinal membrane depolarization was induced by injection of potassium chloride (KCl) into the vitreous humor in CD–1 mice. MMP activity in retinal protein extracts was determined by zymography and protein levels were determined by western blot analysis. MMP–9 localization was determined by immunohistochemistry. Retinal degeneration was assessed by immunostaining of retinal cross sections with antibodies against neurofilament–light (NF–L) and calretinin. Apoptotic cell death was determined by TUNEL staining. Results: KCl, at depolarizing concentrations, induced a dose– and time–related up–regulation in MMP–9 activity and protein levels in the retina. KCl–mediated MMP–9 up–regulation was associated with apoptotic death of cells in the ganglion cell layer (GCL) and inner nuclear layer (INL), and subsequent loss of NF–L–positive ganglion cells and calretinin–positive amacrine cells. Intravitreal injection of KCl along with MK–801, a NMDA–type glutamate receptor antagonist, and NBQX, a non–NMDA–type glutamate receptor antagonist both reduced KCl–mediated MMP–9 up–regulation in the retina. Furthermore, a synthetic inhibitor of MMPs inhibited KCl–mediated MMP–9 up–regulation and led to significant attenuation against KCl–induced retinal damage. Conclusions: These results suggest that MMP–9 up–regulation, in part, plays a causative role in depolarization–induced retinal damage.
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