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Takayuki Oka, Rie Suzuki, Yoshiyuki Tamada, Thomas R. Shearer, Mitsuyoshi Azuma; Involvement of Calpain in Retinal Ganglion Cell Death in a Rat Model of Anterior Ischemic Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3489.
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Anterior ischemic optic neuropathy (AION) is a serious, sudden loss of vision caused by transient ischemia. AION is associated with common cardiovascular risk factors, and no clinically effective treatment exists. Animal studies show that activation of endogenous calpains, a family of Ca2+-activated, neutral, cysteine proteases cause retinal degeneration and dysfunction induced by ischemia/reperfusion, hypoxia, or acute ocular hypertension. The purpose of this study was to determine if calpain-induced proteolysis likewise occurs in a rat model of AION.
Rat AION was induced by photoactivation of intravenously injected Rose Bengal by green laser irradiation of the optic nerve head, causing thrombosis of anterior optic nerve capillaries. Degeneration of the retina and optic nerve was histologically evaluated by H&E and Luxol fast blue staining. Retrograde labeling with Fluorogold was performed to determine the number of surviving retinal ganglion cells (RGCs), and apoptosis was evaluated by TUNEL staining of whole-mounted retinas. Proteolysis of calpain substrates was detected by immunoblotting. To activate endogenous calpains, soluble proteins from rat optic nerves were incubated with calcium, with or without calpain inhibitors.
After laser treatment, edema was observed in optic nerve head followed by demyelination. The number of RGCs decreased in a time dependent manner. TUNEL-positive cells were observed. Calpain substrates α-spectrin and myelin-associated glycoprotein MAG (also a marker protein for oligodendrocytes) were proteolyzed. Incubation of optic nerve proteins with calcium led to similar proteolysis of these substrates, and calpain inhibitors prevented the proteolysis.
Oligodendrocytes are essential for survival of the neuronal cell body and axons, and they are needed for myelin assembly. Our results in the rat AION model suggested that calpain proteolyzed critical proteins in the oligodendrocytes, causing their degeneration and contributing to RGC death. Calpain inhibitor drugs may be useful in AION patients by suppressing oligodendrocyte degeneration and ameliorating RGC degeneration/dysfunction.
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