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S. Priya Narayanan, Alan Saul, Zhimin Xu, Prahalathan Pichavaram; Spermine Oxidase: a novel mediator of diabetes-induced retinal neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5198. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Deregulation of the polyamine metabolic pathway has been implicated in various neurodegenerative diseases. Studies from our laboratory have demonstrated that polyamine oxidation is involved in neuronal and vascular damage in retina (Narayanan et al 2014; Patel et al 2016). The impact of polyamine oxidation and its contribution to retinal neuronal damage induced by diabetes is not yet studied. The current study was undertaken to investigate the role of spermine oxidase (SMO, a polyamine oxidase) in mediating neuronal damage and dysfunction in diabetic retina.
Eight weeks old C57BL6 male mice were made diabetic by streptozotocin injection (STZ, 65 mg/kg, pH 4.5, i.p.) and compared to age-matched controls (CNT). Following the onset of diabetes animals were treated with either vehicle or SMO inhibitor, MDL 72527 (20 mg/kg of body weight, in saline, i.p., 3 times/week). Retinal function was analyzed by electroretinography. Retinal cryostat sections were used for immunofluorescence studies and fresh frozen retinas for Western blot analysis.
A marked increase in SMO expression was observed in diabetic retinas at 4 weeks after the onset of diabetes. Acrolein (a byproduct of polyamine oxidation and potent mediator of oxidative stress) was also markedly increased in the diabetic retinas compared to the controls. Treatment with MDL 72527 greatly reduced this effect. Analysis of inner retinal function using dark-adapted electroretinography showed that the positive scotopic threshold responses (pSTRs, measured at 110 ms and 200 ms), were significantly reduced (p<0.001, N=4-7) in the diabetic (4 weeks) mice. The pSTR amplitudes were greatly improved in the MDL-treated diabetic group (p<0.001, N=4-7). The amplitude at 110 ms was dominated by the b-wave at higher intensities, and was significantly stronger in the MDL72527-treated than in the untreated diabetic mice. These data demonstrate a partial rescue of inner retinal function in the diabetic retina by SMO inhibition. Studies on the impact of SMO inhibition on neuronal survival are currently in progress.
Our results show a specific role for spermine oxidase (SMO) in mediating neuronal injury in the diabetic retina, and demonstrate its potential as a therapeutic target for diabetic retinopathy treatment.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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