Treatment with polyamine oxidase inhibitor reduced neurodegeneration and improved retinal function in diabetic mice

Abstract

PurposeDeregulation of polyamine metabolism has been implicated in various neurodegenerative disease and injury conditions. Studies from our laboratory have demonstrated that polyamine oxidation is a critical mediator of both neuronal and vascular injury in a mouse model of retinopathy of prematurity (Narayanan et al 2014; Patel et al 2016). The current study was undertaken to investigate the role of the polyamine oxidase spermine oxidase (SMO) in mediating neuronal damage and dysfunction in the diabetic retina.MethodsMice (8 weeks old, C57BL6J) were made diabetic by injection of streptozotocin (STZ, 65 mg/kg, pH 4.5, i.p.) and compared to age‐matched controls after 4 to 15 weeks of diabetes. Following the onset of hyperglycemia, mice were treated with either vehicle (normal saline) or SMO inhibitor, MDL 72527 (20 mg/kg of body weight, in saline, intra‐peritoneal, 3 times/week). Retinal neuronal function in living mice was determined by electroretinography (ERG). Retinal structure in the same mice was analyzed by Spectral Domain‐Optical Coherence Tomography (SD‐OCT). Following ERG and SD‐OCT analyses, mice were humanely euthanized, and retinas were collected and processed for immunofluorescence and western blot analyses.ResultsWestern blot analysis showed that expression of SMO was increased in the diabetic retinas compared to controls. Inner retinal function studied by dark‐adapted electroretinography showed that the positive (pSTR) and negative (nSTR) scotopic threshold responses (measured at 110 ms and 200 ms), were significantly reduced (p<0.01, N=5–12) in the diabetic (4–12 weeks) mice as compared with the controls. The pSTR, but not the nSTR amplitudes were greatly improved in the MDL‐treated diabetic mice (p<0.05, N=5–10). The amplitude at 110 ms was dominated by the b‐wave at higher intensities and was significantly stronger in the MDL72527‐treated mice than in the vehicle‐treated diabetic mice. SD‐OCT analysis demonstrated a significant thinning of retina in the diabetic mice (p<0.01, N=5–12), which was improved in the MDL‐treated group. These data demonstrate a partial rescue of inner retinal function and retinal structure by SMO inhibition in the diabetic retina. Studies on the impact of MDL72527 treatment on neuronal survival are currently in progress.ConclusionOur results show the specific involvement of Spermine Oxidase in mediating neuronal injury in the diabetic retina and demonstrate its potential as a therapeutic target for mitigating neuronal injury in diabetic retinopathy.Support or Funding InformationThese studies supported by the National Eye Institute (1R01EY028569 to S.P.N) and Augusta University Culver Vision Discovery institute pilot grant to S.P.N.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.