June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Overexpression of spermine oxidase increases neuronal death and glial activation in a model of retinal excitotoxicity
Author Affiliations & Notes
  • PRAHALATHAN PICHAVARAM
    College of Allied Health Sciences, Augusta University, Augusta, Georgia, United States
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Chintan Patel
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Zhimin Xu
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Esraa Shosha
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • Manuela Cervelli
    Department of Science, Roma Tre University, Rome, Italy
  • Ruth B Caldwell
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
  • S. Priya Narayanan
    Vision Discovery Institute, Augusta University, Augusta, Georgia, United States
    College of Allied Health Sciences, Augusta University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   PRAHALATHAN PICHAVARAM, None; Chintan Patel, None; Zhimin Xu, None; Esraa Shosha, None; Manuela Cervelli, None; Ruth Caldwell, None; S. Priya Narayanan, None
  • Footnotes
    Support  Culver VDI Pilot Grant, NEI-R01-EY011766
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5891. doi:
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      PRAHALATHAN PICHAVARAM, Chintan Patel, Zhimin Xu, Esraa Shosha, Manuela Cervelli, Ruth B Caldwell, S. Priya Narayanan; Overexpression of spermine oxidase increases neuronal death and glial activation in a model of retinal excitotoxicity. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5891.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinal neuronal injury is a major cause of vision impairment in blinding diseases. Cellular damage resulting from dysregulated polyamine metabolism has been demonstrated to be a major player in neurodegenerative conditions. We have shown that inhibition of polyamine oxidase (PAO) significantly reduces retinal excitotoxicity (Patel et al., ARVO 2016). The aim of this study was to determine the impact of overexpressing spermine oxidase (SMO, a member of PAO family) on this process.

Methods : Cre-LoxP strategy was used to create SMO transgenic mice (SMO Tg) that overexpress SMO in calbindin-positive inner retinal neurons. SMO Tg and WT control mice (10 weeks old) were given intravitreal injections of 20 nmoles NMDA (N-Methyl-D-aspartate) or NMLA (N-Methyl-L-aspartate, control). Animals were sacrificed at various time points (1-7 days) for retinas processed for further analysis.

Results : SMO Tg mice overexpress SMO in horizontal and amacrine cells which are ideally situated to synapse with other retinal neurons to influence neuronal function and survival. The retinas of SMO Tg mice developed normally. NMDA treatment caused significant neuronal death in both SMO Tg and WT mice. However, the loss of NeuN-positive ganglion cells in SMO Tg retina was markedly greater than in their WT controls. (p<0.01, N=4-6). The NMDA-induced increase in neuronal death in SMO Tg mice was confirmed by a significant increase in TUNEL positive cells as compared with the WT mice (p<0.05 N=3). Morphometry analysis demonstrated significant INL thinning of the NMDA-treated SMO Tg mice compared to WT (p<0.01). Increased levels of phosphorylated P-38 in NMDA treated-SMO Tg retinas suggest the involvement stress signaling pathways in SMO mediated neuronal damage. Increased glial activation (studied by Iba1 and GFAP immunostaining, N=4-6) was evident in NMDA-treated SMO Tg retinas, suggesting glial involvement in SMO mediated neuronal damage. Comparison of the NMLA-treated WT and SMO Tg mice retinas showed no differences, indicating that SMO activation is required for its damaging effects.

Conclusions : Our study confirms the critical involvement of SMO in excitotoxicity mediated neuro-glial injury in retina and establishes the SMO Tg mouse as an excellent tool to investigate the cellular and molecular mechanisms involved in retinal neurodegenerative diseases such as diabetic retinopathy and glaucoma.

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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