May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
N-Methyl-D-Aspartate (Umda)-Induced Excitotoxicity in Thrombospondin-1 Deficient Mice
Author Affiliations & Notes
  • A. Takamiya
    Ophthalmology, Asahikawa Medical College, Asahikawa, Japan
    Ophthalmology, Schepens Eye Research Institute, Boston, Massachusetts
  • S. Masli
    Ophthalmology, Schepens Eye Research Institute, Boston, Massachusetts
  • A. Yoshida
    Ophthalmology, Asahikawa Medical College, Asahikawa, Japan
  • D. F. Chen
    Ophthalmology, Schepens Eye Research Institute, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  A. Takamiya, None; S. Masli, None; A. Yoshida, None; D.F. Chen, None.
  • Footnotes
    Support  The Sybil B. Harrington Scholar Award from the Research to Prevent Blindness Foundation, the American Health Foundation, the Massachusetts Lion’s Eye Research Fund, the Department of Defense, and NIH/
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 4365. doi:https://doi.org/
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    • Get Citation

      A. Takamiya, S. Masli, A. Yoshida, D. F. Chen; N-Methyl-D-Aspartate (Umda)-Induced Excitotoxicity in Thrombospondin-1 Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4365. doi: https://doi.org/.

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

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Abstract

Purpose: : Thrombspondin-1 (TSP-1) is a glycoprotein which binds to the latent form of transforming growth factor (TGF) beta and converts it into an active form. Growing evidence suggests that TGF-beta serves as a key neurotrophic factor in the central nervous system and that reduced signaling of TGF-beta is associated with neurodegeneration in the adult. To understand the functional significance of TGF-beta signaling in adult retinal neurons, mice deficient in TSP-1 were examined in an experimental model of excitotoxic neural damage.

Methods: : Retinal neural damage was induced in adult wild type (WT) and TSP-1-/- mice by intravitreal injection of a glutamate analog, N-methyl-D-aspartate (NMDA) (20 nmol). Induction of TGF-beta signaling was detected by immunodetection for phosphorylated Smad2 (pSmad2). Retinal neuronal death was determined by TDT-mediated-dUTP nick end labeling (TUNEL) at day 1 after NMDA treatment. At day 7 after the treatment, survival retinal ganglion cells were immunostained with a primary antibody against a ganglion cell specific marker, beta-III tubulin and the number of cells was counted.

Results: : Under the normal condition, pSmad2 signaling was not detected in the retinas of adult mice. NMDA-treatment induced pSmad2 expression in the ganglion cell layer (GCL) of WT mice within 24 hours. Consistent with the notion that TGF-beta is activated by TSP-1, much less pSmad2 positive cells were detected in the GCL of TSP-1-/- mice, while more TUNEL+ cells were counted from retinal sections of TSP-1-/- mice than that of WT mice. Moreover, most of these TUNEL positive cells did not co-localize with pSmad2 immunostaining, strongly suggesting a neuroprotective role of the TGF-beta/Smad2 pathway in excitotoxicity-induced neuronal death. More ganglion cells survived in the retinas of WT mice than that in TSP-1-/- mice at day 7 after NMDA treatment.

Conclusions: : Our results revealed decreased Smad2 phosphorylation and increased retinal ganglion cell death following NMDA-treatment in TSP-1-/- mice than that in WT mouse retinas. The data suggest a role for TSP-1 in protecting retinal neurons against neuroexcitotoxicity-induced cell death, likely, via activation of TGF-beta/Smad2 pathways.

Keywords: ganglion cells • neuroprotection • excitatory neurotransmitters 
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