June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASIC) in optic nerve crush model in rodents
Author Affiliations & Notes
  • Adnan Dibas
    north texas eye institute, Fort worth, Texas, United States
  • Dorota Stankowska
    north texas eye institute, Fort worth, Texas, United States
  • Brett Mueller
    north texas eye institute, Fort worth, Texas, United States
  • Oku Hidehiro
    Osaka Medical School, Osaka, Japan
  • Thomas Yorio
    north texas eye institute, Fort worth, Texas, United States
  • Footnotes
    Commercial Relationships   Adnan Dibas, None; Dorota Stankowska, None; Brett Mueller, None; Oku Hidehiro, None; Thomas Yorio, None
  • Footnotes
    Support  Brightfocus Foundation
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3405. doi:
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    • Get Citation

      Adnan Dibas, Dorota Stankowska, Brett Mueller, Oku Hidehiro, Thomas Yorio; Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASIC) in optic nerve crush model in rodents. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3405.

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

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Abstract

Purpose : Recent observations suggest that acid-sensing ion channels (ASICs) are major contributors to axonopathy in neurodegenerative disorders. The purpose of the current study is to assess the potential involvement of ASIC1 in RGC death and investigate the neuroprotective effects of inhibitors of ASICs in promoting RGC survival following optic nerve crush.

Methods : Optic nerve of the right eye of Wistar rats was crushed. Retinal Ganglion Cells were retrogradely labeled by applying fluoroGold onto the left superior colliculus one week prior to crushing. Changes in ASIC1, α-fodrin, and microtubule-associated protein 2 (MAP2, known substrates of calpain), glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP) expression were also measured in retinal extracts by western blotting. Also, neuroprotective effects of amiloride or psalmotoxin (ASIC1 blockers) were assessed in hypoxic-ex-vivo retinal explant and ON crush injury models.

Results : ASIC1 protein was significantly increased in optic nerve extracts at day 7 following optic nerve crush (ONC) in rats. Activated calpain-1 increased at 2 and 7 days following crush as evidenced by increased degradation of α-fodrin and MAP2. GFAP levels increased significantly at 2 and 7 days post injury. By contrast, GS at 2 days while decreased at 7 days. The inhibition of ASICs with amiloride or psalmostoxin significantly increased RGC survival following ONC. In addition, blocking of ASICs with amiloride or psalmotoxin significantly increased RGC survival from ischemic-like insult. ASIC1 was detected in isolated primary rat RGCs by immunoblot and immunohistochemistry. Acidification (a known activator of ASIC1) increased intracellular Ca2+ ([Ca2+]i) in primary RGCs.

Conclusions : ASIC1 up-regulation-induced influx of extracellular calcium may be responsible for activation of calcium-sensitive calpain-1 in the retina. Calpain-1 induced degradation of essential proteins such as α-fodrin and MAP2 leads to morphological changes and eventually neuronal death. Therefore, blockers of ASIC1 are potential therapeutics in the treatment of optic nerve degeneration.

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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