September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
fMRI Studies: Calpain Inhibitor SNJ-1945 Ameliorates Dysfunction in Injured Rat RGCs
Author Affiliations & Notes
  • Takayuki Oka
    Senju Laboratories of Ocular Sciences, Senju Pharmaceutilal Co Ltd, Kobe, Japan
  • Chiho Yabuta
    Senju Laboratories of Ocular Sciences, Senju Pharmaceutilal Co Ltd, Kobe, Japan
  • Thomas R Shearer
    Department of Integrative Biosciences, Oregon Health & Science University , Portland, Oregon, United States
  • Mitsuyoshi Azuma
    Senju Laboratories of Ocular Sciences, Senju Pharmaceutilal Co Ltd, Kobe, Japan
    Department of Integrative Biosciences, Oregon Health & Science University , Portland, Oregon, United States
  • Footnotes
    Commercial Relationships   Takayuki Oka, Senju Pharma (E); Chiho Yabuta, Senju Pharma (E); Thomas Shearer, Senju Pharma (C); Mitsuyoshi Azuma, Senju Pharma (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3757. doi:
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    • Get Citation

      Takayuki Oka, Chiho Yabuta, Thomas R Shearer, Mitsuyoshi Azuma; fMRI Studies: Calpain Inhibitor SNJ-1945 Ameliorates Dysfunction in Injured Rat RGCs. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3757.

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

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Abstract

Purpose : Over-activation of intracellular calpains, a family of calcium-activated cysteine proteases, is an underlying mechanism for retinal ganglion cell (RGC) death. Retinal degeneration and cell death occur in an in vivo model of diffuse axonal injury caused by mechanical crushing of the optic nerves (OpNs). Treatment with calpain inhibitors ameliorates the loss of RGCs. However, we do not know if the surviving RGCs retain their ability to transmit visual information to the brain. Functional magnetic resonance imaging (fMRI) detects which specific regions of the living brain are activated by peripheral sensory information. The purpose of present experiment was to use fMRI to determine if calpain inhibitor SNJ-1945 ameliorates RGC dysfunction in a rat model of retinal degeneration.

Methods : OpNs in 9 week-old Long-Evans rats were crushed to 0.15 ~ 0.2 mm with forceps for 30 sec. Immediately after crushing, calpain inhibitor SNJ-1945 (25 mg/kg) was administrated orally once daily for 3 weeks. Cerebral blood volume-weighted fMRIs were obtained during eye stimulation with flashing LEDs. Brain activation maps were superimposed on a standard brain template, and statistical analyses were performed with a linear gradient model using statistical parametric mapping software. OpN degeneration and calpain activation were evaluated by histochemistry and immunohistochemistry; Brn3a-positive cell bodies in flat-mounted retinas were counted as RGCs.

Results : Three days after crushing, demyelinated OpNs were observed in the crushed area, and calpain-specific a-spectrin breakdown product accumulated in the distal regions. Four weeks after crushing, RGCs decreased by 40% (p < 0.01, student t-test). fMRI detected brain activation in the superior colliculus (SC) and lateral geniculate nucleus (LGN) in untreated normal rats. Brain activation was completely lost in SC and LGN 4 days after crushing but partially recovered in the SC at 4 weeks. SNJ-1945 significantly accelerated the recovery of brain activation in the SC.

Conclusions : This is the first direct evidence that calpain inhibitor SNJ-1945 helps maintain sensory function in injured RGCs. Treatment with SNJ-1945 may prevent cell death in some injured RGC and thereby allow faster recovery of visual function.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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