May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
TRPV1 Contributes to Pressure-Induced Death and Disruption of Axonal Transport in RGCs
Author Affiliations & Notes
  • R. M. Sappington
    Vanderbilt Univ Eye Inst, Vanderbilt Univ Medical Center, Nashville, Tennessee
  • T. N. Sidorova
    Vanderbilt Univ Eye Inst, Vanderbilt Univ Medical Center, Nashville, Tennessee
  • D. J. Calkins
    Vanderbilt Univ Eye Inst, Vanderbilt Univ Medical Center, Nashville, Tennessee
  • Footnotes
    Commercial Relationships  R.M. Sappington, None; T.N. Sidorova, None; D.J. Calkins, Vanderbilt University, P.
  • Footnotes
    Support  The Glaucoma Research Foundation (Catalyst for a Cure Consortium;DJC, RMS); Fight for Sight (RMS); Research to Prevent Blindness (DJC); NEI Core Grant (P30 EY08126; DJC)
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5481. doi:https://doi.org/
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    • Get Citation

      R. M. Sappington, T. N. Sidorova, D. J. Calkins; TRPV1 Contributes to Pressure-Induced Death and Disruption of Axonal Transport in RGCs. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5481. doi: https://doi.org/.

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

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Abstract

Purpose: : Vision loss in glaucoma is associated with sensitivity to intraocular pressure and death of retinal ganglion cells (RGCs) related to disrupted axonal transport. We asked whether transient receptor potential vanilloid-1 receptor (TRPV1) could contribute to this death and transport deficit, because of its role in mechanosensation and calcium (Ca2+)-dependent death in other neurons.

Methods: : We examined TRPV1 expression in RGCs of rodent, primate and human retina, including glaucomatous retina, using a combination of PCR, ISH, ICC and western blot. We measured RGC apoptosis in organotypic cultures of explanted retina from adult C57/BL6 and TRPV1-/- mice at ambient or elevated hydrostatic pressure following treatment with the TRPV1 agonist capsaicin, the TRPV1 antagonist iodo-resinferatoxin (I-RTX) and the Ca2+ chelator EGTA. We examined transport of the ALEXA 594-conjugated beta subunit of cholera toxin in the ganglion cell and nerve fiber layers of C57 and TRPV1 -/- explants under the conditions listed above.

Results: : TRPV1 localization in RGCs appeared in node-like clusters, with dramatically reduced expression in human glaucomatous retina. In C57 explants, elevated pressure (48hrs) decreased RGC density by 33% and increased TUNEL-reactivity 4-fold. Pharmacological inhibition of TRPV1 with I-RTX (100nM-100pM) reduced this loss by 28% and diminished TUNEL-reactivity by 55%. Chelation of extracellular Ca2+ (950µM) also increased density at elevated pressure by 30% and reduced TUNEL-reactivity by 80%. TRPV1-/- explants exhibited a 2-fold less pressure-induced decrease in RGC density with no change in TUNEL-reactivity from ambient conditions. Exposure to I-RTX and Ca2+ chelation did not significantly alter RGC survival in TRPV1-/- explants. Capsaicin treatment (10mM-100nM) at ambient pressure mimicked the effects of elevated pressure in C57 explants, decreasing RGC density by as much as 50% and increasing TUNEL reactivity by 3-fold, but did not alter RGC survival in TRPV1-/- explants. Elevated pressure (24hrs) and 100nM capsaicin (24hrs) decreased the intensity of RGC somal and axonal CTB labeling in C57 explants by 55% and 62%, respectively. Under both conditions, treatment with I-RTX and EGTA increased CTB labeling to nearly ambient levels. In contrast, TRPV1 -/- explants did not exhibit a statistically significant change in CTB labeling following either elevated pressure or capsaicin.

Conclusions: : Our data suggest that activation of TRPV1 likely contributes to the susceptibility of RGCs to pressure-induced apoptosis as well as to decreases in axonal transport that precede this death.

Keywords: ganglion cells • apoptosis/cell death • ion channels 
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