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Photoreceptor rescue and toxicity induced by different calpain inhibitors

Paquet-Durand, Francois; Sanges, Daniela; McCall, Julianne; Silva, Jose; van Veen, Theo; Marigo, Valerio and Ekström, Per LU (2010) In Journal of Neurochemistry 115(4). p.930-940
Abstract
P>Photoreceptor degeneration is the hallmark of a group of inherited blinding diseases collectively termed retinitis pigmentosa (RP); a major cause of blindness in humans. RP is at present untreatable and the underlying neurodegenerative mechanisms are largely unknown, even though the genetic causes are often established. The activation of calpain-type proteases may play an important role in cell death in various neuronal tissues, including the retina. We therefore tested the efficacy of two different calpain inhibitors in preventing cell death in the retinal degeneration (rd1) human homologous mouse model for RP. Pharmacological inhibition of calpain activity in rd1 organotypic retinal explants had ambiguous effects on photoreceptor... (More)
P>Photoreceptor degeneration is the hallmark of a group of inherited blinding diseases collectively termed retinitis pigmentosa (RP); a major cause of blindness in humans. RP is at present untreatable and the underlying neurodegenerative mechanisms are largely unknown, even though the genetic causes are often established. The activation of calpain-type proteases may play an important role in cell death in various neuronal tissues, including the retina. We therefore tested the efficacy of two different calpain inhibitors in preventing cell death in the retinal degeneration (rd1) human homologous mouse model for RP. Pharmacological inhibition of calpain activity in rd1 organotypic retinal explants had ambiguous effects on photoreceptor viability. Calpain inhibitor XI had protective effects when applied for short periods of time (16 h) but demonstrated substantial levels of toxicity in both wild-type and rd1 retina when used over several days. In contrast, the highly specific calpain inhibitor calpastatin peptide reduced photoreceptor cell death in vitro after both short and prolonged exposure, an effect that was also evident after in vivo application via intravitreal injection. These findings highlight the importance of calpain activation for photoreceptor cell death but also for photoreceptor survival and propose the use of highly specific calpain inhibitors to prevent or delay RP. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CNX295, CAST, apoptosis, calcium, retina
in
Journal of Neurochemistry
volume
115
issue
4
pages
930 - 940
publisher
Wiley-Blackwell
external identifiers
  • wos:000283375000013
  • scopus:77958560768
ISSN
1471-4159
DOI
10.1111/j.1471-4159.2010.06983.x
language
English
LU publication?
yes
id
7a98bf29-0ed5-424b-8b97-88a357f93670 (old id 1720423)
date added to LUP
2010-12-03 15:00:19
date last changed
2018-05-29 10:09:28
@article{7a98bf29-0ed5-424b-8b97-88a357f93670,
  abstract     = {P>Photoreceptor degeneration is the hallmark of a group of inherited blinding diseases collectively termed retinitis pigmentosa (RP); a major cause of blindness in humans. RP is at present untreatable and the underlying neurodegenerative mechanisms are largely unknown, even though the genetic causes are often established. The activation of calpain-type proteases may play an important role in cell death in various neuronal tissues, including the retina. We therefore tested the efficacy of two different calpain inhibitors in preventing cell death in the retinal degeneration (rd1) human homologous mouse model for RP. Pharmacological inhibition of calpain activity in rd1 organotypic retinal explants had ambiguous effects on photoreceptor viability. Calpain inhibitor XI had protective effects when applied for short periods of time (16 h) but demonstrated substantial levels of toxicity in both wild-type and rd1 retina when used over several days. In contrast, the highly specific calpain inhibitor calpastatin peptide reduced photoreceptor cell death in vitro after both short and prolonged exposure, an effect that was also evident after in vivo application via intravitreal injection. These findings highlight the importance of calpain activation for photoreceptor cell death but also for photoreceptor survival and propose the use of highly specific calpain inhibitors to prevent or delay RP.},
  author       = {Paquet-Durand, Francois and Sanges, Daniela and McCall, Julianne and Silva, Jose and van Veen, Theo and Marigo, Valerio and Ekström, Per},
  issn         = {1471-4159},
  keyword      = {CNX295,CAST,apoptosis,calcium,retina},
  language     = {eng},
  number       = {4},
  pages        = {930--940},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {Photoreceptor rescue and toxicity induced by different calpain inhibitors},
  url          = {http://dx.doi.org/10.1111/j.1471-4159.2010.06983.x},
  volume       = {115},
  year         = {2010},
}