Photoreceptor rescue and toxicity induced by different calpain inhibitors.

Abstract

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.

• Authors: François Paquet-Durand, Daniela Sanges, Julianne McCall, José Silva, Theo van Veen, Valeria Marigo, Per Ekström
• Journal: Journal of neurochemistry (J Neurochem) Vol. 115 Issue 4 Pg. 930-40 (Nov 2010) ISSN: 1471-4159 [Electronic] England
• PMID: 20807308 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.

Chemical References

• Calcium-Binding Proteins
• Glycoproteins
• calpain inhibitors
• calpastatin
• Calpain

Topics

• Animals
• Calcium-Binding Proteins (therapeutic use)
• Calpain (antagonists & inhibitors, metabolism)
• Cell Death (drug effects, physiology)
• Glycoproteins (therapeutic use, toxicity)
• Humans
• Mice
• Mice, Inbred C3H
• Mice, Transgenic
• Organ Culture Techniques
• Photoreceptor Cells, Vertebrate (drug effects, enzymology, pathology)
• Retinal Degeneration (chemically induced, enzymology, pathology, prevention & control)
• Retinitis Pigmentosa (chemically induced, enzymology, pathology, prevention & control)