Abstract
Purpose: :
Retinitis Pigmentosa (RP) is a general term for a heterogeneous group of hereditary retinal dystrophies characterized by progressive loss of vision due to the death of photoreceptors. Although several molecular mechanisms underlying photoreceptor cell death have been characterized, the hierarchy among them is far from being understood. The aim of the present work is to establish the sequence of molecular and cellular events taking place in the photoreceptors undergoing degeneration.
Methods: :
We have analyzed the sequence of events leading to cell death in the cone-derived 661W cells and in C57Bl/6 wild type retinas cultured in the presence of Zaprinast (a PDE6 inhibitor) and A23187 (a calcium ionophore), as well as in the rd10 mouse model of RP. We have determined calcium influx, oxidative stress, calpain activation, and apoptosis by flow cytometry, confocal microscopy and several enzymatic assays.
Results: :
The rd10 mouse retinas showed an early increase in calcium content and calpain activation followed by an imbalance in the antioxidant defense system, with increased superoxide and oxygen peroxide production when compared to wild type retinas. A23187 and zaprinast treatments mimicked most of these alterations in the experimental models of RP.
Conclusions: :
The combination of genetic and experimental models of RP provides new cues to establish the hierarchy of events leading to retinal degeneration and may assist to define new and better targets for a therapeutical intervention.
Keywords: retinitis • retinal degenerations: cell biology • calcium