Extracellular ATP induces retinal photoreceptor apoptosis through activation of purinoceptors in rodents.
We have previously demonstrated that photoreceptors express P2X(7) purinoceptors. These excitatory receptors are activated by extracellular adenosine 5'-triphosphate (ATP) and have been implicated in neurodegeneration in other parts of the central nervous system (CNS). In this study we examined whether extracellular ATP could contribute to photoreceptor degeneration in rodents through excessive activation of P2 purinoceptors. Intravitreal injection of high concentrations of extracellular ATP into normal rat eyes induced extensive and selective apoptosis of photoreceptors within 18 hours of injection. Five days after injection the outer nuclear layer was severely degenerated and electroretinographic responses were impaired. Preinjection of the purinergic antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) protected against ATP-mediated apoptosis. The initial phase of ATP-induced photoreceptor death did not temporally coincide with retinal pigment epithelium degeneration or microglial activation, suggesting that cell death was due to direct activation of purinergic receptors on photoreceptors. Finally, we demonstrate that intravitreal injection of PPADS results in a 30% increase in photoreceptor survival in the rd1 mouse, a model of human recessive retinitis pigmentosa (RP). These findings highlight the importance of extracellular ATP in retinal neurodegeneration and provide a potential new avenue for therapeutic intervention in RP.
Puthussery
Theresa
T
Department of Anatomy and Cell Biology, University of Melbourne, 3010, Victoria, Australia.
Fletcher
Erica
E
D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology; D009410:Nerve Degeneration / Q000503:physiopathology; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology* / Q000648:ultrastructure; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D012162:Retinal Degeneration / Q000473:pathology / Q000503:physiopathology; D055213:Retinal Pigment Epithelium / Q000473:pathology / Q000503:physiopathology; D012174:Retinitis Pigmentosa
D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate