Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3 independent

Apoptosis is the mode of photoreceptor cell death in inherited and induced retinal degeneration. However, the molecular mechanisms of photoreceptor ce ll death in human cases and animal models of retinal dystrophies remain und efined. Exposure of Balb/c mice to excessive levels of white Light results in photoreceptor apoptosis, This study delineates the molecular events occu rring during and subsequent to the induction of retinal degeneration by exp osure to white light in Balb/c mice. We demonstrate an early increase in in tracellular calcium levels during photoreceptor apoptosis, an event that is accompanied by significant superoxide generation and mitochondrial membran e depolarization, Furthermore, we show that inhibition of neuronal nitric-o xide synthase (nNOS) by 7-nitroindazole is sufficient to prevent retinal de generation implicating a key role for neuronal nitric oxide (NO) in this mo del. We demonstrate that inhibition of guanylate cyclase, a downstream effe ctor of NO, also prevents photoreceptor apoptosis demonstrating that guanyl ate cyclase too plays an essential role in this model. Finally, our results demonstrate that caspase 3, frequently considered to be one of the key exe cutioners of apoptosis, is not activated during retinal degeneration. In su mmary, the data presented here demonstrate that light-induced photoreceptor apoptosis in vivo is mediated by the activation of nNOS and guanylate cycl ase and is caspase-3-independent.