Nitric oxide has dual opposite roles during early and late phases of apoptosis in cerebellar granule neurons |
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Authors: | Antonella Bobba Anna Atlante Loredana Moro Pietro Calissano Ersilia Marra |
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Institution: | (1) Istituto di Biomembrane e Bioenergetica, Consiglio Nazionale delle Ricerche, Via Amendola 165/A, Bari, 70126, Italy;(2) Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale delle Ricerche, Roma, Italy |
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Abstract: | The involvement and the role of nitric oxide (NO) as a signaling molecule in the course of neuronal apoptosis, whether unique
or modulated during the progression of the apoptotic program, has been investigated in a cellular system consisting of cerebellar
granule cells (CGCs) where apoptosis can be induced by lowering extracellular potassium. Several parameters involved in NO
signaling pathway, such as NO production, neuronal nitric oxide synthase (nNOS) expression, and cyclic GMP (cGMP) production
were examined in the presence or absence of different inhibitors. We provide evidence that nitric oxide has dual and opposite
effects depending on time after induction of apoptosis. In an early phase, up to 3 h of apoptosis, nitric oxide supports survival
of CGCs through a cGMP-dependent mechanism. After 3 h, nNOS expression and activity decreased resulting in shut down of NO
and cGMP production. Residual NO then contributes to the apoptotic process by reacting with rising superoxide anions leading
to peroxynitrite production and protein inactivation. We conclude that whilst NO over-production protects neurons from death
in the early phase of neuronal damage, its subsequent reduction may contribute to neuronal degeneration and ultimate cell
death. |
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Keywords: | Cerebellar granule cells Apoptosis Nitric oxide Nitric oxide synthase Peroxynitrite Cyclic GMP |
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