Nitric Oxide Signaling in Neurodegeneration and Cell Death.

In this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by which nitric oxide (NO) kills neurons. We provide a historical perspective regarding the discovery that glutamate excitotoxicity is mediated by NO. It also contains a discussion of the discovery that neuronal nitric oxide synthase (nNOS) catalytic activity accounts for NADPH diaphorase activity and its localization in the central nervous system. NADPH diaphorase/nNOS neurons are unique in that they are resistant to toxic effects of excess glutamate and that they are resistant to neurodegeneration in a variety of neurodegenerative diseases. NADPH diaphorase/nNOS neurons are resistant to neurotoxicity and neurodegeneration through the overexpression of manganese superoxide dismutase. The review also delves into the mechanisms by which NO kills neurons including NO's activation of the glyceraldehyde-3-phosphate dehydrogenase-dependent cell pathway. In addition, there is a review of parthanatos in which NO combines with the superoxide anion ( [Formula: see text] ) to form peroxynitrite (ONOO- ) that damages DNA and activates poly (ADP-ribose) (PAR) polymerase (PARP). This ultimately leads to activation of the PARP-dependent apoptosis-inducing factor-associated nuclease, the final executioner in NO-dependent cell death. Finally, there is a discussion of potential targets that are under development that target the mechanisms by which NO kills neurons.