Preventing Ca2+-mediated nitrosative stress in neurodegenerative diseases: possible pharmacological strategies.
Overactivation of the NMDA-subtype of glutamate receptor is known to trigger excessive calcium influx, contributing to neurodegenerative conditions. Such dysregulation of calcium signaling results in generation of excessive free radicals, including reactive oxygen and nitrogen species (ROS/RNS), including nitric oxide (NO). In turn, we and our colleagues have shown that these free radicals trigger pathological production of misfolded proteins, mitochondrial dysfunction, and apoptotic pathways in neuronal cells. Here, we discuss emerging evidence that excessive calcium-induced NO production can contribute to the accumulation of misfolded proteins, specifically by S-nitrosylation of the ubiquitin E3 ligase, parkin, and the chaperone enzyme for nascent protein folding, protein-disulfide isomerase. Additionally, excessive calcium-induced NO generation leads to the formation of S-nitrosylated dynamin-related protein 1, which causes abnormal mitochondrial fragmentation and resultant synaptic damage. In this review, we also discuss how two novel classes of pharmacological agents hold promise to interrupt these pathological processes. Firstly, the NMDA receptor antagonists, Memantine and NitroMemantine, block excessive extrasynaptic glutamate excitation while maintaining synaptic transmission, thereby limiting excessive calcium influx and production of ROS/RNS. Secondly, therapeutic pro-electrophiles are activated in the face of oxidative insult, thus protecting cells from calcium-induced oxidative stress via the Keap1/Nrf2 transcriptional pathway.
Nakamura
Tomohiro
T
Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Lipton
Stuart A
SA
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D006801:Humans; D008559:Memantine / Q000627:therapeutic use; D008928:Mitochondria / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D015538:Nitrosation; D018384:Oxidative Stress; D017510:Protein Folding; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D002118:Calcium; D008559:Memantine