Furoxans (1,2,5-Oxadiazole-N-Oxides) as Novel NO Mimetic Neuroprotective and Procognitive Agents

• Published in: Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3076-3087
• Main Authors: Schiefer, Isaac T, VandeVrede, Lawren, Fa’, Mauro, Arancio, Ottavio, Thatcher, Gregory R. J
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - toxicity; Animals; CELL CULTURES; Cells, Cultured; Crystallography, X-Ray; Cysteine - metabolism; GLUCOSE; Guanylate Cyclase - antagonists & inhibitors; Hippocampus - drug effects; Hippocampus - physiology; In Vitro Techniques; INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; LEARNING; Long-Term Potentiation - drug effects; MODULATION; Neurons - cytology; Neurons - drug effects; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Nitric Oxide - physiology; Nitric Oxide Donors - chemical synthesis; Nitric Oxide Donors - chemistry; Nitric Oxide Donors - pharmacology; Nootropic Agents - chemical synthesis; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; OXYGEN; PEPTIDES; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Quinoxalines - pharmacology; Rats; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Signal Transduction; Soluble Guanylyl Cyclase; Stereoisomerism; Structure-Activity Relationship; Synapses - drug effects; Synapses - physiology; THERAPEUTIC USES; THIOLS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201504s

Furoxans (1,2,5-oxadiazole-N-oxides) are thiol-bioactivated NO-mimetics that have not hitherto been studied in the CNS. Incorporation of varied substituents adjacent to the furoxan ring system led to modulation of reactivity toward bioactivation, studied by HPLC-MS/MS analysis of reaction products. Attenuated reactivity unmasked the cytoprotective actions of NO in contrast to the cytotoxic actions of higher NO fluxes reported previously for furoxans. Neuroprotection was observed in primary neuronal cell cultures following oxygen glucose deprivation (OGD). Neuroprotective activity was observed to correlate with thiol-dependent bioactivation to produce NO2 –, but not with depletion of free thiol itself. Neuroprotection was abrogated upon cotreatment with a sGC inhibitor, ODQ, thus supporting activation of the NO/sGC/CREB signaling cascade by furoxans. Long-term potentiation (LTP), essential for learning and memory, has been shown to be potentiated by NO signaling, therefore, a peptidomimetic furoxan was tested in hippocampal slices treated with oligomeric amyloid-β peptide (Aβ) and was shown to restore synaptic function. The novel observation of furoxan activity of potential therapeutic use in the CNS warrants further studies.