Furoxans (1,2,5-Oxadiazole- N -oxides) as novel no mimetic neuroprotective and procognitive agents

Isaac T. Schiefer, Lawren Vandevrede, Mauro Fa', Ottavio Arancio, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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 NO 2 -, 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.

Original languageEnglish (US)
Pages (from-to)3076-3087
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number7
DOIs
StatePublished - Apr 12 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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