title: NOSH-aspirin (NBS-1120), a novel nitric oxide and hydrogen sulfide releasing hybrid, attenuates neuroinflammation induced by microglial and astrocytic activation: a new candidate for treatment of neurodegenerative disorders.
abstract: Hydrogen sulfide (H2 S) and nitric oxide (NO) have been described as gasotransmitters. Anti-inflammatory activity in the central and peripheral nervous systems may be one of their functions. Previously we demonstrated that several SH(-) donors including H2 S-releasing aspirin (S-ASA) exhibited anti-inflammatory and neuroprotective activity in vitro against toxins released by activated microglia and astrocytes. Here we report that NOSH-ASA, an NO- and H2 S-releasing hybrid of aspirin, has a significantly greater anti-inflammatory and neuroprotective effect than S-ASA or NO-ASA. When activated by LPS/IFNγ, human microglia and THP-1 cells release materials that are toxic to differentiated SH-SY5Y cells. These phenomena also occur with IFNγ-stimulated human astroglia and U373 cells. When the cells were treated with the S-ASA or NO-ASA, there was a significant enhancement of neuroprotection. However, NOSH-ASA had significantly more potent protection properties than NO-ASA or S-ASA. The effect was concentration-dependent, as well as incubation time-dependent. Such treatment not only reduced the release of the TNFα and IL-6, but also attenuated activation of P38 MAPK and NFκB proteins. All the compounds tested were not harmful when applied directly to SH-SY5Y cells. These data suggest that NOSH-ASA has significant anti-inflammatory properties and may be a new candidate for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson disease.
authors.affiliation: Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Moonhee
authors.initials: M
authors.lastname: Lee
authors.forename: Edith
authors.initials: E
authors.lastname: McGeer
authors.forename: Ravinder
authors.initials: R
authors.lastname: Kodela
authors.forename: Khosrow
authors.initials: K
authors.lastname: Kashfi
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects*; D001254:Astrocytoma / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004220:Disulfides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013702:Temporal Lobe / Q000166:cytology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C571898:4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-((4-(nitrooxy)butanoyl)oxy)benzoate; D000893:Anti-Inflammatory Agents; D004220:Disulfides; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009566:Nitrates; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; D001241:Aspirin
keywords: Alzheimer disease; IL-6; NO-aspirin; NOSH-aspirin; Parkinson disease; S-aspirin; tumor necrosis factor-α