title: Hydrogen sulfide-releasing NSAIDs attenuate neuroinflammation induced by microglial and astrocytic activation.
abstract: Endogenously generated hydrogen sulfide (H(2)S) may have multiple functions in brain. It has been shown that H(2)S attenuates the expression of pro-inflammatory cytokines by lipopolysaccharide (LPS)-activated microglia. Here we demonstrate a neuroprotective effect of NaSH and three H(2)S-releasing compounds, ADT-OH, S-diclofenac, and S-aspirin. When activated by LPS and gamma-interferon, human microglia and THP-1 cells release materials that are toxic to human neuroblastoma SH-SY5Y cells. These phenomena also occur with gamma-interferon-stimulated human astroglia and U118 cells. When these cell types are pretreated with aspirin, diclofenac, NASH, or ADT-OH, the supernatants are significantly less toxic. When they are treated with the NSAID-H(2)S hybrid molecules S-diclofenac and S-aspirin, which are here referred to as S-NSAIDs, there is a significant enhancement of the protection. The effect is concentration and incubation time dependent. Such pretreatment also reduces the release of the proinflammatory mediators TNFalpha, IL-6, and nitric oxide. The H(2)S-releasing compounds are without effect when applied directly to SH-SY5Y cells. These data suggest that hybrid H(2)S releasing compounds have significant antiinflammatory properties and may be candidates for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson disease.
authors: Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Moonhee
authors: M
authors: Lee
authors: Anna
authors: A
authors: Sparatore
authors: Piero
authors: P
authors: Del Soldato
authors: Edith
authors: E
authors: McGeer
authors: Patrick L
authors: PL
authors: McGeer
mesh_terms: D000393:Air Pollutants / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D013702:Temporal Lobe / Q000166:cytology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000393:Air Pollutants; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D001241:Aspirin; D006862:Hydrogen Sulfide