title: Effects of obovatol on GSH depleted glia-mediated neurotoxicity and oxidative damage.
abstract: Earlier studies indicate that obovatol (OBO), isolated from a medicinal herb Magnolia obovata, has anti-inflammatory and anti-oxidative properties. Depletion of glutathione (GSH) in glial cells with the γ-glutamylcysteine synthase inhibitor D,L-buthionine-S,R-sulfoximine (BSO) is known to produce oxidative stress which, in turn, induces these cells to secrete inflammatory cytokines and other neurotoxic substances. In the present study, we investigated the ability of OBO to protect SH-SY5Y neuroblastoma cells from this effect. Human microglia, astrocytes and their surrogate THP-1 and U373 cell lines were activated by treatment with BSO. Such treatment depleted their intracellular GSH and increased levels of damage to DNA, lipids and proteins (8-OHdG, lipid peroxide, protein carbonyls and 3-nitrotyrosine), and activated the inflammatory pathways P38 MAP kinase and NFκB. These are accompanied by release of proinflammatory factors such as TNFα, IL-6 and nitric oxide. Their conditioned media were toxic to SH-SY5Y cells. All these effects were attenuated by pre-treatment with OBO. Prior treatment of SH-SY5Y cells with OBO also attenuated THP-1 or U373 conditioned media neurotoxicity and also reduced oxidative damage produced by treatment with hydrogen peroxide or BSO. Prior treatment with OBO potentiated survival of SH-SY5Y cells exposed to conditioned medium from BSO-treated THP-1, U373 cells, microglia and astrocytes. The data indicate that OBO could be anti-inflammatory, anti-oxidative and neuroprotective, and be an effective agent for inhibiting pathogenesis in neurological diseases such as Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis in which glial-mediated neuroinflammation and oxidative stress are thought to contribute to disease progression.
authors.affiliation: Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
authors.forename: Moonhee
authors.initials: M
authors.lastname: Lee
authors.forename: Byoung-Mog
authors.initials: BM
authors.lastname: Kwon
authors.forename: Byoung-Mok
authors.initials: BM
authors.lastname: Kwon
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
authors.forename: Edith
authors.initials: E
authors.lastname: McGeer
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D009457:Neuroglia / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010647:Phenyl Ethers / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D010647:Phenyl Ethers; C036795:obovatol; D005978:Glutathione