title: Inflammatory neurodegeneration induced by lipoteichoic acid from Staphylococcus aureus is mediated by glia activation, nitrosative and oxidative stress, and caspase activation.
abstract: In this study we investigated the mechanisms of neuronal cell death induced by lipoteichoic acid (LTA) and muramyl dipeptide (MDP) from Gram-positive bacterial cell walls using primary cultures of rat cerebellum granule cells (CGCs) and rat cortical glial cells (astrocytes and microglia). LTA (+/- MDP) from Staphylococcus aureus induced a strong inflammatory response of both types of glial cells (release of interleukin-1beta, tumour necrosis factor-alpha and nitric oxide). The death of CGCs was caused by activated glia because in the absence of glia (treatment with 7.5 microm cytosine-d-arabinoside to inhibit non-neuronal cell proliferation) LTA + MDP did not cause significant cell death (less than 20%). In addition, staining with rhodamine-labelled LTA confirmed that LTA was bound only to microglia and astrocytes (not neurones). Neuronal cell death induced by LTA (+/- MDP)-activated glia was partially blocked by an inducible nitric oxide synthase inhibitor (1400 W; 100 microm), and completely blocked by a superoxide dismutase mimetic [manganese (III) tetrakis (4-benzoic acid)porphyrin chloride; 50 microm] and a peroxynitrite scavenger [5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron (III); 100 microm] suggesting that nitric oxide and peroxynitrite contributed to LTA-induced cell death. Moreover, neuronal cell death was inhibited by selective inhibitors of caspase-3 (z-DEVD-fmk; 50 microm) and caspase-8 (z-Ile-Glu(O-Me)-Thr-Asp(O-Me) fluoromethyl ketone; 50 microm) indicating that they were involved in LTA-induced neuronal cell death.
authors.affiliation: European Centre for the Validation of Alternative Methods (ECVAM), European Commission Joint Research Centre, Ispra, Italy.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kinsner
authors.forename: Valentina
authors.initials: V
authors.lastname: Pilotto
authors.forename: Susanne
authors.initials: S
authors.lastname: Deininger
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
authors.forename: Sandra
authors.initials: S
authors.lastname: Coecke
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Anna
authors.initials: A
authors.lastname: Bal-Price
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004660:Encephalitis / Q000209:etiology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008070:Lipopolysaccharides; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009573:Nitrites / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D013211:Staphylococcus aureus / Q000737:chemistry*; D013682:Teichoic Acids; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D015850:Interleukin-6; D037102:Lectins; D008070:Lipopolysaccharides; D009573:Nitrites; D017472:Receptors, Interleukin-1; D013682:Teichoic Acids; D014409:Tumor Necrosis Factor-alpha; D003561:Cytarabine; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C009900:lipoteichoic acid; D020169:Caspases