title: A decomposition product of a contaminant implicated in L-tryptophan eosinophilia myalgia syndrome affects spinal cord neuronal cell death and survival through stereospecific, maturation and partly interleukin-1-dependent mechanisms.
abstract: The L-tryptophan eosinophilia myalgia syndrome (L-TRP-EMS), an inflammatory syndrome characterized by eosinophilia, myalgias, perimyositis, fasciitis and neuropathies, occurred in epidemic proportions in the United States in the summer and fall of 1989. The neuropathic clinical features in L-TRP EMS are complex and mixed. In the present study, one of the impurities most highly associated with development of L-TRP EMS, 1,1'-ethylidenebis[L-tryptophan] (EBT), and two of its diastereoisomeric breakdown products, were compared for evidence of neurotoxicity in vitro. In 1-month-old spinal cord cultures derived from fetal mice, synthetic (-)-(1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1S-beta-C) produced a 30 to 35% loss in numbers of neurons. Toxicity was not apparent after treatment with the R-isomer of the same compound or with the parent compound, EBT. Cotreatment of cultures with 1S-beta-C and neutralizing antiserum to interleukin-1 alpha (IL-1 alpha), or with 1S-beta-C and neutralizing antiserum against the murine IL-1 receptor, prevented neuronal cell death associated with 1S-beta-C. Recombinant IL-1 alpha also produced neuronal killing that was not additive to that observed with the 1S-beta-C treatment. In contrast, in immature spinal cord neuronal cultures, the 1S-beta-C, but not the 1R-beta-C or EBT, prevented the 30% cell death which normally occurs in these cultures. Neither neutralizing anti-IL-1 antibody, nor anti-IL-1 receptor antibody blocked the neuronal survival effect, suggesting that 1S-beta-C induces neuronal survival through a receptor-mediated mechanism independent of IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Section on Developmental and Molecular Pharmacology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: D E
authors.initials: DE
authors.lastname: Brenneman
authors.forename: S W
authors.initials: SW
authors.lastname: Page
authors.forename: M
authors.initials: M
authors.lastname: Schultzberg
authors.forename: F S
authors.initials: FS
authors.lastname: Thomas
authors.forename: P
authors.initials: P
authors.lastname: Zelazowski
authors.forename: P
authors.initials: P
authors.lastname: Burnet
authors.forename: R
authors.initials: R
authors.lastname: Avidor
authors.forename: E M
authors.initials: EM
authors.lastname: Sternberg
mesh_terms: D000818:Animals; D002243:Carbolines / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004340:Drug Contamination; D016603:Eosinophilia-Myalgia Syndrome / Q000209:etiology*; D005260:Female; D007375:Interleukin-1 / Q000502:physiology*; D051379:Mice; D011247:Pregnancy; D017472:Receptors, Interleukin-1 / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects*; D013237:Stereoisomerism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D002243:Carbolines; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; C070372:1,1'-ethylidene bis(tryptophan); C038114:1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid; D014364:Tryptophan