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

The L-tryptophan eosinophilia myalgia syndrome (L-TRP-EMS), an inflamm atory syndrome characterized by eosinophilia, myalgias, perimyositis, fasciitis and neuropathies, occurred in epidemic proportions in the Un ited States in the summer and fall of 1989. The neuropathic clinical f eatures 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 diastereoisom eric breakdown products, were compared for evidence of neurotoxicity i n vitro. In 1-month-old spinal cord cultures derived from fetal mice, synthetic (-)-(1S, hyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1S-beta-C) produced a 30 to 35% loss in numbers of neurons. Toxi city was not apparent after treatment with the R-isomer of the same co mpound or with the parent compound, EBT. Cotreatment of cultures with 1S-beta-C and neutralizing antiserum to interleukin-1 alpha (IL-1 a), or with 1 S-beta-C and neutralizing antiserum against the murine IL-1 receptor, prevented neuronal cell death associated with 1S-beta-C. Rec ombinant IL-1 a also produced neuronal killing that was not additive t o 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 o r EBT, prevented the 30% cell death which normally occurs in these cul tures. Neither neutralizing anti-IL-1 antibody, nor anti-IL-1 receptor antibody blocked the neuronal survival effect, suggesting that 1 S-be ta-C induces neuronal survival through a receptor-mediated mechanism i ndependent of IL-1. The stereospecificity suggests that these effects may be receptor mediated. These studies indicate that the 1 S-beta-C e ffects on neuronal survival in immature neurons are maturation-depende nt, and that although the neurotoxic effects of 1 S-beta-C are recepto r-mediated and linked to IL-1 alpha, the neuronal survival-promoting e ffects are receptor-mediated and independent of IL-1. These data suppo rt the hypothesis that 1S-beta-C can cause neuronal cell death, and im ply that this compound may play a role in the etiology of some of the neuropathic features Of L-TRP-EMS.