Fungal tremorgens: the mechanism of action of single nitrogen containing toxins--a hypothesis.

Abstract

Tremorgenic mycotoxins are fungal secondary metabolites with a specific effect on the central nervous system (CNS). Except for a few toxins that are produced by Claviceps paspali, a plant parasitic fungus, most tremorgenic mycotoxins are synthesized by common saprophytic moulds of the genera Penicillium and Aspergillus. Since these compounds produce sustained tremor in the abscence of other neurotoxic effects, several authors have suggested that they are the causative agents of a number of naturally occurring incoordination syndromes in ruminants. The nature of the tremor produced by these compounds in laboratory animals is clinically indistinguishable from that occurring naturally. In particular, the most implicated tremorgenic mycotoxins are those that contain a single nitrogen atom in their molecules. Although individual compounds within this group are produced by unrelated fungal species, they all contain a similar biologically active chemical moiety. To date, their mechanism of action is unknown, and their role in neuropharmacology has not yet been defined. However, the presence of a GABA-like conformation within their active nucleus and the limited torsional flexibility of this moiety suggest that they are partial agonists of GABA (gamma-aminobutyric acid). A hypothetical mode of action of these toxins at the GABA receptor sites is presented and discussed.