Russian knapweed is a perennial weed found in many parts of the world, including southern California. Chronic ingestion of this plant by horses has been reported to cause equine
nigropallidal encephalomalacia (ENE), which is associated with a
movement disorder simulating
Parkinson's disease (PD).
Repin, a principal ingredient purified from Russian knapweed, is a
sesquiterpene lactone containing an alpha-methylenebutyrolactone moiety and
epoxides and is a highly reactive electrophile that can readily undergo conjugation with various
biological nucleophiles, such as
proteins,
DNA, and
glutathione (GSH). We show in this study that
repin is highly toxic to C57BL/6J mice and Sprague-Dawley rats and acutely induces uncoordinated locomotion associated with postural
tremors,
hypothermia, and inability to respond to sonic and tactile stimuli. We also show that
repin intoxication reduces striatal and hippocampal GSH and increases total striatal
dopamine (DA) levels in mice. Striatal microdialysis in rats, however, has demonstrated a significant reduction of extracellular DA levels. These findings, coupled with the absence of any demonstrable change in striatal
DOPAC levels, suggest that
repin acts by inhibiting DA release, a hypothesis that is further supported by our demonstration that, in cultured PC12 cells,
repin inhibits the release of DA without affecting its uptake. We believe, therefore, that inhibition of DA release represents one of the earliest pathogenetic events in ENE, leading eventually to striatal extracellular DA
denervation, oxidative stress, and degeneration of nigrostriatal pathways. Since the neurotoxic effects of
repin appear to be mediated via oxidative stress, and since
repin is a
natural product isolated from a plant in our environment that can cause a
movement disorder associated with degeneration of nigrostriatal pathways, clarification of the mechanism of
repin neurotoxicity may provide new insights into our understanding of the pathogenesis of PD.