Russian knapweed is a perennial weed found in many parts of the world,
including southern California. Chronic ingestion of this plant by hor
ses has been reported to cause equine nigropallidal encephalomalacia (
ENE), which is associated with a movement disorder simulating Parkinso
n's disease (PD). Repin, a principal ingredient purified from Russian
knapweed, is a sesquiterpene lactone containing an alpha-methylenebuty
rolactone moiety and epoxides and is a highly reactive electrophile th
at can readily undergo conjugation with various biological nucleophile
s, 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 a
nd acutely induces uncoordinated locomotion associated with postural t
remors, hypothermia, and inability to respond to sonic and tactile sti
muli. We also show that repin intoxication reduces striatal and hippoc
ampal GSH and increases total striatal dopamine (DA) levels in mice. S
triatal microdialysis in rats, however, has demonstrated a significant
reduction of extracellular DA levels. These findings, coupled with th
e absence of any demonstrable change in striatal DOPAC levels, suggest
that repin acts by inhibiting DA release, a hypothesis that is furthe
r supported by our demonstration that, in cultured PC12 cells, repin i
nhibits the release of DA without affecting its uptake. We believe, th
erefore, that inhibition of DA release represents one of the earliest
pathogenetic events in ENE, leading eventually to striatal extracellul
ar 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 f
rom a plant in our environment that can cause a movement disorder asso
ciated with degeneration of nigrostriatal pathways, clarification of t
he mechanism of repin neurotoxicity may provide new insights into our
understanding of the pathogenesis of PD. (C) 1998 Academic Press.