PARTIAL INHIBITION OF BRAIN SUCCINATE-DEHYDROGENASE BY 3-NITROPROPIONIC ACID IS SUFFICIENT TO INITIATE STRIATAL DEGENERATION IN RAT

Chronic inhibition of succinate dehydrogenase (SDH) by systemic inject ion of the selective inhibitor 3-nitropropionic acid (3NP) has been us ed as an animal model for Huntington's disease (HD). However, the mech anisms by which 3NP produces lesions in the striatum are not fully cha racterized. A quantitative histochemical method was developed to study the level of regional SDH inhibition resulting from intraperitoneal i njection of 3NP or chronic intoxication using osmotic pumps, The resul ts showed that (a) 3NP was an irreversible SDH inhibitor in vivo, (b) the level of SDH inhibition in the striatum (the brain region most vul nerable to 3NP) was similar to that observed in other brain regions no t affected by the toxin, such as the cerebral cortex, and (c) the neur otoxic threshold of SDH inhibition in the brain was 50-60% of control levels. The present study demonstrates that the selective degeneration in the striatum observed after chronic 3NP administration cannot be a scribed to a preferential inhibition of SDH in this particular brain r egion. This work also suggests that the partial decrease in the activi ty of the respiratory chain complex II-III reported in HD patients may be sufficient to induce the selective striatal degeneration observed in this disorder.