Metabolic compromise with systemic 3-nitropropionic acid produces striatal apoptosis in Sprague-Dawley rats but not in BALB/c ByJ mice.
Metabolic compromise with systemic 3-nitropropionic acid (3-NP) results in the degeneration of striatal cells, mimicking the pathology of Huntington's disease (HD). Here we show that 10-week- and 8-month-old BALB/c ByJ mice show an unexpected striatal resilience to single and multiple systemic injections of 3-NP, while Sprague-Dawley rats are vulnerable, albeit in a variable manner. Identification of lesions was made by staining of DNA fragmentation with terminal deoxytransferase-mediated dUTP-biotin nick-end labeling (TUNEL) and hematoxylin/eosin, 1-10 days after injection. Quantitative imaging of histochemistry for succinate dehydrogenase (SDH) activity, the target of 3-NP inhibition, revealed that vulnerable rats reached maximal inhibition in brain at 1 day after 3-NP, whereas mice and resilient rats took 7 days to reach maximal inhibition. All groups of animals reached similar maximal decreases in SDH activity in striatum and cortex. Remarkably, only the fast decline in SDH activity seen in vulnerable rats was associated with TUNEL labeling. In addition, vulnerable rats developed a region within striatum where SDH activity was fully depleted and a similarly depleted region in CA1 hippocampus. While mice did not develop this region in striatum, some developed one in CA1. These regions of SDH depletion in both structures were associated with widespread TUNEL staining, with maximal labeling at 3 days after 3-NP. The existence of an animal strain resilient to 3-NP suggests that there are mediating factors involved in the preferential vulnerability of striatum to metabolic lesioning. The identification of these factors could provide strategies for therapeutic intervention in HD.
Alexi
T
T
Department of Physiological Science, University of California Los Angeles, Los Angeles, California 90095, USA.
Hughes
P E
PE
Knüsel
B
B
Tobin
A J
AJ
D000375:Aging / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009410:Nerve Degeneration / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013385:Succinate Dehydrogenase / Q000378:metabolism
D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid