Modulation of apoptotic regulatory proteins and early activation of cytochrome C following systemic 3-nitropropionic acid administration.
The present study utilized the administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), to mimic the pathology associated with Huntington's disease (HD). 3-NP causes striatal cell degeneration via the inhibition of succinate dehydrogenase. There is growing evidence suggesting the role of apoptosis in 3-NP cell death. TUNEL staining, DNA fragmentation, and changes in bcl-2 mRNA levels have been associated with this metabolic impairment. We wish to further elucidate the apoptotic cascade in this model of HD pathogenesis. 3-NP was administered to rats intraperitoneally at 20mg/kg/day for up to 3 days. At 3 days, characteristic behavioral and morphological effects became evident. While cell death did not become apparent within the first 3 days, there were changes in the levels of apoptotic regulatory proteins and translocation of cytochrome c. Within 24 h after 3-NP administration there were elevations in both bcl-xl and bax. However, bcl-xl protein levels quickly returned to control levels while bax levels continued to increase, resulting in a detrimental bax/bcl-xl ratio. Bax has been demonstrated to facilitate cytochrome c release by forming mitochondrial pores. We saw cytochrome c translocate from the mitochondria to the cytosol approximately 24 h after initial 3-NP administration when compared to saline-injected controls. This evidence generated using the 3-NP degeneration model may help elucidate the apoptotic cascade associated with HD neurodegeneration.
Antonawich
Francis J
FJ
Department of Neurology, State University of New York at Stony Brook, Stony Brook, NY 11794-8121, USA. fantona@neuro.som.sunysb.edu
Fiore-Marasa
Susan M
SM
Parker
Christine P
CP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003292:Convulsants / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D003292:Convulsants; D003574:Cytochrome c Group; D009574:Nitro Compounds; D011422:Propionates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C015392:3-nitropropionic acid