The mitochondrial toxin 3-nitropropionic acid induces differential expression patterns of apoptosis-related markers in rat striatum.
The mitochondrial toxin 3-nitropropionic acid (3-NP) causes selective striatal lesions in rats and serves as an experimental model for the neurodegenerative disorder Huntington's disease (HD). Apoptotic cell death has been implicated for the neuronal degeneration that occurs in HD brains. The present study was designed to investigate whether the 3-NP-induced cell death in rats involves apoptosis and an altered expression of Bcl-2 family proteins. Systemic administration of 3-NP via subcutaneous Alzet pumps resulted in lesions of variable severity with neuronal loss and gliosis in the striatum. Using the terminal transferase-mediated biotinylated-UTP nick end-labelling (TUNEL) of DNA, TUNEL-positive cells exhibiting typical apoptotic morphology were detected only in the striatum of rats with a severe lesion. Furthermore, the neuronal expression of the pro-apoptotic protein Bax was strongly increased in the core of the severe lesion. Expression of the anti-apoptotic marker Bcl-2 was unchanged in this location, but was enhanced in the margins of the lesions. A moderately increased expression of both Bax and Bcl-2 was observed in dark neurones in the mild lesion and in the subtle lesion. The presence of nuclear DNA fragmentation, strong granular Bax expression and an increased Bax/Bcl-2 ratio in the centre of severe lesions suggests the occurrence of apoptotic cell death following 3-NP administration. In contrast, the dark compromised neurones observed in 3-NP-treated animals revealed an equally enhanced expression of both Bax and Bcl-2, but lacked TUNEL-labelling, and are therefore not apoptotic.
Vis
J C
JC
Departments of Neurology and Pathology, University Hospital Nijmegen, Nijmegen, The Netherlands. J.Vis@mailbox.kun.nl
Verbeek
M M
MM
de Waal
R M
RM
ten Donkelaar
H J
HJ
Kremer
B
B
D000818:Animals; D017209:Apoptosis; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009574:Nitro Compounds; D011422:Propionates / Q000008:administration & dosage / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D009574:Nitro Compounds; D011422:Propionates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C015392:3-nitropropionic acid