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 stria tal lesions in rats and serves as an experimental model for the neurodegene rative disorder Huntington's disease (HD). Apoptotic cell death has been im plicated for the neuronal degeneration that occurs in HD brains. The presen t 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 l esions of variable severity with neuronal loss and gliosis in the striatum. Using the terminal transferase-mediated biotinylated-UTP nick end-labellin g (TUNEL) of DNA. TUNEL-positive cells exhibiting typical apoptotic morphol ogy were detected only in the striatum of rats with a severe lesion. Furthe rmore, the neuronal expression of the pro-apoptotic protein Bax was strongl y increased in the core of the severe lesion. Expression of the anti-apopto tic marker Bcl-2 was unchanged in this location, but was enhanced in the ma rgins 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 lesio n. The presence of nuclear DNA fragmentation, strong granular Bax expressio n 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 c ontrast, the dark compromised neurones observed in 3-NP-treated animals rev ealed an equally enhanced expression of both Bax and Bcl-2. but lacked TUNE L-labelling, and are therefore not apoptotic.