3-Nitropropionic acid induces a spectrum of Huntington's disease-like neuropathology in rat striatum

Systemic administration of the mitochondrial toxin 3-nitropropionic acid (3 -NP) to rats results in selective striatal lesions and serves as an experim ental model of Huntington's disease (HD). However, the effects of the 3-NP treatment are unpredictable and result in lesions of variable severity. The present study was aimed at further characterizing the variability of the s triatal lesions induced by systemic administration of 3-NP using osmotic pu mps. Hematoxylin-eosin (HE) and Nissl stains as well as immunohistochemical labelling of astrocytes and striatal neurones were performed to analyse th e neurotoxic effects of 3-NP. In general, chronic systemic administration o f 3-NP resulted in obvious bilateral striatal lesions, which ranged from mi ld to severe, together with a subtle, but detectable behavioural lesion. Se vere type lesions showed marked neuronal loss and an increased expression o f glial fibrillary acidic protein (GFAP) in astrocytes surrounding the lesi on area, whereas in the core of the lesion GFAP-immunoreactivity was absent . The mild type lesion was characterized by a substantial loss of striatal neurones and an increased expression of GFAP-positive astrocytes throughout the lesion. In a number of 3-NP-treated animals, neither type of lesion wa s observed, although these animals demonstrated behavioural changes in the paw test compared to controls. In the striatum of these tested 3-NP-treated animals, compromised rk' neurones were detected, suggestive of subtle and early 3-NP-induced neuronal injury. Similar dark neurones were also detecte d in mild and severe lesions and were immunocytochemically characterized as gamma-aminobutyric acid (GABA) and substance P containing spiny neurones, which belong to the neuronal population that is affected in early HD. These results indicate that systemic administration of 3-NP to rats may result i n a spectrum of striatal pathology of which the morphology of the mild type lesion resembles the characteristic HD neuropathology most closely.