3-Nitropropionic acid animal model and Huntington's disease.

ABSTRACT

Huntington's disease (HD) is a progressive neurodegenerative disorder associated with severe degeneration of basal ganglia neurons, especially the intrinsic neurons of the striatum, and characterized by progressive dementia and involuntary abnormal choreiform movements. Despite our increasing knowledge of the pathophysiology of HD, culminating with the discovery of the gene underlying HD, there has been no cure available to completely cease or reverse the progressive neurodegeneration and behavioral consequences of the disease. Animal models that closely mimic the neurobiological and clinical symptoms of the disease continue to offer alternative approaches for studying HD. Recently, we have reported that systemic administration of 3-nitropropionic acid (3-NP), an inhibitor of the mitochondrial citric acid cycle, results in a progressive locomotor deterioration resembling that of HD. Furthermore, we observed congruent with other reports, that 3-NP produces a very selective striatal degeneration. It differs mechanistically from excitotoxic lesions in that 3-NP irreversibly inhibits the mitochondrial citric acid cycle and leads to depressed ATP levels and elevated lactate concentrations. Recent neurochemical studies have implicated lowered glutamate levels and impaired oxidative energy metabolism as underlying mechanisms for many neurodegenerative disorders, including HD. Because of the mechanistic and pathologic similarities between 3-NP lesions and HD, 3-NP has been proposed as an alternative HD model. We further demonstrated that manipulating the time course of 3-NP injections leads to sustained hyperactivity (early HD) or hypoactivity (late HD). The present review will primarily discuss this progressive behavioral pathology induced by 3-NP that closely resembles that of HD. This body of evidence suggests that the 3-NP model is an improved HD model and may offer a unique system wherein testing of experimental treatments for HD can be carried out across different stages of the disease. This future application of the 3-NP model will be very useful especially in assessing the efficacy of treatment modalities, e.g. neural transplantation, during the progression of the disease.