3-Nitropropionic Acid and Other Metabolic Toxin Lesions of the Striatum

Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with severe degeneration of basal ganglia neurons. Histologically, the striatum displays neurodegeneration of the intrinsic neurons of the striatum, whereas the behavioral symptoms are primarily characterized by progressive dementia and involuntary abnormal choreiform movements. This pathophysiology of HD has been linked to a genetic mutation in the huntingtin gene, which laid the foundation for generating transgenic and knock-in rodents that display a similar genetic defect. Despite this scientific advance in our knowledge of the disease pathophysiology over the last two decades, there is no cure for HD. Conventional animal models, via mitochondrial impairment and excitotoxicity-induced neurodegeneration, which have established cell death pathways in HD remain as mainstream platform for studying the disease. The focus of this book chapter is on the mitochondrial inhibitor 3-nitropropionic acid (3-NP). We previously demonstrated that systemic administration of 3-NP leads to a progressive locomotor deterioration accompanied by a very selective striatal degeneration resembling that of HD. Subsequent studies from our laboratory further showed that manipulating the time course of 3-NP injections leads to sustained hyperactivity (early HD) or hypoactivity (late HD). This mitochondrial impairment model 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. Neurochemical assays lend support to impaired oxidative energy metabolism as key neurodegenerative process in this 3-NP model. Because of the mechanistic and pathologic similarities between 3-NP lesions and HD, 3-NP is considered a suitable HD model. We review here the rodent and non-human primate 3-NP models and other mitochondrial inhibitors similarly employed to lesion the striatum. The goal is to provide a scientific rationale for the continued use of these mitochondrial impairment models which should complement the genetic models in further understanding the disease pathology and to serve as tools for evaluating experimental therapeutics for HD.