3-NITROPROPIONIC ACID ANIMAL-MODEL AND HUNTINGTONS-DISEASE

Huntington's disease (HD) is a progressive neurodegenerative disorder associated with severe degeneration of basal ganglia neurons, especial ly the intrinsic neurons of the striatum, and characterized by progres sive dementia and involuntary abnormal choreiform movements. Despite o ur increasing knowledge of the pathophysiology of HD, culminating with the discovery of the gene underlying HD, there has been no cure avail able 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 contin ue 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 pro gressive locomotor deterioration resembling that of HD. Furthermore, w e observed congruent with other reports, that 3-NP produces a very sel ective striatal degeneration. It differs mechanistically from excitoto xic lesions in that 3-NP irreversibly inhibits the mitochondrial citri c acid cycle and leads to depressed ATP levels and elevated lactate co ncentrations. Recent neurochemical studies have implicated lowered glu tamate levels and impaired oxidative energy metabolism as underlying m echanisms for many neurodegenerative disorders, including HD. Because of the mechanistic and pathologic similarities between 3-NP lesions an d HD, 3-NP has been proposed as an alternative HD model. We further de monstrated that manipulating the time course of 3-NP injections lends to sustained hyperactivity (early HD) or hypoactivity (late HD). The p resent review will primarily discuss this progressive behavioral patho logy induced by 3-NP that closely resembles that of HD. This body of e vidence suggests that the 3-NP model is an improved HD model and may o ffer a unique system wherein testing of experimental treatments for HD can be carried out across different stages of the disease. This futur e application of the 3-NP model will be very useful especially in asse ssing the efficacy of treatment modalities, e.g. neural transplantatio n, during the progression of the disease. (C) 1997 Elsevier Science Lt d.