Metabolic Toxins

3-Nitropropionic Acid (3-NP)

3-NP is a plant and fungal toxin associated with a toxic dystonic syndrome in man, and has its action as an inhibitor of succinate dehydrogenase, a component of ► mitochondrial complex II energy metabolism. In the 1990s, 3NP was optimistically adopted as a particularly efficient metabolic toxin since it appeared to provide selective striatal lesions even after peripheral administration. For reasons that remain poorly understood i.p. injections produce selective destruction of the medium spiny projection neurons of the neostriatum, with relative sparing of the striatal interneurons. This seemed to reproduce the profile of cell loss in HD and was adopted in several labs as a simple and efficient method to reproduce the human pathology. However, the toxin has a number of practical difficulties for experimental application. Standardized dosing can produce very great variability of toxicity with some animals exhibiting very extensive nonspecific lesions and large necrotic holes in the striatum, whereas other identically treated animals have no detectable pathology at all. In order to achieve consistent and relatively selective striatal lesions, it is necessary to administer very many small injections over a regular and extended time period, typically daily over weeks or even months, combined with daily testing with a functional readout that will allow setting a criterion for the cessation of dosing each animal at a comparable stage. The only effective protocols for achieving reliable and reproducible lesions that can be used to then test experimental therapeutics involve a major investment in time and resources that largely offsets the original promise of efficiency offered by the peripheral route of administration.

Other Mitochondrial Toxins

Although 3-NP may be relatively unreliable in its toxicity and specificity, a variety of other toxins similarly affect the mitochondrial energy chain, including malonic acid (MA, malonate), which inhibits the same mitochondrial complex II enzymes as 3-NP, and aminooxyacetic acid (AOAA). Unlike 3-NP, these toxins do not cross the

► blood-brain barrier and so require central injection. Thus, when injected into the striatum, both MA and AoAA induce effective striatal lesions. These toxins have been described as inducing secondary or "indirect" exci-totoxicity to neurons in the area of injection, since the profile of lesion toxicity is similar to that induced by GluR agonists, they potentiate the effects of low doses of the latter EAAs, and their toxicity is partially blocked by the NMDA antagonist MK-801. These metabolic toxins have again been of particular interest as another model of HD since they are associated with a similar cellular impairment in metabolic function as seen in the human disease, and have been argued to model a final common pathway in cell death. Moreover, toxicity is age dependent and selective for medium spiny neurons with relative sparing of striatal interneurons. However, in contrast to the human disease, malonate appears to have a toxic effect also on DA afferents to the striatum, and can be more variable in its effects than the consistent results obtained with the classic EAA excitotoxins.

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