Decreased TCA cycle rate in the rat brain after acute 3-NP treatment measured by in vivo 1H-{13C} NMR spectroscopy

Inhibition of succinate dehydrogenase (SDH) by the mitochondrial toxin 3-nitropropionic acid (3-NP) has gained acceptance as an animal model of Huntington's disease. In this study (13) C NMR spectroscopy was used to measure the tricarboxylic acid (TCA) cycle rate in the rat brain after 3-NP treatment. The time course of both glutamate C4 and C3 (13) C labelling was monitored in vivo during an infusion of [1-(13) C]glucose. Data were fitted by a mathematical model to yield the TCA cycle rate (V-tca ) and the exchange rate between alpha-ketoglutarate and glutamate (V (x) ). 3-NP treatment induced a 18% decrease in V-tca from 0.71 +/- 0.02 mumol/g/min in the control group to 0.58 +/- 0.02 mumol/g/min in the 3-NP group (p < 0.001). V (x) increased from 0.88 +/- 0.08 mumol/g/min in the control group to 1.33 +/- 0.24 mumol/g/min in the 3-NP group (p < 0.07). Fitting the C4 glutamate time course alone under the assumption that V-x is much higher than V-tca yielded V-tca =0.43 mumol/g/min in both groups. These results suggest that both V-tca and V-x are altered during 3-NP treatment, and that both glutamate C4 and C3 labelling time courses are necessary to obtain a reliable measurement of V-tca .