Effects of 3-Nitropropionic Acid on Synaptosomal Energy and Transmitter Metabolism: Relevance to Neurodegenerative Brain Diseases

Abstract: 3-Nitropropionic acid (3-NPA) inhibited synaptosomal respiration in a dose-dependent manner; the degree of inhibition by the same concentration of the compound was greater, however, when respiration was stimulated by concomitant increase in ATP usage. The most rapid event after addition of 3-NPA was a decrease in [creatine phosphate]/[creatine] ([CrP]/[Cr]) and an increase in [lactate]/[pyruvate]. A fall in [ATP]/[ADP] and [GTP]/[GDP] was initially less pronounced but closely followed that in [CrP]/[Cr]. In the absence of glutamine, 3-NPA caused a pronounced decrease in internal aspartate level and a small reduction in glutamate concentration, whereas [GABA] rose; the sum of these three amino acids inside synaptosomes fell, but there were no increases in their external levels. With glutamine in the medium, the reduction in intrasynaptosomal aspartate was accompanied by increases in intrasynaptosomal glutamate and GABA. The external concentration of glutamate rose substantially in the presence of the inhibitor. 3-NPA had no effect on basal release of either glutamate (and GABA) or biogenic amines but increased efflux occurring upon addition of nonsaturating concentrations of the depolarizing agents veratridine and KCI. The results allow the following predictions with respect to the behavior of brain metabolism in neurodegenerative diseases that involve restrictions of mitochondrial function: (1) The extent of inhibition of mitochondrial ATP generation is expected to be greater in cells with high energy demand. The earliest signs of impairment of the respiratory chain function are a fall in [PCr]/[Cr] (or a rise in [Pi]/[CrP]) and an increase in [lactate]/[pyruvate]. (2) A fall in [GTP]/[GDP] can limit protein synthesis. This may be one of the factors that contributes to cell death. (3) An increase in the concentration of inorganic phosphate stimulates neuronal glutaminase activity and leads to a release of glutamate into the external environment; the latter could activate excitatory amino acid receptors. (4) A lowered energy level limits the cell's ability to restore ion gradients. Stimulated release of transmitters from neurons may, therefore, be enhanced and their reuptake delayed.