Ammonia toxicity and cerebral oxidative metabolism

Abstract

Effects of NH 4 Cl on oxidative metabolism of cat cerebral cortex slices and mitochondria incubated in vitro were studied. In slices, addition of 10 mm NH 4 Cl to the incubation medium resulted in significant (16%) reduction of O 2 uptake, doubling of lactic acid production and marked increase of glucose utilization compared to control slices. Mitochondria showed a 30–40% decrease of O 2 consumption in the presence of 15 mm NH 4 Cl when pyruvate or α-ketoglutarate were substrates, but little if any difference from controls with succinate, glutamic acid or γ-aminobutyric acid as substrates. Pyruvate utilization by ammonia-treated mitochondria was inhibited to the same degree as O 2 consumption and was not increased by supplementing the incubation medium with excess succinate. Additions of α-lipoic acid, thiamine pyrophosphate or DPN to such preparations failed to reverse the NH 4 Cl effect. Satisfactory P/O ratios were obtained for all mitochondrial preparations. It is concluded that a primary toxic effect of ammonia on the brain may be direct interference with oxidative decarboxylation of pyruvic and α-ketoglutaric acids.