Brain energy metabolism in a sub-acute rat model of manganese neurotoxicity: an ex vivo nuclear magnetic resonance study using [1-13C]glucose.

Ex vivo high-resolution NMR spectroscopy combined with in vivo injection of [1-13C]glucose was applied to gain insight into the mechanism(s) leading to energy failure in manganese neurotoxicity. In rats treated for 4 days with 50mg/kg MnCl(2) (intraperitoneally, i.p.), the concentration of 13C-labeled lactate increased to 154% compared to control rats. Changes in the absolute amounts of lactate were much less, resulting in increased fractional 13C-enrichments in lactate (indicating relative changes of de novo synthesis from glucose via the glycolytic pathway) to 143% of control values (P < 0.001). Analysis of samples obtained from blood plasma and peripheral organs demonstrate a selective increase of lactate synthesis from [1-13C]glucose in the brain, which is released into the circulation. In parallel, manganese treatment resulted in stimulation of flux through pyruvate dehydrogenase (PDH), leading to accumulation of [4-13C]glutamate, [4-13C]glutamine and [2-13C]GABA to 168, 247 and 144% of control, respectively. The relative flux of glucose through astrocytic pyruvate carboxylase (PC), on the other hand, was impaired by manganese, as evident from a decreased ratio of [2-13C]/[4-13C]glutamate or [2-13C]/[4-13C] glutamine. Consistent with stimulated glucose oxidative metabolism, the fractional 13C-enrichment in [2-13C]acetyl-CoA entering the tricarboxylic acid (TCA) cycle and contributing to glutamate and glutamine synthesis increased to 138 and 156% of control, respectively (P < 0.001). In parallel, the TCA cycling ratio increased to 134% compared to control rats, prior to the label ending up in glutamate. In contrast, glutamine is synthesized mainly during the first TCA cycle turn. The present data provide new evidence in support of changes in brain energy metabolism playing an important role in manganese neurotoxicity. In particular, increased glycolytic flux and lactate synthesis may contribute to the deleterious effects of manganese in the brain. Furthermore, stimulated astrocytic glucose oxidation and glutamine synthesis may be associated with astrocytic pathology and altered astrocytic-neuronal metabolic trafficking in manganese neurotoxicity.