L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism
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ORIGINAL PAPER
L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism Abhijit Das1,2 · Dominik Fröhlich3 · Lavanya B. Achanta1,3 · Benjamin D. Rowlands1,3 · Gary D. Housley3 · Matthias Klugmann3 · Caroline D. Rae1,2 Received: 29 February 2020 / Revised: 25 April 2020 / Accepted: 29 April 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract L-Ornithine-L-aspartate (LOLA), a crystalline salt, is used primarily in the management of hepatic encephalopathy. The degree to which it might penetrate the brain, and the effects it might have on metabolism in brain are poorly understood. Here, to investigate the effects of LOLA on brain energy metabolism we incubated brain cortical tissue slices from guinea pig (Cavea porcellus) with the constituent amino acids of LOLA, L-ornithine or L-aspartate, as well as LOLA, in the presence of [1-13C]D-glucose and [1,2-13C]acetate; these labelled substrates are useful indicators of brain metabolic activity. L-Ornithine produced significant “sedative” effects on brain slice metabolism, most likely via conversion of ornithine to GABA via the ornithine aminotransferase pathway, while L-aspartate showed concentration-dependent excitatory effects. The metabolic effects of LOLA reflected a mix of these two different processes and were concentration-dependent. We also investigated the effect of an intraperitoneal bolus injection of L-ornithine, L-aspartate or LOLA on levels of metabolites in kidney, liver and brain cortex and brain stem in mice (C57Bl6J) 1 h later. No significant changes in metabolite levels were seen following the bolus injection of L-aspartate, most likely due to rapid metabolism of aspartate before reaching the target tissue. Brain cortex glutamate was decreased by L-ornithine but no other brain effects were observed with any other compound. Kidney levels of aspartate were increased after injection of L-ornithine and LOLA which may be due to interference by ornithine with the kidney urea cycle. It is likely that without optimising chronic intravenous infusion, LOLA has minimal impact on healthy brain energy metabolism due to systemic clearance and the blood - brain barrier. Keywords Amino acid metabolism · 13C NMR spectroscopy · Brain energy metabolism · Ornithine · Aspartate · LOLA
Introduction L-ornithine-L-aspartate (LOLA) is a compound used in the management of hepatic encephalopathy [1, 2] where it has shown significant efficacy [3]. It is ingested as a crystalline salt with the L-ornithine and L-aspartate hydrogen bond Special issue in honor of Professor Michael Robinson. * Caroline D. Rae [email protected] 1
Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia
2
School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia
3
Translational Neuroscience Facility, School of Medical Sciences, The University of New South Wales, Kensington 2052, Australia
separating on dissolution or exposure to gastric acidity. Both of these
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