Skip to main content

Advertisement

SpringerLink
Log in

L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

A Correction to this article was published on 07 July 2020

This article has been updated

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

Data from this work will be available shortly after publication via the UNSW data repository or via request to the corresponding author.

Change history

  • 07 July 2020

    The original version of this published article, the bottom right hand panels of Figs.��3���6 were labelled as ���Isotopomers formed from [1-13C]D-glucose���. This is incorrect and should read ���Isotopomers formed from [1,2-13C]acetate���. This has been corrected by publishing this correction article.

References

  1. Goh ET, Stokes CS, Sidhu SS, Vilstrup H, Gluud LL (2018) Morgan MY L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 5:CD012410

    PubMed  Google Scholar 

  2. Kircheis G, Wettstein M, Vom Dahl S, Häussinger D (2002) Clinical efficacy of L-ornithine–L-aspartate in the management of hepatic encephalopathy. Metab Brain Dis 17:453–462

    CAS  PubMed  Google Scholar 

  3. Butterworth RF (2019) Beneficial effects of L-ornithine L-aspartate for prevention of overt hepatic encephalopathy in patients with cirrhosis: a systematic review with meta-analysis. Metab. Brain Dis. 35:75–81

    PubMed  PubMed Central  Google Scholar 

  4. Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF (1999) L-Ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 30:636–640

    CAS  PubMed  Google Scholar 

  5. O’Kane RL, Vina JR, Simpson I, Zaragoza R, Mokashi A, Hawkins RA (2006) Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+. Am J Physiol Endocrinol Metab 291:E412–E419

    PubMed  Google Scholar 

  6. Stoll J, Wadhwani KC, Smith OR (1993) Identification of the cationic amino acid transporter (system y+) of the rat blood-brain barrier. J Neurochem 60:1956–1959

    CAS  PubMed  Google Scholar 

  7. Jäger K, Wolf S, Dobrowolny H, Steiner J, Nave H, Maronde E, Bogerts B, Bernstein HG (2013) Differential topochemistry of three cationic amino acid transporter proteins, hCAT1, hCAT2 and hCAT3, in the adult human brain. Amino Acids 44:423–433

    PubMed  Google Scholar 

  8. Haitina T, Lindblom J, Renstrom T, Fredriksson R (2006) Fourteen novel human members of mitochondrial solute carrier family 25 (SLC25) widely expressed in the central nervous system. Genomics 88:779–790

    CAS  PubMed  Google Scholar 

  9. Yoneda Y, Roberts E, Dietz GW (1982) A new synaptosomal biosynthetic pathway of glutamate and GABA from ornithine and its negative feedback inhibition by GABA. J Neurochem 38:1686–1694

    CAS  PubMed  Google Scholar 

  10. Daune G, Seiler N (1988) Interrelationships between ornithine, glutamate, and GABA. II. Consequences of inhibition of GABA-T and ornithine aminotransferase in brain. Neurochem Res 13:69–75

    CAS  PubMed  Google Scholar 

  11. Kurata K, Nagasawa M, Tomonaga S, Aoki M, Morishita K, Denbow DM, Furuse M (2011) Orally administered L-ornithine elevates brain L-ornithine levels and has an anxiolytic-like effect in mice. Nutr Neurosci 14:243–248

    CAS  PubMed  Google Scholar 

  12. Tetsuka K, Takanaga H, Ohtsuki S, Hosoya KI, Terasaki T (2003) The l-isomer‐selective transport of aspartic acid is mediated by ASCT2 at the blood–brain barrier. J Neurochem 87:891–901

    CAS  PubMed  Google Scholar 

  13. Hosoya KI, Sugawara M, Asaba H, Terasaki T (1999) Blood-brain barrier produces significant efflux of L‐aspartic acid but not D‐aspartic. Acid J Neurochem 73:1206–1211

    CAS  PubMed  Google Scholar 

  14. Oppedisano F, Pochini L, Galluccio M, Indiveri C (2007) The glutamine/amino acid transporter (ASCT2) reconstituted in liposomes: Transport mechanism, regulation by ATP and characterization of the glutamine/glutamate antiport. Biochimica et Biophysica Acta (BBA) -. Biomembranes 1768:291–298

    CAS  Google Scholar 

  15. Bröer A, Brookes N, Ganapathy V, Dimmer KS, Wagner CA, Lang F, Bröer S (1999) The astroglial ASCT2 amino acid transporter as a mediator of glutamine efflux. J Neurochem 73:2184–2194

    PubMed  Google Scholar 

  16. Toth E, Lajtha A (1981) Elevation of cerebral levels of nonessential amino acids in vivo by administration of large doses. Neurochem Res 6:1309–1317

    CAS  PubMed  Google Scholar 

  17. Hindmarsh JT, Kilby D, Wiseman G (1966) Effect of amino acids on sugar absorption. J Physiol 186:166–174

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Shank RP, Campbell GL (1983) Ornithine as a precursor of glutamate and GABA: uptake and metabolism by neuronal and glial enriched cellular material. J Neurosci Res 9:47–57

    CAS  PubMed  Google Scholar 

  19. Hertz L, Rothman DL (2017) Glutamine-glutamate cycle flux is similar in cultured astrocytes and brain and both glutamate production and oxidation are mainly catalyzed by aspartate aminotransferase. Biology 6:17

    PubMed Central  Google Scholar 

  20. Fröhlich D, Suchowerska AK, Voss C, He R, Wolvetang E, von Jonquieres G, Simons C, Fath T, Housley GD, Klugmann M (2018) Expression pattern of the aspartyl-tRNA synthetase DARS in the human brain. Front Mol Neurosci 11:81

    PubMed  PubMed Central  Google Scholar 

  21. Fröhlich D, Suchowerska AK, Spencer ZHT, von Jonquieres G, Klugmann CB, Bongers A, Delerue F, Stefen H, Ittner LM, Fath T, Housley GD, Klugmann M (2017) In vivo characterization of the aspartyl-tRNA synthetase DARS: Homing in on the leukodystrophy HBSL. Neurobiol Dis 97:24–35

    PubMed  Google Scholar 

  22. Taft RJ, Vanderver A, Leventer RJ, Damiani SA, Simons C, Grimmond SM, Miller D, Schmidt J, Lockhart PJ, Pope K (2013) Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am J Hum Genet 92:774–780

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Rae C, Balcar V A (2014) Chip off the old block: the brain slice as a model for metabolic studies of brain compartmentation and neuropharmacology. In: Hirrlinger J, Waagepetersen HS (eds) Brain energy metabolism. Springer, New York, pp 217–241

    Google Scholar 

  24. Rae CD, Davidson JE, Maher AD, Rowlands BD, Kashem MA, Nasrallah FA, Rallipalli SK, Cook JM, Balcar VJ (2014) Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations. J Neurochem 129:304–314

    CAS  PubMed  Google Scholar 

  25. Le Belle JE, Harris NG, Williams SR, Bhakoo KK (2002) A comparison of cell and tissue extraction techniques using high-resolution 1H NMR spectroscopy. NMR Biomed 15:37–44

    PubMed  Google Scholar 

  26. Rowlands BD, Lau CL, Ryall JG, Thomas DS, Klugmann M, Beart PM, Rae CD (2015) Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism. J Neurosci Res 93:1147–1156

    CAS  PubMed  Google Scholar 

  27. Achanta LB, Rowlands BD, Thomas DS, Housley GD, Rae CD (2017) β-hydroxybutyrate boosts mitochondrial and neuronal metabolism but is not preferred over glucose under activated conditions. Neurochem Res 42:1710–1723

    CAS  PubMed  Google Scholar 

  28. Rowlands BD, Klugmann M, Rae CD (2017) Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation. J Neurochem 140:903–918

    CAS  PubMed  Google Scholar 

  29. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  30. Rae C, Lawrance ML, Dias LS, Provis T, Bubb WA, Balcar VJ (2000) Strategies for studies of potentially neurotoxic mechanisms involving deficient transport of L-glutamate: antisense knockout in rat brain in vivo and changes in the neurotransmitter metabolism following inhibition of glutamate transport in guinea pigs brain slices. Brain Res Bull 53:373–381

    CAS  PubMed  Google Scholar 

  31. Nasrallah FA, Maher AD, Hanrahan JR, Balcar VJ, Rae CD (2010) γ-Hydroxybutyrate and the GABAergic footprint. A metabolomic approach to unpicking the actions of GHB. J Neurochem 115:58–67

    CAS  PubMed  Google Scholar 

  32. Maher AD, Solo V, Rae CD (2013) Magnetic resonance-based metabolomics for understanding neurological disorders: current status and considerations. Curr Metab 1:2–14

    CAS  Google Scholar 

  33. Rae CD, Williams SR (2017) Glutathione in the human brain: review of its roles and measurement by magnetic resonance spectroscopy. Anal Biochem 529:127–143

    CAS  PubMed  Google Scholar 

  34. Furlong TM, Duncan JR, Corbit LH, Rae CD, Rowlands BD, Maher AD, Nasrallah FA, Milligan CJ, Petrou S, Lawrence AJ (2016) Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling. J Neurochem 139:806–822

    CAS  PubMed  Google Scholar 

  35. Erecińska M, Silver IA (1990) Metabolism and role of glutamate in mammalian brain. Prog Neurobiol 35:245–296

    PubMed  Google Scholar 

  36. Rae C, Moussa CE-H, Griffin JL, Parekh SB, Bubb WA, Hunt NH, Balcar VJ (2006) A metabolomic approach to ionotropic glutamate receptor subtype function: a nuclear magnetic resonance in vitro investigation. J Cereb Blood Flow Metab 26:1005–1017

    CAS  PubMed  Google Scholar 

  37. Albrecht J, Hilgier W, Januszewski S, Quack G (1996) Contrasting effects of thioacetamide-induced liver damage on the brain uptake indices of ornithine, arginine and lysine: modulation by treatment with ornithine aspartate. Metab Brain Dis 11:229–237

    CAS  PubMed  Google Scholar 

  38. Vogels B, Karlsen O, Maas M, Boveé W, Chamuleau R (1997) L-ornithine vs. L-ornithine-L-aspartate as a treatment for hyperammonemia-induced encephalopathy in rats. J Hepatol 26:174–182

    CAS  PubMed  Google Scholar 

  39. Stoll B, McNelly S, Buscher H-P, Häussinger D (1991) Functional hepatocyte heterogeneity in glutamate, aspartate and α-ketoglutarate uptake: a histoautoradiographical study. Hepatology 13:247–253

    CAS  PubMed  Google Scholar 

  40. Foulkes EC (1971) Effects of heavy metals on renal aspartate transport and the nature of solute movement in kidney cortex slices. Biochim Biophys Acta (BBA) Biomembr 241:815–822

    CAS  Google Scholar 

  41. Wu F, Orlefors H, Bergstrom M, Antoni G, Omura H, Eriksson B, Watanabe Y, Langstrom B (2000) Uptake of 14C- and 11C-labeled glutamate, glutamine and aspartate in vitro and in vivo. Anticancer Res 20:251–256

    CAS  PubMed  Google Scholar 

  42. Grover VP, McPhail MJ, Wylezinska-Arridge M, Crossey MM, Fitzpatrick JA, Southern L, Saxby BK, Cook NA, Cox IJ, Waldman AD (2017) A longitudinal study of patients with cirrhosis treated with L-ornithine L-aspartate, examined with magnetization transfer, diffusion-weighted imaging and magnetic resonance spectroscopy. Metab Brain Dis 32:77–86

    CAS  PubMed  Google Scholar 

  43. Kakoki M, Kim H-S, Arendshorst WJ, Mattson DL (2004) l-Arginine uptake affects nitric oxide production and blood flow in the renal medulla. Am J Physiol-Regul Integr Comp Physiol 287:R1478–R1485

    CAS  PubMed  Google Scholar 

  44. Albrecht J, Hilgier W, Januszewski S, Kapuściński A, Quack G (1994) Increase of the brain uptake index for L-ornithine in rats with hepatic encephalopathy. Neuroreport 5:671–673

    CAS  PubMed  Google Scholar 

  45. Skowrońska M, Albrecht J (2012) Alterations of blood brain barrier function in hyperammonemia. Overv Neurotox Res 21:236–244

    Google Scholar 

Download references

Acknowledgements

The authors are grateful to the staff of the UNSW Mark Wainwright Analytical Centre for technical support. The authors would also like to acknowledge the lifetime contribution of Mike Robinson to the field of neurochemistry, his encouragement of the young and the pursuit of science, and we dedicate this article to his contributions. We have greatly enjoyed and benefitted from our professional interactions over the years and have treasured his personal friendship.

Funding

This work was supported by the Australian Research Council (DP180101702) and the Medical Research Future Fund (MRFF-ARLKO).

Author information

Authors and Affiliations

  1. Neuroscience Research Australia, Barker St, Randwick, NSW, 2031, Australia

    Abhijit Das, Lavanya B. Achanta, Benjamin D. Rowlands & Caroline D. Rae

  2. School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia

    Abhijit Das & Caroline D. Rae

  3. Translational Neuroscience Facility, School of Medical Sciences, The University of New South Wales, Kensington, 2052, Australia

    Dominik Fröhlich, Lavanya B. Achanta, Benjamin D. Rowlands, Gary D. Housley & Matthias Klugmann

Authors
  1. Abhijit Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dominik Fröhlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lavanya B. Achanta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benjamin D. Rowlands
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gary D. Housley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias Klugmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Caroline D. Rae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Caroline D. Rae.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

Ethics approval for this work was obtained from the institutional (UNSW) Animal Care Ethics Committee.

Informed Consent

All authors have consented to the submission and publication of this manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Special issue in honor of Professor Michael Robinson.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Das, A., Fröhlich, D., Achanta, L.B. et al. L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism. Neurochem Res 45, 1438–1450 (2020). https://doi.org/10.1007/s11064-020-03044-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-020-03044-9

Keywords

Search

Navigation