Skip to main content

Advertisement

SpringerLink
Log in

Acute Hyperammonemia and Systemic Inflammation is Associated with Increased Extracellular Brain Adenosine in Rats: A Biosensor Study

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

Abstract

Acute liver failure (ALF) can lead to brain edema, cerebral hyperperfusion and intracranial hypertension. These complications are thought to be mediated by hyperammonemia and inflammation leading to altered brain metabolism. As increased levels of adenosine degradation products have been found in brain tissue of patients with ALF we investigated whether hyperammonemia could induce adenosine release in brain tissue. Since adenosine is a potent vasodilator and modulator of cerebral metabolism we furthermore studied the effect of adenosine receptor ligands on intracranial pressure (ICP) and cerebral blood flow (CBF). We measured the adenosine concentration with biosensors in rat brain slices exposed to ammonia and in a rat model with hyperammonemia and systemic inflammation. Exposure to ammonia in concentrations from 0.15–10 mM led to increases in the cortical adenosine concentration up to 18 µM in brain slices. In vivo recordings showed a tendency towards increased adenosine levels in rats with hyperammonemia and systemic inflammation compared to a control group (3.7 ± 0.7 vs. 0.8 ± 0.2 µM, P = 0.06). This was associated with a significant increase in ICP and CBF. Intervention with the non-selective adenosine receptor antagonist theophyllamine, the A2A receptor antagonist ZM241385, or the A1 receptor agonist N6-Cyclopentyladenosine did not reduce ICP or CBF. In conclusion, our results show that the adenosine concentration in cortex increases during exposure to ammonia, and is associated with a rise in intracranial pressure and cerebral perfusion. However adenosine receptor antagonism/agonism did not reduce the ICP or CBF which indicates that adenosine may not be of direct importance for these cerebral complications in ALF.

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

Similar content being viewed by others

References

  1. Bjerring PN, Eefsen M, Hansen BA, Larsen FS (2009) The brain in acute liver failure. A tortuous path from hyperammonemia to cerebral edema. Metab Brain Dis 24(1):5–14

    Article  PubMed  Google Scholar 

  2. Bjerring PN, Larsen FS (2013) Changes in cerebral oxidative metabolism in patients with acute liver failure. Metab Brain Dis 28(2):179–182

  3. Bjerring PN, Hauerberg J, Jorgensen L, Frederiksen HJ, Tofteng F, Hansen BA et al (2010) Brain hypoxanthine concentration correlates to lactate/pyruvate ratio but not intracranial pressure in patients with acute liver failure. J Hepatol 53(6):1054–1058

    Article  CAS  PubMed  Google Scholar 

  4. Phillis JW (2004) Adenosine and adenine nucleotides as regulators of cerebral blood flow: roles of acidosis, cell swelling, and KATP channels. Crit Rev Neurobiol 16(4):237–270

    Article  CAS  PubMed  Google Scholar 

  5. Klinger M, Freissmuth M, Nanoff C (2002) Adenosine receptors: g protein-mediated signalling and the role of accessory proteins. Cell Signal 14(2):99–108

    Article  CAS  PubMed  Google Scholar 

  6. Shin HK, Park SN, Hong KW (2000) Implication of adenosine A(2A) receptors in hypotension-induced vasodilation and cerebral blood flow autoregulation in rat pial arteries. Life Sci 67(12):1435–1445

    Article  CAS  PubMed  Google Scholar 

  7. Schubert P, Ogata T, Marchini C, Ferroni S, Rudolphi K (1997) Protective mechanisms of adenosine in neurons and glial cells. Ann N Y Acad Sci 15(825):1–10

    Article  Google Scholar 

  8. Baumgold J, Nikodijevic O, Jacobson KA (1992) Penetration of adenosine antagonists into mouse brain as determined by ex vivo binding. Biochem Pharmacol 43(4):889–894

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Morii S, Ngai AC, Ko KR, Winn HR (1987) Role of adenosine in regulation of cerebral blood flow: effects of theophylline during normoxia and hypoxia. Am J Physiol 253(1 Pt 2):H165–H175

    CAS  PubMed  Google Scholar 

  10. Kusano Y, Echeverry G, Miekisiak G, Kulik TB, Aronhime SN, Chen JF, et al. (2009) Role of adenosine A2 receptors in regulation of cerebral blood flow during induced hypotension. J Cereb Blood Flow Metab

  11. Okamura N, Hashimoto K, Shimizu E, Kumakiri C, Komatsu N, Iyo M (2004) Adenosine A1 receptor agonists block the neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine. Neuropsychopharmacology 29(3):544–550

    Article  CAS  PubMed  Google Scholar 

  12. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P (1999) Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 29(3):648–653

    Article  CAS  PubMed  Google Scholar 

  13. Uchino T, Endo F, Matsuda I (1998) Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis 21(Suppl 1):151–159

    Article  PubMed  Google Scholar 

  14. Pedersen HR, Ring-Larsen H, Olsen NV, Larsen FS (2007) Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital. J Hepatol 47(2):245–252

    Article  CAS  PubMed  Google Scholar 

  15. Kaminsky Y, Kosenko E (2009) Brain purine metabolism and xanthine dehydrogenase/oxidase conversion in hyperammonemia are under control of NMDA receptors and nitric oxide. Brain Res 6(1294):193–201

    Article  Google Scholar 

  16. Boy C, Meyer PT, Kircheis G, Holschbach MH, Herzog H, Elmenhorst D et al (2008) Cerebral A1 adenosine receptors (A1AR) in liver cirrhosis. Eur J Nucl Med Mol Imaging 35(3):589–597

    Article  CAS  PubMed  Google Scholar 

  17. Sims RE, Dale N (2014) Activity-dependent adenosine release may be linked to activation of Na(+)-K(+) ATPase: an in vitro rat study. PLoS One 9(1):e87481

    Article  PubMed Central  PubMed  Google Scholar 

  18. Kosenko E, Kaminsky Y, Grau E, Minana MD, Marcaida G, Grisolia S et al (1994) Brain Atp depletion induced by acute ammonia intoxication in rats is mediated by activation of the Nmda receptor and Na+, K+-Atpase. J Neurochem 63(6):2172–2178

    Article  CAS  PubMed  Google Scholar 

  19. Strauss G, Hansen BA, Kirkegaard P, Rasmussen A, Hjortrup A, Larsen FS (1997) Liver function, cerebral blood flow autoregulation, and hepatic encephalopathy in fulminant hepatic failure. Hepatology 25(4):837–839

    Article  CAS  PubMed  Google Scholar 

  20. Aggarwal S, Kramer D, Yonas H, Obrist W, Kang Y, Martin M et al (1994) Cerebral hemodynamic and metabolic changes in fulminant hepatic failure: a retrospective study. Hepatology 19(1):80–87

    Article  CAS  PubMed  Google Scholar 

  21. Rivera-Oliver M, Diaz-Rios M (2014) Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review. Life Sci 101(1–2):1–9

    Article  PubMed Central  PubMed  Google Scholar 

  22. Dethloff TJ, Knudsen GM, Larsen FS (2008) Cerebral blood flow autoregulation in experimental liver failure. J Cereb Blood Flow Metab 28(5):916–926

    Article  PubMed  Google Scholar 

  23. Stephan J, Haack N, Kafitz KW, Durry S, Koch D, Hochstrate P et al (2012) Kir4.1 channels mediate a depolarization of hippocampal astrocytes under hyperammonemic conditions in situ. Glia 60(6):965–978

    Article  PubMed  Google Scholar 

  24. Rangroo TV, Thrane AS, Wang F, Cotrina ML, Smith NA, Chen M et al (2013) Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. Nat Med 12:1643–1648

    Article  Google Scholar 

  25. Basheer R, Porkka-Heiskanen T, Strecker RE, Thakkar MM, McCarley RW (2000) Adenosine as a biological signal mediating sleepiness following prolonged wakefulness. Biol Signals Recept 9(6):319–327

    Article  CAS  PubMed  Google Scholar 

  26. Montagnese S, De PC, De RM, Corrias M, Turco M, Merkel C et al (2014) Sleep-wake abnormalities in patients with cirrhosis. Hepatology 59(2):705–712

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

Nicholas Dale is a founder and shareholder in Sarissa Biomedical Ltd.

Author information

Authors and Affiliations

  1. Department of Hepatology, Rigshospitalet, 2100, Copenhagen, Denmark

    Peter Nissen Bjerring & Fin Stolze Larsen

  2. School of Life Sciences, University of Warwick, Coventry, UK

    Nicholas Dale

Authors
  1. Peter Nissen Bjerring
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas Dale
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fin Stolze Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Nissen Bjerring.

Additional information

Special Issue: In honor of Michael Norenberg.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bjerring, P.N., Dale, N. & Larsen, F.S. Acute Hyperammonemia and Systemic Inflammation is Associated with Increased Extracellular Brain Adenosine in Rats: A Biosensor Study. Neurochem Res 40, 258–264 (2015). https://doi.org/10.1007/s11064-014-1357-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1357-4

Keywords

Search

Navigation