Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient’s survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat’s death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood–brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Akgören, N., Fabricius, M., & Lauritzen, M. (1994). Importance of nitric oxide for local increases of blood flow in rat cerebellar cortex during electrical stimulation. Proceedings of the National Academy of Sciences of the United States of America, 91(13), 5903–5907.
Bernal, W., Hall, C., Karvellas, C. J., Auzinger, G., Sizers, E., & Wendon, J. (2007). Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology, 46(6), 1844–1852.
Bhatia, V., Singhal, A., Panda, S. K., & Acharya, S. K. (2008). A 20-year single-center experience with acute liver failure during pregnancy: Is the prognosis really worse? Hepatology, 48(5), 1577–1585.
Butterworth, R. F. (2003). Brain edema in acute liver failure. Indian Journal of Gastroenterology, 22(Suppl 2), S59–S61.
Cauli, O., López-Larrubia, P., Rodrigo, R., Agusti, A., Boi, J., Nieto-Charques, L., et al. (2011). Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats. Gastroenterology, 140(2), 638–645.
Cauli, O., López-Larrubia, P., Rodrigues, T. B., Cerdán, S., & Felipo, V. (2007). Magnetic resonance analysis of the effects of acute ammonia intoxication on rat brain. Role of NMDA receptors. Journal of Neurochemistry, 103, 1334–1343.
Cauli, O., Rodrigo, R., Boix, J., Piedrafita, B., Agusti, A., & Felipo, V. (2008). Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain. American Journal of Physiology. Gastrointestinal and Liver Physiology, 295(3), G503–G511.
Chi, O. Z., Liu, X., & Weiss, H. R. (2003). Effects of inhibition of neuronal nitric oxide synthase on NMDA-induced changes in cerebral blood flow and oxygen consumption. Experimental Brain Research, 148(2), 256–260.
Clemmesen, J. O., Larsen, F. S., Kondrup, J., Hansen, B. A., & Ott, P. (1999). Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology, 29(3), 648–653.
Corbalán, R., Chatauret, N., Behrends, S., Butterworth, R. F., & Felipo, V. (2002). Region selective alterations of soluble guanylate cyclase content and modulation in brain of cirrhotic patients. Hepatology, 3(5), 1155–1162.
Duarte, C. D., Zhang, J., & Ellis, S. (1997). The SHR as a small animal model for radiocontrast renal failure. Relation of nephrotoxicity to animal’s age, gener, strain and dose of radiocontrast. Renal Failure, 19, 723–743.
Duszczyk, M., Gadamski, R., Ziembowicz, A., Danysz, W., & Lazarewicz, J. W. (2005). NMDA receptor antagonism does not inhibit induction of ischemic tolerance in gerbil brain in vivo. Neurotoxicity Research, 7(4), 283–292.
Felipo, V., Miñana, M. D., Cabedo, H., & Grisolía, S. (1994). L-carnitine increases the affinity of glutamate for quisqualate receptors and prevents glutamate neurotoxicity. Neurochemical Research, 19, 373–377.
Hara, S., Mukai, T., Kuriiwa, F., Iwata, N., Kano, S., & Endo, T. (1996). Local changes in oxygen tension and blood flow in the brain under hyperthermia induced by intracerebroventricular NMDA in rats. Brain Research, 737(1–2), 339–342.
Hayashi, T., Katsumi, Y., Mukai, T., Inoue, M., Nagahama, Y., Oyanagi, C., et al. (2002). Neuronal nitric oxide has a role as a perfusion regulator and a synaptic modulator in cerebellum but not in neocortex during somatosensory stimulation—an animal PET study. Neuroscience Research, 44(2), 155–165.
Hermenegildo, C., Marcaida, G., Montoliu, C., Grisolía, S., Miñana, M. D., & Felipo, V. (1996). NMDA receptor antagonists prevent acute ammonia toxicity in mice. Neurochemical Research, 21(10), 1237–1244.
Hermenegildo, C., Monfort, P., & Felipo, V. (2000). Activation of NMDA receptors in rat brain in vivo following acute ammonia intoxication. Characterization by in vivo brain microdialysis. Hepatology, 31, 709–715.
Jalan, R. (2005). Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure. Neurochemistry International, 47(1–2), 78–83.
Jalan, R., & Bernuau, J. (2007). Induction of cerebral hyperemia by ammonia plus endotoxin: Does hyperammonemia unlock the blood–brain barrier? Journal of Hepatology, 47(2), 168–171.
Jalan, R., Olde Damink, S. W., Hayes, P. C., Deutz, N. E., & Lee, A. (2004). Pathogenesis of intracranial hypertension in acute liver failure: Inflammation, ammonia and cerebral blood flow. Journal of Hepatology, 41(4), 613–620.
Karolczak, D., Sawicka, E., Dorszewska, J., Radel, A., Bodnar, M., Błaszczyk, A., et al. (2013). Memantine—neuroprotective drug in aging brain. Polish Journal of Pathology, 64, 196–203.
Kosenko, E., Kaminsky, Y., Grau, E., Miñana, M. D., Marcaida, G., Grisolía, S., et al. (1994). Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and of Na/K ATPase. Journal of Neurochemistry, 63, 2172–2178.
Leung, J. C., Marphis, T., Craver, R. D., & Silverstein, D. M. (2004). Altered NMDA receptor expression in renal toxicity: Protection with a receptor antagonist. Kidney International, 66(1), 167–176.
Magistretti, P. J., & Pellerin, L. (1999). Astrocytes couple synaptic activity to glucose utilization in the brain. News in Physiological Sciences, 14, 177–182.
Marcaida, G., Felipo, V., Hermenegildo, C., Miñana, M. D., & Grisolía, S. (1992). Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Letters, 296(1), 67–68.
Marmarou, A., Poll, W., Shulman, K., & Bhagavan, H. (1978). A simple gravimetric technique for measurement of cerebral edema. Journal of Neurosurgery, 49, 530–537.
Mayer, M. L., Westbrook, G. L., & Guthrie, P. B. (1984). Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurons. Nature, 309, 261–263.
Miñana, M. D., Hermenegildo, C., Llansola, M., Montoliu, C., Grisolía, S., & Felipo, V. (1996). Carnitine and choline derivatives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons. Journal of Pharmacology and Experimental Therapeutics, 279, 194–199.
Montoliu, C., Llansola, M., Cucarella, C., Grisolía, S., & Felipo, V. (1997). Activation of the metabotropic glutamate receptor mGluR5 prevents glutamate toxicity in primary cultures of cerebellar neurons. Journal of Pharmacology and Experimental Therapeutics, 281, 643–647.
Offenhauser, N., Thomsen, K., Caesar, K., & Lauritzen, M. (2005). Activity-induced tissue oxygenation changes in rat cerebellar cortex: Interplay of postsynaptic activation and blood flow. Journal of Physiology, 565(Pt 1), 279–294.
Park, C. K., Nehls, D. G., Teasdale, G. M., & McCulloch, J. (1989). Effect of the NMDA antagonist MK-801 on local cerebral blood flow in focal cerebral ischaemia in the rat. Journal of Cerebral Blood Flow and Metabolism, 9(5), 617–622.
Paxinos, G., & Watson, C. (1996). The rat brain in stereotaxic coordinates. New York: Academic Press.
Pellicer, B., Herraiz, S., Cauli, O., Rodrigo, R., Asensi, M., Cortijo, J., et al. (2011). Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats. BJOG, 118(5), 615–623.
Pelligrino, D. A., Gay, R. L., I. I. I., Baughman, V. L., & Wang, Q. (1996). NO synthase inhibition modulates NMDA-induced changes in cerebral blood flow and EEG activity. American Journal of Physiology, 271(3 Pt 2), H990–H995.
Rancillac, A., Rossier, J., Guille, M., Tong, X. K., Geoffroy, H., Amatore, C., et al. (2006). Glutamatergic control of microvascular tone by distinct GABA neurons in the cerebellum. Journal of Neuroscience, 26(26), 6997–7006.
Sasaki, D., Yamada, A., Umeno, H., Kurihara, H., Nakatsuji, S., Fujihira, S., et al. (2011). Comparison of the course of biomarker changes and kidney injury in a rat model of drug-induced acute kidney injury. Biomarkers, 16(7), 553–566.
Suzuki, H., Inoue, Y., Nishiyama, A., Mikami, K., & Gen, K. (2013). Clinical efficacy and changes in the dosages of concomitantly used psychotropic drugs in memantine therapy in Alzheimer’s disease with behavioral and psychological symptoms on dementia. Therapeutic Advances in Psychopharmacology, 3, 123–128.
Tofteng, F., Hauerberg, J., Hansen, B. A., Pedersen, C. B., Jørgensen, L., & Larsen, F. S. (2006). Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. Journal of Cerebral Blood Flow and Metabolism, 26(1), 21–27.
Tseng, C. S., Chen, S. M., Chien, S. C., & Hsu, K. Y. (2011). Pharmacokinetics of p-aminohippuric acid and inulin in rabbits with aristolochic acid nephropathy. Advances in Pharmacological Sciences. doi:10.1155/2011/204501.
Warner, M. A., Neill, K. H., Nadler, J. V., & Crain, B. J. (1991). Regionally selective effects of NMDA receptor antagonists against ischemic brain damage in the gerbil. Journal of Cerebral Blood Flow and Metabolism, 11, 600–610.
Weiss, H. R., Sinha, A. K., & Lu, X. (1996). Effect of up-regulation of NMDA receptors on cerebral O2 consumption and blood flow in rat. Brain Research, 730(1–2), 193–198.
Wittlich, F., Kohno, K., Mies, G., Norris, D. G., & Hoehn-Berlage, M. (1995). Quantitative measurement of regional blood flow with gadolinium diethylenetriaminepentaacetate bolus track NMR imaging in cerebral infarcts in rats: Validation with the iodo[14C]antipyrine technique. Proceedings of the National Academy of Sciences of the United States of America, 92(6), 1846–1850.
Yang, G., Chen, G., Ebner, T. J., & Iadecola, C. (1999). Nitric oxide is the predominant mediator of cerebellar hyperemia during somatosensory activation in rats. American Journal of Physiology, 277(6 Pt 2), R1760–R1770.
Yang, C. C., Chien, C. T., Wu, M. H., Ma, M. C., & Chen, C. F. (2008). NMDA receptor blocker ameliorates ischemia–reperfusion-induced renal dysfunction in rat kidneys. American Journal of Physiology. Renal Physiology, 294(6), F1433–F1440.
Yang, G., & Iadecola, C. (1998). Activation of cerebellar climbing fibers increases cerebellar blood flow: Role of glutamate receptors, nitric oxide, and cGMP. Stroke, 29(2), 499–508.
Ytrebø, L. M., Kristiansen, R. G., Maehre, H., Fuskevåg, O. M., Kalstad, T., Revhaug, A., et al. (2009). l-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology, 50(1), 165–174.
Supported by grants from Ministerio de Ciencia Innovacion Spain (SAF2008-00062, SAF2011-23051; CSD2008-00005; PS09/00806; PI10/01434) and Consellería Educación (PROMETEO-2009-027; ACOMP/2011/053; ACOMP/2012/066) and Conselleria Sanitat (AP-043-10, AP-004/11, AP-087/11) Generalitat Valenciana.
Conflict of interest
None of the authors has any conflict of interests.
About this article
Cite this article
Cauli, O., González-Usano, A., Cabrera-Pastor, A. et al. Blocking NMDA Receptors Delays Death in Rats with Acute Liver Failure by Dual Protective Mechanisms in Kidney and Brain. Neuromol Med 16, 360–375 (2014). https://doi.org/10.1007/s12017-013-8283-5
- Acute liver failure
- NMDA receptor
- Intracranial pressure
- Blood flow
- Tubular injury
- Glomerular filtration rate