Carnitine and choline derivatives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons
Abstract
Carnitine prevents acute ammonia toxicity in animals. We propose that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and have shown that carnitine prevents glutamate neurotoxicity. The aim of this work was to assess whether other compounds containing a trimethylamine group are able to prevent ammonia toxicity in mice and/or glutamate toxicity in primary neuronal cultures. It is shown that betaine, trimethylamine-N-oxide, choline, acetylcholine, carbachol and acetylcarnitine prevent ammonia toxicity in mice. They also prevent glutamate but not N-methyl-D-aspartate neurotoxicity. Choline, acetylcholine and acetylcarnitine afford partial (approximately 50%) protection at nanomolar concentrations and nearly complete protection at micromolar concentrations. Trimethylamine-N-oxide, carbachol and betaine afford nearly complete protection at approximately 0.2 mM. The protective effect against glutamate neurotoxicity is prevented by 2-amino-3-phosphonopropionic acid, an antagonist of metabotropic glutamate receptors. Atropine, an antagonist of muscarinic receptors, prevents the protective effect of most of the above compounds against ammonia toxicity in mice and against glutamate toxicity in cultured neurons. These results support the idea that acute ammonia toxicity is mediated by activation of N-methyl-D-aspartate receptors and that glutamate neurotoxicity could be prevented by activating metabotropic glutamate receptors and/or muscarinic receptors.
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Circulating TMAO may play a role in protection from hyperammonemia and from glutamate neurotoxicity.
“circulating TMAO may play a role in the protection from hyperammonemia (Kloiber et al., 1988) and from glutamate neurotoxicity (Minana et al., 1996).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Minana et al., 1996
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“In mammals, acute ammonia intoxication is mediated by activation of NMDA receptors (Hermenegildo et al., 1996; Kosenko et al., 1999); and, excessive activation of these receptors is neurotoxic, leading to oxidative stress, neuronal degeneration and death (Miñana et al., 1996).”
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Trimethylamine oxide accumulation in marine animals: relationship to acylglycerol storagej
Seibel, B. A., & Walsh, P. J. (2002) · Journal of Experimental Biology · doi:10.1242/jeb.205.3.297 · Cited by 202 · see citing works
Hermenegildo, C., Montoliu, C., Llansola, M., et al. (1998) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1998.00329.x · Cited by 177 · see citing works
Self-citationBlocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication
Kosenko, E. A., Kaminski, Y., Lopata, O., Muravyov, N., & Felipo, V. (1999) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(98)00339-6 · Cited by 163 · see citing works
“Excessive activation of these receptors is neurotoxic, leading to neuronal degeneration and death [10–12], that, as is the case for ammonia-induced death of animals, is preceded by depletion of ATP [13].”
BackgroundSelf-citationChing, B., Chew, S. F., Wong, W. P., et al. (2009) · Aquatic Toxicology · doi:10.1016/j.aquatox.2009.09.004 · Cited by 134 · see citing works
Excretory nitrogen metabolism and defence against ammonia toxicity in air‐breathing fishes
Chew, S. F., & Ip, Y. K. (2014) · Journal of Fish Biology · doi:10.1111/jfb.12279 · Cited by 111 · see citing works
“, 1999) is neurotoxic, leading to oxidative stress, neuronal degeneration and death (Miñana et al., 1996).”
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Self-citationPraveenraj, S. S., Sonali, S., Anand, N., Hediyal, T. A., Vichitra, C., Kalyan, M., Kanna, P. V., Chandana, K. A., Paneyala, S., Mahalakshmi, A. M., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02990-5 · Cited by 112 · see citing works
High ammonia tolerance in fishes of the family Batrachoididae (Toadfish and Midshipmen)
Wang, Y., & Walsh, P. J. (2000) · Aquatic Toxicology · doi:10.1016/s0166-445x(99)00101-0 · Cited by 103 · see citing works
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Schenker, S., & Bay, M. K. (1997) · Clinics in Liver Disease · doi:10.1016/s1089-3261(05)70262-2 · Cited by 102 · see citing works
Toxicological profile for ammonia
Roney, N., & Llados, F. (2004) · Cited by 92 · see citing works
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Self-citationKosenko, E. A., Kaminsky, Y., Stavroskaya, I. G., et al. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02785-2 · Cited by 90 · see citing works
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“2004) and ammonia-induced death of animals (Marcaida et al. 1992; Hermenegildo et al. 1996; Miñana et al. 1996; Felipo et al. 1998).”
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“Inhibition of ammonia-induced toxicity abolished by l-AP3 Mice acutely administered high doses of ammonia Miñana et al. (1996)”
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“…and Bolen, 2003) and function (Baskakov et al., 1998) from various environmental perturbants including, hydrostatic pressure (Gillett et al., 1997), urea and ammonia toxicity (Yancey and Somero, 1980; Miñana et al., 1996), and temperature stress (Treberg et al., 2005; Villalobos and Renfro, 2007).”
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“It was shown that betaine, trimethylamineN-oxide, choline, acetylcholine, carbachol, and acetyl-L carnitine prevent ammonia toxicity in mice (Mi˜nana et al., 1996).”
BackgroundSelf-citationMiñana, M., Llansola, M., Hermenegildo, C., et al. (1997) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-5945-0_3 · Cited by 25 · see citing works
Self-citationTo Break or to Brake Neuronal Network Accelerated by Ammonium Ions?
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Maas, A. E., Seibel, B. A., & Walsh, P. J. (2012) · Polar Biology · doi:10.1007/s00300-012-1158-7 · Cited by 23 · see citing works
“In this regard, Seibel and Walsh (2002) previously reported that Clione limacina antarctica has high levels of trimethylamine oxide (TMAO) that is known to counteract ammonia toxicity in some species (Kloiber et al. 1988; Minana et al. 1996).”
BackgroundCauli, O., González‐Usano, A., Cabrera‐Pastor, A., et al. (2013) · NeuroMolecular Medicine · doi:10.1007/s12017-013-8283-5 · Cited by 23 · see citing works
“…be achieved, for example, with carnitine and choline derivatives, which potentiate activation of metabotropic glutamate receptors and prevent NMDA receptor-mediated excitotoxicity in cultured neurons and ammonia-induced death in rats (Felipo et al. 1994; Miñana et al. 1996; Montoliu et al. 1997).”
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The betaine content of sweat from adolescent females
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“Betaine protects the kidney from high concentrations of electrolytes and urea [2,36,37], prevents myosin structural change due to urea [9], and protects against ammonia toxicity of neurons [14].”
BackgroundRao, K. V. R., & Qureshi, I. A. (1999) · Neuropharmacology · doi:10.1016/s0028-3908(98)00160-9 · Cited by 20 · see citing works
Montoliu, C., Llansola, M., Sáez, R., et al. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00104-5 · Cited by 18 · see citing works
Self-citationTaştekın, A., Gepdíremen, A., Örs, R., et al. (2005) · Brain and Development · doi:10.1016/j.braindev.2005.02.006 · Cited by 17 · see citing works
“[20] demonstrated that L-carnitine decreased glutamate-induced neuronal cell death from 80 to 30% while NMDA-induced neuronal cell death from 72% to only 43%.”
BackgroundIp, Y. K., Hou, Z., Chen, X. L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069512 · Cited by 16 · see citing works
“Excessive activation of N-methyl-ᴅaspartate-type glutamate receptors by ammonia [6,7] is neurotoxic, leading to oxidative stress, neuronal degeneration and death [8].”
BackgroundChen, X. L., Wee, N. L. J., Hiong, K. C., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084298 · Cited by 16 · see citing works
Llansola, M., & Felipo, V. (2002) · Brain Research · doi:10.1016/s0006-8993(02)02905-0 · Cited by 14 · see citing works
Self-citationAndersson, M., Jacobsson, S. O. P., Jonsson, K., et al. (2000) · Archives of Toxicology · doi:10.1007/s002040050669 · Cited by 14 · see citing works
“Thus, carbachol reduces glutamate toxicity, a result consistent with rodent studies (MinÄ ana et al. 1996).”
BackgroundResultLlansola, M., & Felipo, V. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2009.12.016 · Cited by 13 · see citing works
“, 2008) and by acute ammonia intoxication (Marcaida et al., 1992; Hermenegildo et al., 1996, 2000; Miñana et al., 1996).”
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Taştekın, A., Gepdíremen, A., Örs, R., et al. (2006) · Brain and Development · doi:10.1016/j.braindev.2006.01.004 · Cited by 13 · see citing works
“It has been shown in limited studies that LC prevents glutamate- and/or kainic acid (KA)-induced neurotoxicity in neuronal cell culture [10–12].”
BackgroundMetabolic retroconversion of trimethylamine N-oxide and the gut microbiotaPreprint
Hoyles, L., Jiménez-Pranteda, M. L., Chilloux, J., Brial, F., Myridakis, A., Aranias, T., Magnan, C., Gibson, G., Sanderson, J., Nicholson, J., et al. (2018) · Microbiome · doi:10.1101/225581 · Cited by 211 · see citing works
“Circulating TMAO has been suggested to play a role in protection from hyperammonemia in mice, acting as an osmoprotectant, and from glutamate neurotoxicity in mice and primary cultures of neurons [15, 16].”
BackgroundEffect of L-carnitine on postischemic inhibition of protein synthesis in the rat brain
Bürda, J., Viade, M., Danielisová, V., et al. (2009) · General Physiology and Biophysics · doi:10.4149/gpb_2009_03_242 · Cited by 3 · see citing works
Self-citationBockus, A. B. (2016) · doi:10.23860/diss-bockus-abigail-2016 · Cited by 3 · see citing works
“…and Bolen, 2003) and function (Baskakov et al., 1998) from various environmental perturbants including, hydrostatic pressure (Gillett et al., 1997), urea and ammonia toxicity (Yancey and Somero, 1980; Minana et al., 1996), and temperature stress (Treberg et al., 2005; Villalobos and Renfro, 2007).”
BackgroundL-carnitine in Hyperammonemia and Hepatic Encephalopathy
Missler, J., & Zwingm, C. (2012) · InTech eBooks · doi:10.5772/29855 · Cited by 2 · see citing works
“Minana et al. (2002) compared the in vivo and in vitro effects of different trimethylamine-containing compounds on ammonia toxicity in mice and against glutamate and NMDA toxicity in primary cultures of neurons (Tables 1 and 2).”
ResultAlsenosy, A. A., Ghoneim, H. A., Ibrahim, S., et al. (2021) · Damanhour Journal of Veterinary Sciences · doi:10.21608/djvs.2020.53743.1031
Carnitine Deficiency in Patients with Liver Diseases
Nakayama, N. (2026) · Springer eBooks · doi:10.1007/978-981-95-7797-2_15
Sex-specific differences in DNA damage and repair mechanisms in colorectal cancer
Gierat, N., Hoskins, A., Miller, E., Mahammad, S., Duran, V., Negrete, A. O., & Basha, R. M. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-43976-6.00008-9
- Authors
- Miñana, M. D., Hermenegildo, C., Llsansola, M., Montoliu, C., Grisolía, S., & Felipo, V
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1996-10
- Volume
- 279
- Issue
- 1
- Pages
- 194-199
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W1903340256
- Cited by
- 60
- References
- 0
- Citations by year
- 2026: 3 · 2022: 1 · 2021: 2 · 2019: 1 · 2018: 3 · 2016: 4 · 2015: 1 · 2014: 1 · 2013: 4 · 2012: 3
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- ammonia toxicity, glutamate excitotoxicity, L-carnitine, choline, acetylcholine, carbachol, acetyl-L-carnitine, trimethylamine N-oxide, betaine, NMDA receptor, metabotropic glutamate receptors, muscarinic receptors, neuroprotection, atropine
- MeSH terms
- Ammonia, Animals, Carnitine, Cells, Cultured, Choline, Cycloleucine, Male, Methylamines, Neurons, Receptors, N-Methyl-D-Aspartate, Rats, Wistar, Glutamic Acid, Mice, Rats
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