Protective effect of the energy precursor creatine against toxicity of glutamate and β-amyloid in rat hippocampal neurons

Brewer, Gregory J.; Wallimann, Theo W.

doi:10.1046/j.1471-4159.2000.0741968.x

Cited by 230Alzheimer's disease research and treatmentsNeurological Disorders and TreatmentsNeuroscience and Neuropharmacology Research

Protective effect of the energy precursor creatine against toxicity of glutamate and β-amyloid in rat hippocampal neurons

Brewer, Gregory J., Wallimann, Theo W.·2000·Journal of Neurochemistry

DOI 10.1046/j.1471-4159.2000.0741968.x

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Abstract

The loss of ATP, which is needed for ionic homeostasis, is an early event in the neurotoxicity of glutamate and beta-amyloid (A(beta)). We hypothesize that cells supplemented with the precursor creatine make more phosphocreatine (PCr) and create larger energy reserves with consequent neuroprotection against stressors. In serum-free cultures, glutamate at 0.5-1 mM was toxic to embryonic hippocampal neurons. Creatine at >0.1 mM greatly reduced glutamate toxicity. Creatine (1 mM) could be added as late as 2 h after glutamate to achieve protection at 24 h. In association with neurotoxic protection by creatine during the first 4 h, PCr levels remained constant, and PCr/ATP ratios increased. Morphologically, creatine protected against glutamate-induced dendritic pruning. Toxicity in embryonic neurons exposed to A(beta) (25-35) for 48 h was partially prevented by creatine as well. During the first 6 h of treatment with A(beta) plus creatine, the molar ratio of PCr/ATP in neurons increased from 15 to 60. Neurons from adult rats were also partially protected from a 24-h exposure to A(beta) (25-35) by creatine, but protection was reduced in neurons from old animals. These results suggest that fortified energy reserves are able to protect neurons against important cytotoxic agents. The oral availability of creatine may benefit patients with neurodegenerative diseases.

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In vitro, creatine elevates phosphocreatine and ATP levels and increases oxidative phosphorylation in synaptosomes and isolated brain mitochondria.
“In vitro, creatine elevates phosphocreatine and ATP levels11 and increases oxidative phosphorylation in synaptosomes and isolated brain mitochondria.12”
From Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [11]
The beneficial effects of creatine supplementation on memory performance may be related to creatine's ability to influence brain bioenergetics.
“These beneficial effects from creatine supplementation on memory performance may be related to creatine’s ability to influence brain bioenergetics.”
From Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [11]

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Self-citation
The Beneficial Effect of Phosphocreatine Accumulation in the Creatine Kinase Transgenic Mouse Liver in Endotoxin-Induced Hepatic Cell Death
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AR-R15896AR blocks the early NMDA-induced loss of MAP2 in primary cortical cultures
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The creatine kinase system and pleiotropic effects of creatine
Wallimann, T., Tokarska-Schlattner, M., & Schlattner, U. (2011) · Amino Acids · doi:10.1007/s00726-011-0877-3 · Cited by 797 · see citing works
Self-citation
Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse
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Mitochondria, Oxidative Damage, and Inflammation in Parkinson's Disease
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Functions and effects of creatine in the central nervous system
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Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate
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Creatine Increases Survival and Delays Motor Symptoms in a Transgenic Animal Model of Huntington's Disease
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Mitochondria: A therapeutic target in neurodegeneration
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Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders
Tarnopolsky, M. A., & Beal, M. F. (2001) · Annals of Neurology · doi:10.1002/ana.1028 · Cited by 244 · see citing works
Bioenergetic approaches for neuroprotection in Parkinson's disease
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Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease
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Combination therapy with Coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s Diseases
Yang, L., Calingasan, N. Y., Wille, E. J., Cormier, K., Smith, K., Ferrante, R. J., & Beal, M. F. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06074.x · Cited by 232 · see citing works
Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates
Dolder, M., Walzel, B., Speer, O., Schlattner, U., & Wallimann, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208705200 · Cited by 219 · see citing works
Self-citation
Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?
Wyss, M., & Schulze, A. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00088-x · Cited by 210 · see citing works
Mitochondrial Creatine Kinase Activity Prevents Reactive Oxygen Species Generation
Meyer, L. E., Machado, L. B., Santiago, A. P. S. A., da‐Silva, W. S., Felice, F. G. D., Holub, O., de Oliveira, M. F., & Galina, A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604123200 · Cited by 210 · see citing works
The biological basis of injury and neuroprotection in the fetal and neonatal brain
Rees, S. M., Harding, R., & Walker, D. W. (2011) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2011.04.004 · Cited by 203 · see citing works
Creatine and the creatine transporter: A review
Snow, R. J., & Murphy, R. M. (2001) · Molecular and Cellular Biochemistry · doi:10.1023/a:1011908606819 · Cited by 197 · see citing works
Synthesis and transport of creatine in the CNS: Importance for cerebral functions
Béard, E., & Braissant, O. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06935.x · Cited by 192 · see citing works
Antioxidant strategies for Alzheimer's disease
Grundman, M., & Delaney, P. (2002) · Proceedings of The Nutrition Society · doi:10.1079/pns2002146 · Cited by 193 · see citing works
Neuroprotective effects of creatine
Beal, M. F. (2011) · Amino Acids · doi:10.1007/s00726-011-0851-0 · Cited by 191 · see citing works
Cerebral creatine deficiency syndromes: Clinical aspects, treatment and pathophysiology
Stockler, S., Schutz, P. W., & Salomons, G. S. (2007) · Subcellular Biochemistry · doi:10.1007/978-1-4020-6486-9_8 · Cited by 180 · see citing works
Creatine and Its Potential Therapeutic Value for Targeting Cellular Energy Impairment in Neurodegenerative Diseases
Adhihetty, P. J., & Beal, M. F. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8053-y · Cited by 184 · see citing works
Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK‐Mi and CK‐B suggest a novel neuron–glial relationship for brain energy homeostasis
Tachikawa, M., Fukaya, M., Terasaki, T., Ohtsuki, S., & Watanabe, M. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03478.x · Cited by 172 · see citing works
In sickness and in health: the widespread application of creatine supplementation
Gualano, B., Roschel, H., Lancha, A. H., Brightbill, C. E., & Rawson, E. S. (2012) · Amino Acids · doi:10.1007/s00726-011-1132-7 · Cited by 172 · see citing works
Creatine for treating muscle disorders
Kley, R. A., Tarnopolsky, M. A., & Vorgerd, M. (2013) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004760.pub4 · Cited by 169 · see citing works
Exploring the therapeutic role of creatine supplementation
Gualano, B., Artioli, G. G., Poortmans, J. R., & Lancha Junior, A. H. (2010) · Amino Acids · doi:10.1007/s00726-009-0263-6 · Cited by 156 · see citing works
Pathogenesis of ganglion “cell death” in glaucoma and neuroprotection: focus on ganglion cell axonal mitochondria
Osborne, N. N. (2008) · Progress in brain research · doi:10.1016/s0079-6123(08)01124-2 · Cited by 157 · see citing works
Mitoenergetic failure in Alzheimer disease
Parihar, M. S., & Brewer, G. J. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00232.2006 · Cited by 149 · see citing works
Self-citation
Global and targeted gene expression and protein content in skeletal muscle of young men following short-term creatine monohydrate supplementation
Safdar, A., Yardley, N. J., Snow, R., Melov, S., & Tarnopolsky, M. A. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.00157.2007 · Cited by 149 · see citing works
Proton MRS in acute traumatic brain injury: Role for glutamate/glutamine and choline for outcome prediction
Shutter, L., Tong, K. A., & Holshouser, B. A. (2004) · Journal of Neurotrauma · doi:10.1089/neu.2004.21.1693 · Cited by 142 · see citing works
Prophylactic Creatine Administration Mediates Neuroprotection in Cerebral Ischemia in Mice
Zhu, S., Li, M., Figueroa, B. E., Liu, A., Stavrovskaya, I. G., Pasinelli, P., Beal, M. F., Brown, R. H., Kristal, B. S., Ferrante, R. J., et al. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1278-04.2004 · Cited by 138 · see citing works
On the mechanisms of neuroprotection by creatine and phosphocreatine
Brustovetsky, N., Brustovetsky, T., & Dubinsky, J. M. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00052.x · Cited by 135 · see citing works
Pharmacokinetics of the Dietary Supplement Creatine
Persky, A. M., Brazeau, G. A., & Hochhaus, G. (2003) · Clinical Pharmacokinetics · doi:10.2165/00003088-200342060-00005 · Cited by 132 · see citing works
Creatine in the central nervous system: From magnetic resonance spectroscopy to creatine deficiencies
Račkayová, V., Cudalbu, C., Pouwels, P. J. W., & Braissant, O. (2016) · Analytical Biochemistry · doi:10.1016/j.ab.2016.11.007 · Cited by 130 · see citing works
Creatine supplementation lowers brain glutamate levels in Huntington?s disease
Bender, A., Auer, D. P., Merl, T., Reilmann, R., Saemann, P., Yassouridis, A., Bender, J., Weindl, A., Dose, M., Gasser, T., et al. (2005) · Journal of Neurology · doi:10.1007/s00415-005-0595-4 · Cited by 129 · see citing works
Improved Reperfusion and Neuroprotection by Creatine in a Mouse Model of Stroke
Prass, K., Royl, G., Lindauer, U., Freyer, D., Megow, D., Dirnagl, U., Stöckler-Ipsiroglu, G., Wallimann, T., & Priller, J. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600351 · Cited by 128 · see citing works
Self-citation
Current concepts in the pathogenesis of urea cycle disorders
Braissant, O. (2010) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2010.02.010 · Cited by 128 · see citing works
Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice
Passaquin, A., Renard, M., Kay, L., Challet, C., Mokhtarian, A., Wallimann, T., & Rüegg, U. T. (2002) · Neuromuscular Disorders · doi:10.1016/s0960-8966(01)00273-5 · Cited by 127 · see citing works
Self-citation
Cyclophilin D, a Component of the Permeability Transition-Pore, Is an Apoptosis Repressor
Schubert, A., & Grimm, S. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-0476 · Cited by 128 · see citing works
Attenuation of acute inflammatory response by atorvastatin after spinal cord injury in rats
Pannu, R., Barbosa, E., Singh, A. K., & Singh, I. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20345 · Cited by 126 · see citing works
Mitochondria as targets for chemotherapy
Gogvadze, V. G., Orrenius, S., & Zhivotovsky, B. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0323-0 · Cited by 125 · see citing works
The Creatine Kinase/Creatine Connection to Alzheimer′s Disease: CK Inactivation, APP‐CK Complexes and Focal Creatine Deposits
Bürklen, T. S., Schlattner, U., Homayouni, R., Gough, K. M., Rak, M., Szeghalmi, A. V., & Wallimann, T. (2006) · BioMed Research International · doi:10.1155/jbb/2006/35936 · Cited by 119 · see citing works
Self-citation
Hyperammonemia-induced toxicity for the developing central nervous system
Cagnon, L., & Braissant, O. (2007) · Brain Research Reviews · doi:10.1016/j.brainresrev.2007.06.026 · Cited by 116 · see citing works
The KATP Channel Activator Diazoxide Ameliorates Amyloid-β and Tau Pathologies and Improves Memory in the 3xTgAD Mouse Model of Alzheimer's Disease
Liu, D., PITTA, M. G. R., Lee, J.-H., Ray, B., Lahiri, D. K., Furukawa, K., Mughal, M. R., Jiang, H., Villarreal, J. S., Cutler, R. G., et al. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101017 · Cited by 113 · see citing works
Mitochondrial Creatine Kinase in Contact Sites: Interaction with Porin and Adenine Nucleotide Translocase, Role in Permeability Transition and Sensitivity to Oxidative Damage
Dolder, M., Wendt, S., & Wallimann, T. (2001) · Neurosignals · doi:10.1159/000046878 · Cited by 114 · see citing works
Self-citation
Design and Evaluation of Multifunctional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria
Sharma, A., Soliman, G. M., Al‐Hajaj, N., Sharma, R. B., Maysinger, D., & Kakkar, A. K. (2011) · Biomacromolecules · doi:10.1021/bm201538j · Cited by 110 · see citing works
Identification of new kinase clusters required for neurite outgrowth and retraction by a loss-of-function RNA interference screen
Loh, S. H. Y., Francescut, L., Lingor, P., Bähr, M., & Nicotera, P. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402258 · Cited by 108 · see citing works
Creatine and Creatine Deficiency Syndromes: Biochemical and Clinical Aspects
Nasrallah, F., Feki, M., & Kaabachi, N. (2010) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2009.07.015 · Cited by 103 · see citing works
Stimulatory effects of creatine on metabolic activity, differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell cultures
Gerber, I., Gwynn, I. A., Alini, M., & Wallimann, T. (2005) · European Cells and Materials · doi:10.22203/ecm.v010a02 · Cited by 97 · see citing works
Self-citation
Neuroprotection of Creatine Supplementation in Neonatal Rats with Transient Cerebral Hypoxia-Ischemia
Adcock, K. H., Nedelcu, J., Loenneker, T., Martin, E., Wallimann, T., & Wagner, B. P. (2002) · Developmental Neuroscience · doi:10.1159/000069043 · Cited by 97 · see citing works
Self-citation
Transport characteristics of guanidino compounds at the blood-brain barrier and blood-cerebrospinal fluid barrier: relevance to neural disorders
Tachikawa, M., & Hosoya, K. (2011) · Fluids and Barriers of the CNS · doi:10.1186/2045-8118-8-13 · Cited by 94 · see citing works
Proton MR Spectroscopy Detected Glutamate/Glutamine Is Increased in Children with Traumatic Brain Injury
Ashwal, S., Holshouser, B. A., Tong, K., Serna, T., Osterdock, R. J., Gross, M., & Kido, D. K. (2004) · Journal of Neurotrauma · doi:10.1089/neu.2004.21.1539 · Cited by 93 · see citing works
Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder
Yüksel, Ç., Du, F., Ravichandran, C. T., Goldbach, J. R., Thida, T., Lin, P., Dora, B., Gelda, J., O'Connor, L., Sehovic, S., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.13 · Cited by 91 · see citing works
Neuron-Glia Interactions as Therapeutic Targets in Neurodegeneration
Salmina, A. B. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0988 · Cited by 86 · see citing works
β-Amyloid Neurotoxicity Is Exacerbated during Glycolysis Inhibition and Mitochondrial Impairment in the Rat Hippocampus in Vivo and in Isolated Nerve Terminals: Implications for Alzheimer's Disease
Arias, C., Montiel, T., Quiroz‐Baez, R., & Massieu, L. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7912 · Cited by 82 · see citing works
A review of creatine supplementation in age-related diseases: more than a supplement for athletes
Smith, R. N., Agharkar, A. S., & Gonzales, E. B. (2014) · F1000Research · doi:10.12688/f1000research.5218.1 · Cited by 82 · see citing works
Mitochondrial Dysfunction in Parkinson's Disease: Pathogenesis and Neuroprotection
Mounsey, R. B., & Teismann, P. (2010) · Parkinson s Disease · doi:10.4061/2011/617472 · Cited by 82 · see citing works
“Heads Up” for Creatine Supplementation and its Potential Applications for Brain Health and Function
Candow, D. G., Forbes, S. C., Ostojić, S. M., Prokopidis, K., Stock, M. S., Harmon, K. K., & Faulkner, P. (2023) · Sports Medicine · doi:10.1007/s40279-023-01870-9 · Cited by 95 · see citing works
The Phosphocreatine Circuit: Molecular and Cellular Physiology of Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by Creatine Supplementation
Wallimann, T., Tokarska-Schlattner, M., Neumann, D., Epand, R. M., Epand, R. F., Andres, R. H., Widmer, H. R., Hornemann, T., Saks, V. A., Agarkova, I., et al. (2007) · Wiley eBooks · doi:10.1002/9783527621095.ch7 · Cited by 81 · see citing works
Self-citation
Synergistic Action of Dendritic Mitochondria and Creatine Kinase Maintains ATP Homeostasis and Actin Dynamics in Growing Neuronal Dendrites
Fukumitsu, K., Fujishima, K., Yoshimura, A., Wu, Y. K., Heuser, J., & Kengaku, M. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4115-14.2015 · Cited by 80 · see citing works
Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue
Andres, R. H., Huber, A. W., Schlattner, U., Pérez-Bouza, A., Krebs, S. H., Seiler, R. W., Wallimann, T., & Widmer, H. R. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.03.004 · Cited by 80 · see citing works
Self-citation
Octameric mitochondrial creatine kinase induces and stabilizes contact sites between the inner and outer membrane
Speer, O., Bäck, N., Bürklen, T. S., Brdiczka, D. G., Koretsky, A. P., Wallimann, T., & Eriksson, O. (2005) · Biochemical Journal · doi:10.1042/bj20040386 · Cited by 75 · see citing works
Self-citation
Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy
Dickinson, H., Ellery, S., Ireland, Z., LaRosa, D., Snow, R., & Walker, D. W. (2014) · BMC Pregnancy and Childbirth · doi:10.1186/1471-2393-14-150 · Cited by 74 · see citing works
“PCr has also been shown to promote the uptake of glutamate into synaptic vesicles [78], and may account for the neuroprotective capacity of creatine against glutamate toxicity in neuronal cell culture [79].”
Background
Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials
Prokopidis, K., Giannos, P., Triantafyllidis, K. K., Kechagias, K. S., Forbes, S. C., & Candow, D. G. (2023) · Nutrition Reviews · doi:10.1093/nutrit/nuac064 · Cited by 71 · see citing works
Neuronal plasticity and stressor toxicity during aging
Brewer, G. J. (2000) · Experimental Gerontology · doi:10.1016/s0531-5565(00)00121-2 · Cited by 71 · see citing works
Self-citation
In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7
Adanyeguh, I. M., Henry, P., Nguyen, T. M., Rinaldi, D., Jauffret, C., Valabrègue, R., Emir, U. E., Deelchand, D. K., Brice, A., Eberly, L. E., et al. (2015) · Movement Disorders · doi:10.1002/mds.26181 · Cited by 69 · see citing works
The therapeutic role of creatine in Huntington's disease
Ryu, H., Rosas, H. D., Hersch, S. M., & Ferrante, R. J. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.04.008 · Cited by 69 · see citing works
Additive anticonvulsant effects of creatine supplementation and physical exercise against pentylenetetrazol-induced seizures
Rambo, L. M., Ribeiro, L. R., Oliveira, M. S., Furian, A. F., Lima, F. D., Souza, M. A., Silva, L. F. A., Retamoso, L. T., Corte, C. L. D., Puntel, G. O., et al. (2009) · Neurochemistry International · doi:10.1016/j.neuint.2009.04.007 · Cited by 69 · see citing works
Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats
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Authors: Brewer, G. J., & Wallimann, T. W.
Affiliations: SIU Medicine (US)
ORCID: Brewer, Gregory J.
Wallimann, Theo W.
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 2000-05
Volume: 74
Issue: 5
Pages: 1968-1978
ISSN: 0022-3042 (ISSN-L)
1471-4159
DOI: 10.1046/j.1471-4159.2000.0741968.x
OpenAlex: W1971233715
Cited by: 230
References: 96
Citations by year: 2026: 5 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 9 · 2021: 4 · 2020: 6 · 2019: 10 · 2018: 10 · 2017: 3 · 2016: 10 · 2015: 9 · 2014: 12 · 2013: 6 · 2012: 4
FWCI: 6.75
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3012 d)
Locations: Journal of Neurochemistry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (R01 AG 13435, R01AG013435)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: creatine, neuroprotection, glutamate excitotoxicity, amyloid-beta, hippocampal neurons, phosphocreatine, ATP depletion, energy reserves, dendritic pruning, aging, neurodegenerative diseases
MeSH terms: Aging, Animals, Cells, Cultured, Creatine, Dendrites, Energy Metabolism, Hippocampus, Intracellular Membranes, Neurons, Phosphocreatine, Amyloid beta-Peptides, Neuroprotective Agents, Glutamic Acid, Rats

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Protective effect of the energy precursor creatine against toxicity of glutamate and β-amyloid in rat hippocampal neurons

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