The potential role of creatine supplementation in neurodegenerative diseases

Article information

Phys Act Nutr. 2023;27(4):48-54
Publication date (electronic) : 2023 December 31
doi :
1Department of Sport and Exercise Science, Seoul Women’s University, Seoul, Republic of Korea
2Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University, Seoul, Republic of Korea
*Corresponding author : Yea-Hyun Leem, Ph.D. Department of Molecular Medicine, School of Medicine, Ewha Womans University, 808-1 Magok-dong, Gangseogu, Seoul 07804, Republic of Korea. Tel: +82-2-6986-6279 Fax: +82-2-6986-7014 E-mail:
Received 2023 December 10; Revised 2023 December 25; Accepted 2023 December 29.



The maintenance of energy balance in the body, especially in energy-demanding tissues like the muscles and the central nervous system, depends on creatine (Cr). In addition to improving muscle function, Cr is necessary for the bioenergetics of the central nervous system because it replenishes adenosine triphosphate without needing oxygen. Furthermore, Cr possesses anti-oxidant, anti-apoptotic, and anti-excitotoxic properties. Clinical research on neurodegenerative illnesses has shown that Cr supplementation results in less effective outcomes. With a brief update on the possible role of Cr in human, animal, and in vitro experiments, this review seeks to offer insights into the ideal dosage regimen.


Using specified search phrases, such as “creatine and neurological disorder,” “creatine supplementation and neurodegenerative disorders,” and “creatine and brain,” we searched articles in the PubMed database and Google Scholar. We investigated the association between creatine supplementation and neurodegenerative illnesses by examining references.


The neuroprotective effects of Cr were observed in in vitro and animal models of certain neurodegenerative diseases, while clinical trials failed to reproduce favorable outcomes.


Determining the optimal creatinine regime for increasing brain creatinine levels is essential for maintaining brain health and treating neurodegeneration.


Creatine (Cr), which is synthesized when glycine and methionine are endogenously converted into phosphocreatine (PCr), is crucial for preserving the energy equilibrium throughout the body, particularly in energy-intensive tissues such as the muscular and central nervous systems [1,2]. Cr is essential for the creatine phosphate shuttle, which moves Pi from mitochondria into the cytosol to form PCr and supports cellular bioenergetics [3]. The endogenous synthesis of Cr provides approximately half of the daily requirement, with the remainder originating from food, primarily red meat, fish, or dietary supplements [4]. Approximately 95% of Cr in the body is stored in the muscle, with the remaining 5% located in the heart, brain, and testes [5,6]. Approximately 2/3 of this stored Cr is in the form of PCr, with the remaining 5% being free creatinine [5,7]. The ergogenic role of Cr supplementation in improving muscle strength, lean mass, and exercise performance in both athletes and active leisure participants has been extensively documented since the 1970s [8]. In addition to enhancing muscle performance, Cr is essential for the bioenergetics of the central nervous system because it replenishes adenosine triphosphate (ATP) without the need for oxygen. In addition to its bioenergetics, Cr has been reported to have anti-apoptotic, anti-excitotoxic, and anti-oxidative properties in vivo and in vitro [3,9-11]. Therefore, researchers have investigated possible applications of Cr interventions in preclinical and clinical settings. A range of Cr regimens have demonstrated advantageous effects in vitro and in animal studies. However, most clinical trials have been unable to replicate favorable results. These findings suggest that preventive interventions for neuroprotection in at-risk patients are the most promising area. Nonetheless, supplementation with Cr significantly benefits Cr-deficient disorders in humans [12-14]. Therefore, determining the optimal dosage regime to increase brain Cr levels is essential for maintaining brain health. This short review aims to provide insight into establishing the optimal dosage regime via an update on the potential role of Cr in brain function in humans, animals, and in vitro studies.

Cr biosynthesis and dietary transportation in the brain

Cr is provided through dietary consumption and endogenous synthesis in the whole body. The primary dietary sources of this nitrogenous organic acid are fish, red meat, and, to a lesser extent, dairy products [4]. Dietary Cr is absorbed by a specific Na+/Cl- creatine transporter (SLC6A8) via an unidentified mechanism, which subsequently enters the bloodstream and travels throughout the body [15]. Furthermore, two enzymatic processes are involved in the endogenous synthesis of Cr. These processes involve the following: l-arginine glycine aminotransferase (AGAT) converts l-arginine and glycine into guanidinoacetate (GAA) and l-ornithine in the mitochondrial intermembrane space; N-guanidinoacetate methyltransferase (GAMT) transfers a methyl group from S-adenosylmethionine (SAM) to GAA to produce creatine; and a specific creatine plasma membrane transporter, SLC6A8, is observed in the kidney, brain, and liver [16,17]. Dietary Cr enters the brain through the blood-brain barrier (BBB) through SLC6A8, which is expressed in the microcapillaries of the BBB, neurons, and oligodendrocytes but not in perivascular astrocytes [17-19]. In the brain, both AGAT and GAMT are expressed in astrocytes, and released Cr is taken up by neurons expressing SLC6A8, a specific Cr transporter [20]. This suggests that the balance between endogenous production in the brain and dietary uptake may alter intracellular Cr content. Consequently, increasing intracellular Cr content may benefit brain function by increasing bioenergetics and strengthening neuroprotective functions.

Role of brain Cr in mitochondrial function of the neural system

Factors affecting brain Cr levels include aging, reduced physical activity, depression, and psychiatric abnormalities [21,22]. Cr supplementation elicits beneficial effects under brain Cr deficit-related conditions, including physiological stress such as exercise and sleep deprivation and pathophysiological states such as creatine deficiency syndrome, mild traumatic brain injury, Alzheimer’s disease, and depression [22,23]. Although the underlying molecular mechanisms are poorly understood, the pleiotropic effects of Cr may be associated with mitochondrial bioenergetics. The higher diffusion capacity and ability to reverse transfer its N-phosphoryl group to the ADP of PCr can resolve the issue of the ATP diffusion ratio when the cell is insufficient to maintain energy demands. Due to its high energy requirements, brain tissue is susceptible to mitochondrial damage, reactive oxygen species (ROS), and energy depletion [24,25]. According to in vitro and in vivo investigations, supplementation with Cr prevents intracellular Ca2+ and ROS accumulation, delays membrane depolarization, shields ATP depletion, and delays the opening of the mitochondrial permeability transition pore [26-28]. ROS-induced nitration of proteins and mitochondrial DNA and mitochondrial dysfunction characterized by swollen mitochondrial morphology, altered membrane potential, and ATP reduction are implicated in neurodegenerative diseases, aging, and cognitive decline. Therefore, improving mitochondrial function and reducing oxidative stress may be relevant treatments for neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS).

The beneficial roles of Cr

Cr as a bioenergetics

Cr is necessary for glutamate clearance during excitatory synaptic transmission in the brain. For example, mice lacking CK isoforms display aberrant behaviors, such as impaired spatial learning and deficiencies in establishing and maintaining mossy fiber connections in the hippocampus [29,30]. Therefore, Cr supplementation may provide powerful cellular bioenergetics by regulating the PCr/ATP system in the brain.

Cr as an anti-oxidant

Cr appears to have direct and indirect anti-oxidant effects. Through an ADP-recycling mechanism, Cr protected rat mitochondrial DNA from oxidative damage in a dose-dependent manner [27,31]. Moreover, Cr protects against radicals such as superoxide anion (O2−), peroxinitrite (ONOO−), and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical [11]. Furthermore, creatine has an indirect anti-oxidant effect on differentiated mouse myotube cultures (C2C12) through the upregulation of two significant anti-oxidant enzymes observed in the cytoplasm and mitochondria, peroxiredoxin-4 and thioredoxin-independent peroxide reductase, respectively [32]. Based on previous findings, Cr has been speculated to possess anti-oxidant properties, thereby protecting the nervous system against oxidative stress.

Cr as an anti-inflammatory factor

In addition to its anti-oxidant role, Cr has an anti-inflammatory function, although its molecular mechanism is poorly understood. For example, creatine reduces endothelial permeability and neutrophil adhesion to endothelial cells by suppressing the adhesion molecules ICAM-1 and E-selectin expression on endothelial cells [33]. According to in vivo research, creatine may decrease the expression of Toll-Like Receptor (TLR) 2, a protein bound to the plasma membrane that identifies acylated bacterial lipoproteins on macrophages, which are important cells involved in the early stages of the immune response; this, in turn, may have contributed to the reduction in experimentally induced inflammation [34]. Additionally, a recent study provided preliminary evidence that supplementation with creatine can prevent tumor-induced skeletal muscle atrophy in rats by reducing the proinflammatory environment caused by the tumor [35]. Based on these studies, Cr supplementation may exert anti-inflammatory effects on the brain.

Cr supplementation and Alzheimer’s disease (AD)

Alzheimer’s disease is the most prevalent neurodegenerative disease, characterized by the accumulation of extracellular plaques, majorly consisting of amyloid-β peptide, and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau [29]. Reduced judgment, memory impairment, aphasia, miscalculation, agnosia, and other symptoms are the main clinical symptoms [36]. The primary molecular mechanisms of AD are now understood to be abnormal tau protein phosphorylation and abnormal Aβ deposition. Aβ and tau proteins have a certain relationship and work together to mediate the progression of AD [37]. Aging and neurodegenerative disorders are strongly linked to mitochondrial dysfunction, which produces the ATP required for neurons to survive and function at their best. Hyperphosphorylated tau pathology and typical Aβ deposition in AD can result from neuronal mitochondrial dysfunction. Consequently, tau pathology and Aβ deposition exacerbate this mitochondrial defect. Memory loss and synaptic toxicity are ultimately brought on by intracellular Ca2+ imbalance and energy deficiency brought on by Aβ42 oligomers resulting from mitochondrial dysfunction. In patients with AD, brain CK is profoundly inactivated by oxidation, and toxic aggregates co-reside at the Cr-rich site [38], suggesting that creatine metabolism is closely related to neuronal loss. Studies have suggested that Cr supplementation exerts positive effects in AD models. For example, this compound supplementation hampered transglutaminase-catalyzed protein aggregation in sedimentation studies, protected hippocampal neurons against amyloid-β neurotoxicity, and produced internalization of NMDA receptors under the presence of amyloid-β peptides in cortical neuronal cultures [38-40]. Recently, by upregulating the expression of high-molecular-weight species and downregulating the low-molecular-weight 12 kDa mOC87 Aβ oligomer—the only Aβ species where higher concentration was correlated with worse cognitive impairment in this study—Cr supplementation changed the way Aβ was processed in female 3xTg mice [41]. 3xTg mice of both sexes with increased concentrations of Cr in their hippocampi showed reduced levels of pTau/Tau in both sexes [41]. These findings imply that CrM may have bioenergetic effects in AD that affect tau and A-beta protein phosphorylation and processing. Despite the beneficial role of Cr in AD-related experiments, only the neuroprotective effects of Cr in patients with AD have been reported since AD pathophysiology is more complex and multifaceted. Therefore, further research is required to determine how well an optimal Cr regimen protects against AD pathophysiology and pathology in humans.

Cr supplementation and Parkinson’s disease (PD)

Parkinson’s disease is the second most common neurodegenerative disease, characterized by progressive dopaminergic neuronal loss in the substantia nigra par compacta and intracellular inclusion of α-synuclein aggregates termed Lewy body (LB) [42]. Symptoms of this disorder include resting tremors, bradykinesia, muscle rigidity, blurred vision, depression, and dementia [43,44]. Missense mutations in the SNCA genes (A53T, A53E, H50Q, G51D, E46K, and A30P) have been reported through genetic testing in patients with early-onset PD [45]. In the brain, α-Syn can interact with specific cell types through a variety of mechanisms, such as glial cell phagocytosis and degradation of α-Syn, glial cell activation of inflammatory pathways, α-Syn transmission between glial cells and neurons, and interactions with peripheral immune cells [46]. These findings have raised the possibility that α-Syn plays a role in the development of familial PD. Additional evidence supporting the role of mitochondrial dysfunction in Parkinson’s comes from genetic studies concentrating on the monogenic forms of the disease. Most proteins encoded by pathogenic mutations in PINK1 (PARK6), PRKN (PARK2), DJ-1 (PARK7), SNCA (PARK1), FBXO7 (PARK15), CHCHD2 (PARK22), and VPS13C (PARK23) are known to be involved in the mitochondrial quality control system [47]. These mutations can cause familial PD. Complex I in the mitochondrial electron transport system is closely associated with PD pathogenesis, in which complex I activity is inhibited by typical PD-mimicking neurotoxins such as 6-hydroxydopamine (6-OHDA), rotenone, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This induced dopaminergic neuronal death. In an MPTP model, Cr supplementation exerted a neuroprotective effect, as indicated by significantly reduced dopaminergic neuronal loss [48]. In addition, Cr co-treatment with rofecoxib (a clooxygenase-2 inhibitor) or coenzyme Q10 resulted in a greater reduction in dopaminergic neuronal loss than either treatment alone [49,50], suggesting that combination therapy is more effective at improving PD-related features. Moreover, Cr treatment diminished abnormal involuntary movements in an L-dopa-induced dyskinesia rat model [51]. These results imply that supplementation with Cr may have both beneficial and therapeutic effects compared to the adverse effects of conventional treatment. More recently, Cr derivatives showed neuroprotective and anti-oxidant effects in models of 6-hydroxydopamine-induced (on synaptosomes), tert-butyl hydroperoxide-induced (mitochondria), and iron/ascorbate-induced (microsomes) oxidative stress [52]. This effect is attributed to the maintenance of low glutathione levels, ROS scavenging, and membrane stabilization against free radicals. Similar to AD, in clinical trials, Cr treatment resulted in improved mood but not motor performance, as measured by the Unified PD rating scale [53,54]. In contrast, studies showed the neuroprotective impact of Cr treatment in patients with PD, as proven by Cr-treated improvement in upper-body strength and co-treatment with Cr and coenzyme Q10-administrated decreased cognitive decline [55,56]. Consequently, it may be necessary to conduct large-scale clinical trials with long-term follow-up to determine clinical outcomes.

Cr supplementation and Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons in the entire CNS and spinal cord, eventually resulting in muscular paralysis and subsequent death [57]. Neurodegenerative pathogenesis is closely associated with gliosis, oxidative stress, glutamate excitotoxicity, mitochondrial defects, and abnormal protein folding [58]. The primary neuropathological characteristic of ALS is the extensive loss of lower motor neurons in the brainstem and anterior horn of the spinal cord [59]. Although the precise pathogenesis remains unknown, according to Grad et al. [59], ALS usually affects adults and manifests as a progressive loss of motor function, leading to respiratory failure and death. In SOD1-G93A mutant mice, lower levels of ATP and CK activity were observed before disease onset [60]. This suggests improving the effects of Cr supplementation in patients with ALS. In a mouse model of ALS, the neuroprotective effects of Cr supplementation were demonstrated, in which Cr supplementation reduced neuronal loss in the motor cortex and substantia nigra and reduced ROS-induced damage, along with the induction of behavioral recovery [60,61]. However, several human studies have shown that the beneficial effects of Cr in animal studies have failed to reproduce motor and respiratory functions in patients [62-64]. The disparity between research conducted on humans and animals could indicate that Cr treatment started later in humans than in animals before symptoms appeared in the former case.

Cr supplementation and Huntington’s disease (HD)

Amplification of the CAG repeats in exon 1 of the huntingtin gene results in a mutant form of the huntingtin protein (mHtt), which causes HD, an autosomal-dominant illness. Disease symptoms include progressive choreoathetotic movements, cognitive impairment, and neuropsychiatric illnesses, which ultimately lead to death [65]. mHtt causes neuronal death, mainly in GABAergic neurons, related to reduced mitochondrial complex II and III activities, facilitating cerebral lactate levels and a PCr/inorganic phosphate ratio in the muscle [66,67]. Cr treatment reduces lesion size, ameliorates convulsive behavior, and dampens lactate generation in rats stereotaxically injected with 3-nitropropionic acid (3-NPA, an irreversible succinate dehydrogenase inhibitor) or malonate (a reversible succinate dehydrogenase inhibitor) [48,68]. Moreover, Cr supplementation increases survival and body weight, delays motor symptoms, and reduces brain lesion size [69,70]. Recent studies have shown that Cr supplementation improves neural progenitor cell survival depending on the developmental stage of HD [71], implying that promising findings from studies investigating the translational applications of Cr supplementation in NSC and NPC cell replacement therapies suggest that Cr may enhance cell graft survival and promote differentiation toward GABAergic phenotypes in striatal transplantation models. However, in clinical trials, Cr-treated improvement was not observed as measured by the Unified HD Rating Scale used to evaluate cognition, motor function, and functional ability [72,73]. In contrast, a few clinical trials have reported beneficial effects in patients with HD. For example, a Cr-enhanced diet induces increased brain glutamate levels and decreased serum levels of 8-hydrocy-2-deoxyguanosine, a marker of oxidative insult to DNA, in patients with HD [74,75]. Moreover, in patients likely to develop HD, high-dose Cr therapy significantly reduces cortical and striatal atrophy [76]. These results suggest that Cr can delay disease progression and symptoms.

Cr supplementation and creatine deficiency syndromes

Mutations in AGAT, GAMT, and SLC6A8, which control Cr production and transportation, result in creatine-deficiency disorders [77]. These syndromes manifest as mental retardation, autism, brain atrophy, delayed speech acquisition, and epilepsy [77,78]. The pathological characteristics of these diseases include Cr depletion and the deposition of arginine and GAA. Among these syndromes, creatine supplementation elicits significant consequences for AGAT and GAMT mutations [79,80], suggesting that creatine supplementation can potentially be a therapeutic approach for defects in Cr-synthesizing enzymes. SLC6A8 deficiency is less effective against neurological symptoms because of the impermeability of Cr into the BBB [81,82]. More recently, a study showed that di-acetyl Cr ethyl ester, a Cr derivative that travels across biological membranes with high lipophilicity, suppresses electrophysiological failure and elevates Cr levels in hippocampal slice systems [83]. Moreover, Cr supplementation restores memory impairment, abnormal CK activity, and dysregulated redox homeostasis in GAA deposition-induced Cr deficiency models [12,84]. Therefore, Cr supplementation has therapeutic potential against impaired Cr metabolism, such as Cr deficiency.


Cr is a potent stimulator of cellular bioenergetics, which increases the availability of high-energy phosphate in energy-demanding tissues, including the brain and muscles. In addition to serving as an energy reservoir, Cr possesses secondary effects, including anti-oxidant and anti-inflammatory properties, although the exact mechanism remains unknown. Due to its beneficial effects, Cr has been used to treat several neurological abnormalities. The beneficial effects of Cr are associated with mitochondrial function, and Cr supplementation has significant effects on noxious energy metabolism, such as ATP depletion. Various Cr regimens have demonstrated advantageous effects in in vitro and animal research on several neurodegenerative diseases. However, most clinical trials have been unable to replicate favorable results. These findings suggest that preventive interventions for neuroprotection in at-risk patients are the most promising area. To determine the best Cr supplementation for improving the pathophysiology of neurodegenerative illnesses, a few issues need to be resolved in future research. Future preclinical research must determine the putative molecular mechanisms underlying the beneficial effects of Cr on neurological defects. Future research in the clinical domain must examine more inquiries, taking into account the degree and phases of disease development and the timing and dosage of Cr treatment. In addition, larger sample sizes are required for reproducible clinical studies. Clinical applications for elevating brain Cr levels may consider several issues, including disease severity, timing of supplementation during disease onset and progression, and Cr-derivative enhancement of BBB permeability. Therefore, identifying the optimal regimen to increase brain Cr levels is essential for maintaining brain health and treating neurodegeneration.


This work was supported by a research grant from Seoul Women’s University (2023-0089).


1. Bonilla DA, Kreider RB, Stout JR, Forero DA, Kerksick CM, Roberts MD, Rawson ES. Metabolic basis of creatine in health and disease: a bioinformatics-assisted review. Nutrients 2021;13:1238.
2. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000;80:1107–213.
3. Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids 2011;40:1271–96.
4. Brosnan ME, Brosnan JT. The role of dietary creatine. Amino Acids 2016;48:1785–91.
5. Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci 1992;83:367–74.
6. Kreider RB, Stout JR. Creatine in health and disease. Nutrients 2021;13:447.
7. Hultman E, Soderlund K, Timmons JA, Cederblad G, Greenhaff PL. Muscle creatine loading in men. J Appl Physiol 1996;81:232–7.
8. Hall M, Trojian TH. Creatine supplementation. Curr Sports Med Rep 2013;12:240–4.
9. O’Gorman E, Beutner G, Dolder M, Koretsky AP, Brdiczka D, Wallimann T. The role of creatine kinase in inhibition of mitochondrial permeability transition. FEBS Lett 1997;414:253–7.
10. Xu CJ, Klunk WE, Kanfer JN, Xiong Q, Miller G, Pettegrew JW. Phosphocreatine-dependent glutamate uptake by synaptic vesicles. A comparison with atp-dependent glutamate uptake. J Biol Chem 1996;271:13435–40.
11. Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun 2002;290:47–52.
12. Kolling J, Longoni A, Siebert C, Dos Santos TM, Marques EP, Carletti J, Pereira LO, Wyse ATS. Severe hyperhomocysteinemia decreases creatine kinase activity and causes memory impairment: neuroprotective role of creatine. Neurotox Res 2017;32:585–93.
13. Kolling J, Scherer EB, Siebert C, Marques EP, Dos Santos TM, Wyse ATS. Creatine prevents the imbalance of redox homeostasis caused by homocysteine in skeletal muscle of rats. Gene 2014;545:72–9.
14. Wyse ATS, Netto CA. Behavioral and neurochemical effects of proline. Metab Brain Dis 2011;26:159–72.
15. Peral MJ, García-Delgado M, Durán JM, De La Horra MC, Wallimann T, Speer O, Ilundáin A. Human, rat and chicken small intestinal Na+ - Cl- -creatine transporter: functional, molecular characterization and localization. J Physiol 2002;545:133–44.
16. Barcelos RP, Stefanello ST, Mauriz JL, Gonzalez-Gallego J, Soares FAA. Creatine and the liver: metabolism and possible interactions. Mini Rev Med Chem 2016;16:12–8.
17. da Silva RP, Clow K, Brosnan JT, Brosnan ME. Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas. Br J Nutr 2014;111:571–7.
18. Braissant O, Bachmann C, Henry H. Expression and function of AGAT, GAMT and CT1 in the mammalian brain. Subcell Biochem 2007;46:67–81.
19. Saunders NR, Dziegielewska KM, Møllgård K, Habgood MD, Wakefield MJ, Lindsay H, Stratzielle N, Ghersi-Egea JF, Liddelow SA. Influx mechanisms in the embryonic and adult rat choroid plexus: a transcriptome study. Front Neurosci 2015;9:123.
20. Braissant O, Béard E, Torrent C, Henry H. Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 2010;37:423–33.
21. Laakso MP, Hiltunen Y, Könönen M, Kivipelto M, Koivisto A, Hallikainen M, Soininen H. Decreased brain creatine levels in elderly apolipoprotein E epsilon 4 carriers. J Neural Transm 2003;110:267–75.
22. Rawson ES, Venezia AC. Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids 2011;40:1349–62.
23. Roschel H, Gualano B, Ostojic SM, Rawson ES. Creatine supplementation and brain health. Nutrients 2021;13:586.
24. Grimm A, Friedland K, Eckert A. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer’s disease. Biogerontology 2016;17:281–96.
25. Leuner K, Hauptmann S, Abdel-Kader R, Scherping I, Keil U, Strosznajder JB, Eckert A, Mülle WE. Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’s disease? Antioxid Redox Signal 2007;9:1659–75.
26. Shen H, Goldberg MP. Creatine pretreatment protects cortical axons from energy depletion in vitro. Neurobiol Dis 2012;47:184–93.
27. Meyer LE, Machado LB, Santiago AP, Da-Silva WS, de Felice FG, Holub O, Oliveira MF, Galina A. Mitochondrial creatine kinase activity prevents reactive oxygen species generation: antioxidant role of mitochondrial kinase-dependent ADP re-cycling activity. J Biol Chem 2006;281:37361–71.
28. Dolder M, Walzel B, Speer O, Schlattner U, Wallimann T. Inhibition of the mitochondrial permeability transition by creatine kinase substrates. Requirement for microcompartmentation. J Biol Chem 2003;278:17760–6.
29. Oliet SH, Piet R, Poulain DA. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 2001;292:923–6.
30. Streijger F, Oerlemans F, Ellenbroek BA, Jost CR, Wieringa B, Van der Zee CEEM. Structural and behavioural consequences of double deficiency for creatine kinases BCK and UbCKmit. Behav Brain Res 2005;157:219–34.
31. Guidi C, Potenza L, Sestili P, Martinelli C, Guescini M, Stocchi L, Zeppa S, Polidori E, Annibalini G, Stocchi V. Differential effect of creatine on oxidatively-injured mitochondrial and nuclear DNA. Biochim Biophys Acta 2008;1780:16–26.
32. Young JF, Larsen LB, Malmendal A, Nielsen NC, Straadt IK, Oksbjerg N, Bertram HC. Creatine-induced activation of antioxidative defence in myotube cultures revealed by explorative NMR based metabonomics and proteomics. J Int Soc Sports Nutr 2010;7:9.
33. Nomura A, Zhang M, Sakamoto T, Ishii Y, Morishima Y, Mochizuki M, Kimura T, Uchida Y, Sekizawa K. Anti-inflammatory activity of creatine supplementation in endothelial cells in vitro. Br J Pharmacol 2003;139:715–20.
34. Leland KM, McDonald TL, Drescher KM. Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages. Int Immunopharmacol 2011;11:1341–7.
35. Cella PS, Marinello PC, Borges FH, Ribeiro DF, Chimin P, Testa MTJ, Guirro PB, Duarte JA, Cecchini R, Guarnier FA, Deminice R. Creatine supplementation in Walker-256 tumor-bearing rats prevents skeletal muscle atrophy by attenuating systemic inflammation and protein degradation signaling. Eur J Nutr 2020;59:661–9.
36. Andrade-Guerrero J, Santiago-Balmaseda A, Jeronimo-Aguilar P, Vargas-Rodriguez I, Cadena-Suarez A, Sanchez-Garibay C, Pozo-Molina G, Méndez-Catalá CF, Cardenas-Aguayo M, Diaz-Cintra S, Pacheco-Herrero M, Luna-Muñoz J, Soto-Rojas LO. Alzheimer’s disease: an updated overview of its genetics. Int J Mol Sci 2023;24:3754.
37. Wang H, Sun M, Li W, Liu X, Zhu M, Qin H. Biomarkers associated with the pathogenesis of Alzheimer’s disease. Front Cell Neurosci 2023;17:1279046.
38. Burguera EF, Love BJ. Reduced transglutaminase-catalyzed protein aggregation is observed in the presence of creatine using sedimentation velocity. Anal Biochem 2006;350:113–9.
39. Brewer GJ, Wallimann TW. Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochem 2000;74:1968–78.
40. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 2005;8:1051–8.
41. Snow WM, Cadonic C, Cortes-Perez C, Adlimoghaddam A, Chowdhury SK, Thomson E, Anozie A, Bernstein MJ, Gough K, Fernyhough P, Suh M, Albensi BC. Sex-specific effects of chronic creatine supplementation on hippocampal-mediated spatial cognition in the 3xTg mouse model of Alzheimer’s disease. Nutrients 2020;12:3589.
42. Gazewood JD, Richards DR, Clebak K. Parkinson disease: an update. Am Fam Physician 2013;87:267–73.
43. Chaudhuri KR, Schapira AHV. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8:464–74.
44. Aarsland D. Cognitive impairment in Parkinson’s disease and dementia with Lewy bodies. Parkinsonism Relat Disord 2016;22:S144–8.
45. Guerrero-Ferreira R, Taylor NM, Mona D, Ringler P, Lauer ME, Riek R, Britschgi M, Stahlberg H. Cryo-EM structure of alpha-synuclein fibrils. Elife 2018;7e36402.
46. Zhang N, Yan Z, Xin H, Shao S, Xue S, Cespuglio R, Wang S. Relationship among αsynuclein, aging and inflammation in Parkinson’s disease (Review). Exp Ther Med 2023;27:23.
47. Choong CJ, Mochizuki H. Involvement of mitochondria in Parkinson’s disease. Int J Mol Sci 2023;24:17027.
48. Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 1998;18:156–63.
49. Klivenyi P, Kiaei M, Gardian G, Calingasan NY, Beal MF. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 2004;88:576–82.
50. Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, Beal MF. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s diseases. J Neurochem 2009;109:1427–39.
51. Valastro B, Dekundy A, Danysz W, Quack G. Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Behav Brain Res 2009;197:90–6.
52. Kostadinova I, Kondeva-Burdina M, Marinov L, Vezenkov LL, Simeonova R. Newly synthesized creatine derivatives as potential neuroprotective and antioxidant agents on in vitro models of Parkinson’s disease. Life (Basel) 2023;13:139.
53. Bender A, Auer DP, Merl T, Reilmann R, Saemann P, Yassouridis A, Bender J, Weindl A, Dose T, Gasser M, Klopstock T. Creatine supplementation lowers brain glutamate levels in Huntington’s disease. J Neurol 2005;252:36–41.
54. Kieburtz K, Tilley BC, Elm JJ, Babcock D, Hauser R, Ross GW, Augustine AH, Augustine EU, Aminoff MJ, Bodis-Wollner IG, Boyd J, Cambi F, Chou K, Christine CW, Cines M, Dahodwala N, Derwent L, Dewey RB Jr, Hawthorne K, Houghton DJ, Kamp C, Leehey M, Lew MF, Liang GS, Luo ST, Mari Z, Morgan JC, Parashos S, Pérez A, Petrovitch H, Rajan S, Reichwein S, Roth JT, Schneider JS, Shannon KM, Simon DK, Simuni T, Singer C, Sudarsky L, Tanner CM, Umeh CC, Williams K, Wills AM. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. JAMA 2015;313:584–93.
55. Hass CJ, Collins MA, Juncos JL. Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: a randomized trial. Neurorehabil Neural Repair 2007;21:107–15.
56. Li Z, Wang P, Yu Z, Cong Y, Sun H, Zhang J, Zhang J, Sun C, Zhang Y, Ju X. The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson’s disease. Eur Neurol 2015;73:205–11.
57. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis 2009;4:3.
58. Turner BJ, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 2008;85:94–134.
59. Grad LI, Rouleau GA, Ravits J, Cashman NR. Clinical spectrum of Amyotrophic Lateral Sclerosis (ALS). Cold Spring Harb Perspect Med 2017;7:a024117.
60. Wendt S, Dedeoglu A, Speer O, Wallimann T, Beal MF, Andreassen OA. Reduced creatine kinase activity in transgenic amyotrophic lateral sclerosis mice. Free Radic Biol Med 2002;32:920–6.
61. Dupuis L, Oudart H, René F, Gonzalez de Aguilar JL, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A 2004;101:11159–64.
62. Drory VE, Gross D. No effect of creatine on respiratory distress in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2002;3:43–6.
63. Rosenfeld J, King RM, Jackson CE, Bedlack RS, Barohn RJ, Dick A, Phillips LH, Chapin J, Gelinas DF, Lou JS. Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS. Amyotroph Lateral Scler 2008;9:266–72.
64. Pastula DM, Moore DH, Bedlack RS. Creatine for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2010;:CD005225.
65. Quinn N, Schrag A. Huntington’s disease and other choreas. J Neurol 1998;245:709–16.
66. Grünewald T, Beal MF. Bioenergetics in Huntington’s disease. Ann N Y Acad Sci 1999;893:203–13.
67. Calabresi P, Gubellini P, Picconi B, Centonze D, Pisani A, Bonsi P, Greengard P, Hipskind RA, Borrelli E, Bernardi G. Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine. J Neurosci 2001;21:5110–20.
68. Royes LFF, Fighera MR, Furian AF, Oliveira MS, Myskiw JC, Fiorenza NG, Petry JC, Coelho RC, Mello CF. Effectiveness of creatine monohydrate on seizures and oxidative damage induced by methylmalonate. Pharmacol Biochem Behav 2006;83:136–44.
69. Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 2000;20:4389–97.
70. Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne SE, Schilling G, Borchelt DR, Hersch SM, Ross CA, Beal MF. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis 2001;8:479–91.
71. Andres RH, Ducray AD, Andereggen L, Hohl T, Schlattner U, Wallimann T, Widmer HR. The effects of creatine supplementation on striatal neural progenitor cells depend on developmental stage. Amino Acids 2016;48:1913–27.
72. Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R. Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology 2003;61:925–30.
73. Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT. High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study. Neurology 2005;64:1655–6.
74. Bender A, Koch W, Elstner M, Schombacher Y, Bender J, Moeschl M, Gekeler F, Muller-Myhsok B, Gasser T, Tatsch K, Klopstock T. Creatine supplementation in Parkinson disease: a placebo controlled randomized pilot trial. Neurology 2006;67:1262–4.
75. Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 2006;66:250–2.
76. Rosas HD, Doros G, Gevorkian S, Malarick K, Reuter M, Coutu JP, Triggs TD, Wilkens PJ, Matson W, Salat DH, Hersch SM. PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology 2014;82:850–7.
77. Stöckler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M, Frahm J. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 1994;36:409–13.
78. Item CB, Stöckler-Ipsiroglu S, Stromberger C, Mühl A, Alessandrì MG, Bianchi MC, Tosetti M, Fornai F, Cioni G. Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 2001;69:1127–33.
79. Battini R, Alessandrì MG, Leuzzi V, Moro F, Tosetti M, Bianchi MC, Cioni G. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr 2006;148:828–30.
80. Silvia LC, Chandramohan A, Palanisamy S. Guanidinoacetate methyltransferase deficiency: a treatable cause of developmental delay diagnosed by magnetic resonance spectroscopy. Ann Indian Acad Neurol 2022;25:1196–8.
81. Orsenigo MN, Faelli A, DeBiase S, Sironi C, Laforenza U, Paulmichl M, Tosco M. Jejunal creatine absorption: what is the role of the basolateral membrane? J Membr Biol 2005;207:183–95.
82. Valayannopoulos V, Boddaert N, Chabli A, Barbier V, Desguerre I, Philippe A, Afenjar A, Mazzuca M, Cheillan D, Munnich A, de Keyzer Y, Jakobs C, Salomons GS, de Lonlay P. Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis 2012;35:151–7.
83. Adriano E, Gulino M, Arkel A, Salis G, Damonte N, Liessi E, Millo P, Garbati P, Balestrino M. Di-acetyl creatine ethyl ester, a new creatine derivative for the possible treatment of creatine transporter deficiency. Neurosci Lett 2018;665:217–23.
84. Kolling J, Scherer EB, Siebert C, Marques EP, Dos Santos TM, Wyse ATS. Creatine prevents the imbalance of redox homeostasis caused by homocysteine in skeletal muscle of rats. Gene 2014;545:72–9.

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