Potential for use of creatine supplementation following mild traumatic brain injury

Philip John Ainsley Dean, Gozdem Arikan, Bertram Opitz, Annette Sterr, Philip John Ainsley Dean, Gozdem Arikan, Bertram Opitz, Annette Sterr

Abstract

There is significant overlap between the neuropathology of mild traumatic brain injury (mTBI) and the cellular role of creatine, as well as evidence of neural creatine alterations after mTBI. Creatine supplementation has not been researched in mTBI, but shows some potential as a neuroprotective when administered prior to or after TBI. Consistent with creatine's cellular role, supplementation reduced neuronal damage, protected against the effects of cellular energy crisis and improved cognitive and somatic symptoms. A variety of factors influencing the efficacy of creatine supplementation are highlighted, as well as avenues for future research into the potential of supplementation as an intervention for mTBI. In particular, the slow neural uptake of creatine may mean that greater effects are achieved by pre-emptive supplementation in at-risk groups.

Keywords: behavioral symptoms; brain injury; clinical outcome; concussion; creatine; magnetic resonance spectroscopy; mild TBI; neurobiology; neuroprotection; postconcussion syndrome; treatment.

Conflict of interest statement

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1. . The neurometabolic cascade after…
Figure 1.. The neurometabolic cascade after mTBI, and its overlap with creatine biology (in red).
(A) How diffuse injury after mTBI results in large-scale membrane depolarisation (a ‘spreading depression’-like state), reduced blood flow and increased intracellular calcium. (B) The generalised cellular energy crisis, where large amounts of ATP are required to repolarise the membranes and counteract the ‘spreading depression’-like state. This occurs in a low oxygen environment, with dysfunctional mitochondria (due to calcium sequestering), resulting in increased glycolysis and lactic acid formation, along with increased oxidative stress and potential formation of mPTP. (C) The secondary effects of increased intracellular calcium. Red boxes and arrows indicate the role and influence of creatine within mTBI neuropathology. ADP: Adenosine di-phosphate; ATP: Adenosine tri-phosphate; BB-CK: Braincreatine kinase; Cr: Creatine; mPTP: Mitochondrial permeability transition pore; mTBI: Mild traumatic brain injury; PCr: Phosphocreatine; ROS: Reactive oxygen species; uMt-CK: Ubiquitous mitochondrial creatine kinase.

References

    1. Knapik JJ, Steelman RA, Hoedebecke SS, Austin KG, Farina EK, Lieberman HR. Prevalence of dietary supplement use by athletes: systematic review and meta-analysis. Sports. 2016;46(1):103–123.
    1. Gualano B, Roschel H, Lancha-Jr AH, Brightbill CE, Rawson ES. In sickness and in health: the widespread application of creatine supplementation. Amino Acids. 2012;43(2):519–529.
    1. Riesberg LA, Weed SA, Mcdonald TL, Eckerson JM, Drescher KM. Beyond muscles: the untapped potential of creatine. Int. Immunopharmacol. 2016;37:31–42.
    1. Rae CD, Broer S. Creatine as a booster for human brain function. How might it work? Neurochem. Int. 2015;89:249–259.
    1. Allen PJ. Creatine metabolism and psychiatric disorders: does creatine supplementation have therapeutic value? Neurosci. Biobehav. Rev. 2012;36(5):1442–1462.
    1. Hill CS, Coleman MP, Menon DK. Traumatic axonal injury: mechanisms and translational opportunities. Trends Neurosci. 2016;39(5):311–324.
    1. Perasso L, Spallarossa P, Gandolfo C, Ruggeri P, Balestrino M. Therapeutic use of creatine in brain or heart ischemia: available data and future perspectives. Med. Res. Rev. 2013;33(2):336–363.
    1. Gasparovic C, Yeo R, Mannell M, et al. Neurometabolite concentrations in gray and white matter in mild traumatic brain injury: an 1H-magnetic resonance spectroscopy study. J. Neurotrauma. 2009;26(10):1635–1643.
    1. Blennow K, Hardy J, Zetterberg H. The neuropathology and neurobiology of traumatic brain injury. Neuron. 2012;76(5):886–899.
    1. Gaetz M. The neurophysiology of brain injury. Clin. Neurophysiol. 2004;115(1):4–18.
    1. Kumar A, Loane DJ. Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav. Immun. 2012;26(8):1191–1201.
    1. Bigler ED, Maxwell WL. Neuropathology of mild traumatic brain injury: relationship to neuroimaging findings. Brain Imaging Behav. 2012;6(2):108–136.
    1. Kan EM, Ling EA, Lu J. Microenvironment changes in mild traumatic brain injury. Brain Res. Bull. 2012;87(4–5):359–372.
    1. Johnson VE, Stewart W, Smith DH. Axonal pathology in traumatic brain injury. Exp. Neurol. 2013;246:35–43.
    1. Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury. Clin. Sports. Med. 2011;30(1):33–48. vii-viii.
    1. Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury – an update. Phys. Med. Rehabil. Clin. N. Am. 2016;27(2):373–393.
    1. Giza CC, Hovda DA. The neurometabolic cascade of concussion. J. Athl. Train. 2001;36(3):228–235.
    1. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014;75(Suppl. 4):S24–S33.
    1. Khurana VG, Kaye AH. An overview of concussion in sport. J. Clin. Neurosci. 2012;19(1):1–11.
    1. Rabinowitz AR, Li X, Levin HS. Sport and nonsport etiologies of mild traumatic brain injury: similarities and differences. Annu. Rev. Psychol. 2014;65:301–331.
    1. Signoretti S, Lazzarino G, Tavazzi B, Vagnozzi R. The pathophysiology of concussion. PM. R. 2011;3(10 Suppl. 2):S359–S368.
    1. Smith RN, Agharkar AS, Gonzales EB. A review of creatine supplementation in age-related diseases: more than a supplement for athletes. F1000Res. 2014;3:222.
    1. Beard E, Braissant O. Synthesis and transport of creatine in the CNS: importance for cerebral functions. J. Neurochem. 2010;115(2):297–313.
    1. Brosnan ME, Brosnan JT. The role of dietary creatine. Amino Acids. 2016;48(8):1785–1791.
    1. Gualano B, Rawson ES, Candow DG, Chilibeck PD. Creatine supplementation in the aging population: effects on skeletal muscle, bone and brain. Amino Acids. 2016;48(8):1793–1805.
    1. Rae CD. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem. Res. 2014;39(1):1–36.
    1. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR. Functions and effects of creatine in the central nervous system. Brain Res. Bull. 2008;76(4):329–343.
    1. Gualano B, Artioli GG, Poortmans JR, Lancha Junior AH. Exploring the therapeutic role of creatine supplementation. Amino Acids. 2010;38(1):31–44.
    1. Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids. 2011;40(5):1271–1296.
    1. Klivenyi P, Calingasan NY, Starkov A, et al. Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase. Neurobiol. Dis. 2004;15(3):610–617.
    1. Briones TL, Woods J, Rogozinska M. Decreased neuroinflammation and increased brain energy homeostasis following environmental enrichment after mild traumatic brain injury is associated with improvement in cognitive function. Acta Neuropathol. Commun. 2013;1(1):57.
    1. Johnson B, Gay M, Zhang K, et al. The use of magnetic resonance spectroscopy in the subacute evaluation of athletes recovering from single and multiple mild traumatic brain injury. J. Neurotrauma. 2012;29(13):2297–2304.
    1. Kirov Ii, Tal A, Babb JS, et al. Proton MR spectroscopy correlates diffuse axonal abnormalities with post-concussive symptoms in mild traumatic brain injury. J. Neurotrauma. 2013;30(13):1200–1204.
    1. Sivak S, Bittsansky M, Grossmann J, et al. Clinical correlations of proton magnetic resonance spectroscopy findings in acute phase after mild traumatic brain injury. Brain Inj. 2014;28(3):341–346.
    1. Chen J, Jin H, Zhang Y, et al. MRS and diffusion tensor image in mild traumatic brain injuries. Asian Pac. J. Trop. Med. 2012;5(1):67–70.
    1. Kierans AS, Kirov Ii, Gonen O, et al. Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. Neurology. 2014;82(6):521–528.
    1. Yeo RA, Gasparovic C, Merideth F, Ruhl D, Doezema D, Mayer AR. A longitudinal proton magnetic resonance spectroscopy study of mild traumatic brain injury. J. Neurotrauma. 2011;28(1):1–11.
    1. Vagnozzi R, Signoretti S, Floris R, et al. Decrease in N-acetylaspartate following concussion may be coupled to decrease in creatine. J. Head Trauma Rehabil. 2013;28(4):284–292.
    1. Dean PJ, Otaduy MC, Harris LM, Mcnamara A, Seiss E, Sterr A. Monitoring long-term effects of mild traumatic brain injury with magnetic resonance spectroscopy: a pilot study. Neuroreport. 2013;24(12):677–681.
    1. Minati L, Aquino D, Bruzzone MG, Erbetta A. Quantitation of normal metabolite concentrations in six brain regions by in-vivoH-MR spectroscopy. J. Med. Phys. 2010;35(3):154–163.
    1. George EO, Roys SR, Sours C, et al. Longitudinal and prognostic evaluation of mild traumatic brain injury: a 1H-MRS study. J. Neurotrauma. 2014;31(11):1018–1028.
    1. Kirov Ii, Tal A, Babb JS, Lui YW, Grossman RI, Gonen O. Diffuse axonal injury in mild traumatic brain injury: a 3D multivoxel proton MR spectroscopy study. J. Neurol. 2013;260(1):242–252.
    1. Poole VN, Abbas K, Shenk TE, et al. MR spectroscopic evidence of brain injury in the non-diagnosed collision sport athlete. Dev. Neuropsychol. 2014;39(6):459–473.
    1. Poole VN, Breedlove EL, Shenk TE, et al. Sub-concussive hit characteristics predict deviant brain metabolism in football athletes. Dev. Neuropsychol. 2015;40(1):12–17.
    1. Levin HS, Wilde E, Troyanskaya M, et al. Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae. J. Neurotrauma. 2010;27(4):683–694.
    1. Lipton ML, Kim N, Zimmerman ME, et al. Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology. 2013;268(3):850–857.
    1. Maruta J, Suh M, Niogi SN, Mukherjee P, Ghajar J. Visual tracking synchronization as a metric for concussion screening. J. Head Trauma Rehabil. 2010;25(4):293–305.
    1. Mcallister TW, Ford JC, Flashman LA, et al. Effect of head impacts on diffusivity measures in a cohort of collegiate contact sport athletes. Neurology. 2014;82(1):63–69.
    1. Messe A, Caplain S, Pelegrini-Issac M, et al. Structural integrity and postconcussion syndrome in mild traumatic brain injury patients. Brain Imaging Behav. 2012;6(2):283–292.
    1. Wu TC, Wilde EA, Bigler ED, et al. Evaluating the relationship between memory functioning and cingulum bundles in acute mild traumatic brain injury using diffusion tensor imaging. J. Neurotrauma. 2010;27(2):303–307.
    1. Keightley ML, Saluja RS, Chen JK, et al. A functional magnetic resonance imaging study of working memory in youth after sports-related concussion: is it still working? J. Neurotrauma. 2013;31(5):437–451.
    1. Mayer AR, Mannell MV, Ling J, Gasparovic C, Yeo RA. Functional connectivity in mild traumatic brain injury. Hum. Brain Mapp. 2011;32(11):1825–1835.
    1. Messe A, Caplain S, Pelegrini-Issac M, et al. Specific and evolving resting-state network alterations in post-concussion syndrome following mild traumatic brain injury. PLoS ONE. 2013;8(6):e65470.
    1. Sours C, Zhuo J, Janowich J, Aarabi B, Shanmuganathan K, Gullapalli RP. Default mode network interference in mild traumatic brain injury – a pilot resting state study. Brain Res. 2013;1537:201–215.
    1. Stevens MC, Lovejoy D, Kim J, Oakes H, Kureshi I, Witt ST. Multiple resting state network functional connectivity abnormalities in mild traumatic brain injury. Brain Imaging Behav. 2012;6(2):293–318.
    1. Dean PJA, Sato JR, Vieira G, Mcnamara A, Sterr A. Multimodal imaging of mild traumatic brain injury and persistent postconcussion syndrome. Brain and Behavior. 2015;5(1):45–61.
    1. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol. Rev. 2000;80(3):1107–1213.
    1. Braissant O, Henry H, Beard E, Uldry J. Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids. 2011;40(5):1315–1324.
    1. Havenetidis K. The use of creatine supplements in the military. J. R. Army Med. Corps. 2016;162(4):242–248.
    1. Bender A, Klopstock T. Creatine for neuroprotection in neurodegenerative disease: end of story? Amino Acids. 2016;48(8):1929–1940.
    1. Alves CR, Santiago BM, Lima FR, et al. Creatine supplementation in fibromyalgia: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res. (Hoboken) 2013;65(9):1449–1459.
    1. Levental U, Bersudsky Y, Dwalatzky T, Lerner V, Medina S, Levine J. A pilot open study of long term high dose creatine augmentation in patients with treatment resistant negative symptoms schizophrenia. Isr. J. Psychiatry Relat. Sci. 2015;52(1):6–10.
    1. Sullivan PG, Geiger JD, Mattson MP, Scheff SW. Dietary supplement creatine protects against traumatic brain injury. Ann. Neurol. 2000;48(5):723–729.
    1. Saraiva AL, Ferreira AP, Silva LF, et al. Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury. Brain Res. Bull. 2012;87(2–3):180–186.
    1. Scheff SW, Dhillon HS. Creatine-enhanced diet alters levels of lactate and free fatty acids after experimental brain injury. Neurochem. Res. 2004;29(2):469–479.
    1. Genius J, Geiger J, Bender A, Moller HJ, Klopstock T, Rujescu D. Creatine protects against excitoxicity in an in vitro model of neurodegeneration. PLoS ONE. 2012;7(2):e30554.
    1. Sakellaris G, Kotsiou M, Tamiolaki M, et al. Prevention of complications related to traumatic brain injury in children and adolescents with creatine administration: an open label randomized pilot study. J. Trauma. 2006;61(2):322–329.
    1. Sakellaris G, Nasis G, Kotsiou M, Tamiolaki M, Charissis G, Evangeliou A. Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study. Acta Paediatr. 2008;97(1):31–34.
    1. Sakellaris GS, Partalis NI, Nasis GD, et al. Outcome of traumatic dysarthria and lingual problems of understanding with creatine administration. an open label randomized pilot study. J. Trauma Treat. 2012;1(3):1–4.
    1. Dean PJ, Sterr A. Long-term effects of mild traumatic brain injury on cognitive performance. Front. Hum. Neurosci. 2013;7:30.
    1. Hammett ST, Wall MB, Edwards TC, Smith AT. Dietary supplementation of creatine monohydrate reduces the human fMRI BOLD signal. Neurosci. Lett. 2010;479(3):201–205.
    1. Turner CE, Byblow WD, Gant N. Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation. J. Neurosci. 2015;35(4):1773–1780.
    1. Persky AM, Brazeau GA, Hochhaus G. Pharmacokinetics of the dietary supplement creatine. Clin. Pharmacokinet. 2003;42(6):557–574.
    1. Braissant O. Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. J. Inherit. Metab. Dis. 2012;35(4):655–664.
    1. Yazigi Solis M, De Salles Painelli V, Giannini Artioli G, Roschel H, Concepcion Otaduy M, Gualano B. Brain creatine depletion in vegetarians? A cross-sectional (1)H-magnetic resonance spectroscopy ((1)H-MRS) study. Br. J. Nutr. 2014;111(7):1272–1274.
    1. Kalhan SC, Gruca L, Marczewski S, Bennett C, Kummitha C. Whole body creatine and protein kinetics in healthy men and women: effects of creatine and amino acid supplementation. Amino Acids. 2016;48(3):677–687.
    1. Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am. J. Physiol. 1999;277(3 Pt 2):R698–R704.
    1. Lyoo IK, Kong SW, Sung SM, et al. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine–monohydrate. Psychiatry Res. 2003;123(2):87–100.
    1. Pan JW, Takahashi K. Cerebral energetic effects of creatine supplementation in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007;292(4):R1745–R1750.
    1. Turner CE, Russell BR, Gant N. Comparative quantification of dietary supplemented neural creatine concentrations with (1)H-MRS peak fitting and basis spectrum methods. Magn. Reson. Imaging. 2015;33(9):1163–1167.
    1. Alves CR, Merege Filho CA, Benatti FB, et al. Creatine supplementation associated or not with strength training upon emotional and cognitive measures in older women: a randomized double-blind study. PLoS ONE. 2013;8(10):e76301.
    1. Benton D, Donohoe R. The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br. J. Nutr. 2011;105(7):1100–1105.
    1. 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(5):1349–1362.
    1. Wunderle K, Hoeger KM, Wasserman E, Bazarian JJ. Menstrual phase as predictor of outcome after mild traumatic brain injury in women. J. Head Trauma Rehabil. 2013;29(5):E1–E8.
    1. Sayeed I, Stein DG. Progesterone as a neuroprotective factor in traumatic and ischemic brain injury. Prog. Brain Res. 2009;175:219–237.
    1. Kim HJ, Kim CK, Carpentier A, Poortmans JR. Studies on the safety of creatine supplementation. Amino Acids. 2011;40(5):1409–1418.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj