Neurochemical Research

, Volume 29, Issue 2, pp 469–479 | Cite as

Creatine-Enhanced Diet Alters Levels of Lactate and Free Fatty Acids After Experimental Brain Injury

  • Stephen W. Scheff
  • Harabhajan S. Dhillon


Free fatty acids (FFA) and lactic acid are markers of secondary cellular injury following traumatic brain injury (TBI). We previously showed that animals fed a creatine (Cr)-enriched diet are afforded neuroprotection following TBI. To further characterize the neuroprotective Cr diet, we studied neurochemical changes in cortex and hippocampus following a moderate injury. Adult rats were fed either a control or Cr-supplemented diet (0.5%, 1%) for 2 weeks before TBI. At 30 min or 6 h after injury, tissue was processed for quantitative analysis of neurochemical changes. Both lactate and FFA were significantly increased in all tissues ipsilateral to the injury. Cr-fed animals had significantly lower levels, although the levels were elevated compared to sham controls. Animals fed a 1% Cr-diet were afforded greater neuroprotection than animals fed a 0.5% Cr diet. These results support the idea that a Cr-enriched diet can provide substantial neuroprotection in part by suppressing secondary brain injury.

Brain damage excitotoxicity lactic acid neuroprotection trauma 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Faden, A. I., Demediuk, P., Panter, S. S., and Vink, R. 1989. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800.Google Scholar
  2. 2.
    Globus, M. Y.-T., Alonso, O., Dietrich, W. D., Busto, R., and Ginsberg, M. D. 1995. Glutamate release and free radical production following brain injury: Effects of post-traumatic hypothermia. J. Neurochem. 65:1704–1711.Google Scholar
  3. 3.
    Gorman, L. K., Pang, K., Frick, K. M., Givens, B., and Olton, D. S. 1994. Acetylcholine release in the hippocampus: Effects of cholinergic and GABAergic compounds in the medial septal area. Neurosci. Lett. 166:199–202.Google Scholar
  4. 4.
    Kawamata, T., Katayama, Y., Hovda, D. A., Yoshino, A., and Becker, D. P. 1995. Lactate accumulation following concussive brain injury: The role of ionic fluxes induced by excitatory amino acids. Brain Res. 674:196–204.Google Scholar
  5. 5.
    Nilsson, P., Hillered, L., Ponten, U., and Ungerstedt, U. 1990. Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J. Cereb. Blood Flow Metab. 10:631–637.Google Scholar
  6. 6.
    Palmer, A. M., Marion, D. W., Botscheller, M. L., Swedlow, P. E., Styren, S. D., and DeKosky, S. T. 1993. Traumatic brain injury-induced excitotoxicity assessed in a controlled cortical impact model. J. Neurochem. 61:2015–2024.Google Scholar
  7. 7.
    Delahunty, T. M. 1992. Mild traumatic brain injury enhances muscarinic receptor-linked inositol phosphate production in rat hippocampus. Brain Res. 594:307–310.Google Scholar
  8. 8.
    Dhillon, H. S., Carbary, T., Dose, J., Dempsey, R. J., and Prasad, M. R. 1995. Activation of phosphatidylinositol bisphosphate signal transduction pathway after experimental brain injury: A lipid study. Brain Res. 698:100–106.Google Scholar
  9. 9.
    Dhillon, H. S., Yang, L., Padmaperuma, B., Dempsey, R. J., Fiscus, R. R., and Renuka Prasad, M. 1995. Regional concentrations of cyclic nucleotides after experimental brain injury. J. Neurotrauma 12:1035–1043.Google Scholar
  10. 10.
    Hayes, R. L., Jenkins, L. W., and Lyeth, B. G. 1992. Neurotransmitter-mediated mechanisms of traumatic brain injury: acetylcholine and excitatory amino acids. J. Neurotrauma 9:S173–S187.Google Scholar
  11. 11.
    Lyeth, B. G., Gong, Q.-Z., Dhillon, H. S., and Prasad, M. R. 1996. Effects of muscarinic receptor antagonism on the phosphatidylinositol bisphosphate signal transduction pathway after experimental brain injury. Brain Res. 742:63–70.Google Scholar
  12. 12.
    Prasad, M. R., Dhillon, H. S., Carbary, T., Dempsey, R. J., and Scheff, S. W. 1994. Enhanced phosphodiestric breakdown of phosphatidylinositol bisphosphate after experimental brain injury. J. Neurochem. 63:773–776.Google Scholar
  13. 13.
    Kristian, T. and Siesjo, B. K. 1998. Calcium in ischemic cell death. Stroke 29:705–718.Google Scholar
  14. 14.
    Vink, R. 1993. Nuclear magnetic resonance characterization of secondary mechanisms following traumatic brain injury. Mol. Chem. Neuropathol. 18:279–297.Google Scholar
  15. 15.
    Prasad, M. P., Ramaiah, C., McIntosh, T. K., Dempsey, R. J., Hipkens, S., and Yurek, D. 1994. Regional levels of lactate and norepinephrine after experimental brain injury. J. Neurochem. 63:1086–1094.Google Scholar
  16. 16.
    Hovda, D. A., Becker, D. P., and Katayama, Y. 1992. Secondary injury and acidosis. J. Neurotrauma 9 (Suppl 1):S47–S60.Google Scholar
  17. 17.
    Dhillon, H. S., Donaldson, D., Dempsey, R. J., and Prasad, M. R. 1994. Regional levels of free fatty acids and Evans blue extravasation after experimental brain injury. J. Neurotrauma 11:405–415.Google Scholar
  18. 18.
    Dhillon, H. S., Dose, J. M., Scheff, S. W., and Prasad, M. R. 1997. Time course of changes in lactate and free fatty acids after experimental brain injury and relationship to morphologic damage. Exp. Neurol. 146:240–249.Google Scholar
  19. 19.
    Balestrino, M., Rebaudo, R., and Lunardi, G. 1999. Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: Dose-effect relationship. Brain Res. 816:124–130.Google Scholar
  20. 20.
    Holtzman, D., Togliatti, A., Khait, I., and Jensen, F. 1998. Creatine increases survival and suppresses seizures in the hypoxic immature rat. Pediatr. Res. 44:410–414.Google Scholar
  21. 21.
    Klivenyi, P., Ferrante, R. J., Matthews, R. T., Bogdanov, M. B., Klein, A. M., Andreassen, O. A., Mueller, G., Wermer, M., Kaddurah-Daouk, R., and Beal, M. F. 1999. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat. Med. 5:347–350.Google Scholar
  22. 22.
    Matthews, R. T., Yang, L., Jenkins, B. G., Ferrante, R. J., Rosen, B. R., Kaddurah-Daouk, R., and Beal, M. F. 1998. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J. Neurosci. 18:156–163.Google Scholar
  23. 23.
    Wilken, B., Ramirez, J. M., Probst, I., Richter, D. W., and Hanefeld, F. 1998. Creatine protects the central respiratory network of mammals under anoxic conditions. Pediatr. Res. 43:8–14.Google Scholar
  24. 24.
    Sullivan, P. G., Geiger, J. D., Mattson, M. P., and Scheff, S. W. 2000. Dietary supplement creatine protects against traumatic brain injury. Ann. Neurol. 48:723–729.Google Scholar
  25. 25.
    Baldwin, S. A. and Scheff, S. W. 1996. Intermediate filament change in astrocytes following mild cortical contusion. Glia 16:266–275.Google Scholar
  26. 26.
    Sullivan, P. G., Keller, J. N., Mattson, M. P., and Scheff, S. W. 1998. Traumatic brain injury alters synaptic homeostasis: Implications for impaired mitochondrial and transport function. J. Neurotrauma 15:789–798.Google Scholar
  27. 27.
    Baldwin, S. A., Fugaccia, I., Brown, D. R., Brown, L. V., and Scheff, S. W. 1996. Blood-brain barrier breach following cortical contusion in the rat. J. Neurosurg. 85:476–481.Google Scholar
  28. 28.
    Baldwin, S. A., Gibson, T., Callihan, C. T., Sullivan, P. G., Palmer, E., and Scheff, S. W. 1997. Neuronal cell loss in the CA3 subfield of the hippocampus following cortical contusion utilizing the optical disector method for cell counting. J. Neurotrauma 14:385–398.Google Scholar
  29. 29.
    Scheff, S. W., Baldwin, S. A., Brown, R. W., and Kraemer, P. J. 1997. Morris water maze deficits in rats following traumatic brain injury: Lateral controlled cortical impact. J. Neurotrauma 14:615–627.Google Scholar
  30. 30.
    Sullivan, P. G., Bruce-Keller, A., Rabchevsky, A. G., Christakos, S., St Clair, D. K., Mattson, M. P., and Scheff, S. W. 1999. Exacerbation of damage and altered NFkB activation in mice lacking tumor necrosis factor receptors following traumatic brain injury. J. Neurosci. 19:6248–6256.Google Scholar
  31. 31.
    Scheff, S. W. and Sullivan, P. G. 1999. Cyclosporin A significantly ameiliorates cortical damage following experimental traumataic brain injury in rodents. J. Neurotrauma 16:783–792.Google Scholar
  32. 32.
    Ponten, U., Ratcheson, R. A., Salford, L. G., and Siesjo, B. K. 1973. Optimal freezing conditions for cerebral metabolites in rats. J. Neurochem. 21:1127–1138.Google Scholar
  33. 33.
    Tzigaret, C., McIntosh, T. K., Okiyama, K., Jenkins, W. L., and Prasad, M. R. 1993. Measurement of hippocampal levels of cellular second messengers following in situ freezing. J. Neurochem. 60:827–834.Google Scholar
  34. 34.
    Bligh, E. G. and Dyer, W. J. 1959. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37:911–917.Google Scholar
  35. 35.
    Dhillon, H. S., Carman, H. M., Zhang, D., Scheff, S. W., and Prasad, M. R. 1999. Severity of experimental brain injury on lactate and free fatty acid accumulation and Evans blue extravasation in the rat cortex and hippocampus. J. Neurotrauma 16:455–469.Google Scholar
  36. 36.
    Katayama, Y., Becker, D. P., Tamura, T., and Hovda, D. A. 1990. Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J. Neurosurg. 73:889–900.Google Scholar
  37. 37.
    McIntosh, T. K. 1993. Novel pharmacologic therapies in the treatment of experimental traumatic brain injury: A review. J. Neurotrauma 10:215–261.Google Scholar
  38. 38.
    Frandsen, A. and Schousboe, A. 1993. Excitatory amino acid-mediated cytotoxicity and calcium homeostasis in cultured neurons. J. Neurochem. 60:1202–1211.Google Scholar
  39. 39.
    Bally, P. R., Cahill, G. F., and Leboeuf, B. 1960. Studies on rat adipose tissue in vitro: V. Effects of glucose and insulin on themetabolism of palmitate-I-C14. J. Biol. Chem. 235:333.Google Scholar
  40. 40.
    Shapiro, B., Chowers, I., and Rose, G. 1955. Assimilation of fatty acids by adipose tissue. Page 347in Frazer, A. C. Biochemical Problems of Lipids, Butterworth, London & Interscience, New York.Google Scholar
  41. 41.
    Brewer, G. J. and Wallimann, T. W. 2000. Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J. Neurochem. 74:1968–1978.Google Scholar
  42. 42.
    Ferrante, R. J., Andreassen, O. A., Jenkins, B. G., Dedeoglu, A., Kuemmerle, S., Kubilus, J. K., Kaddurah-Daouk, R., Hersch, S. M., and Beal, M. F. 2000. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J. Neurosci. 20:4389–4397.Google Scholar
  43. 43.
    Hausmann, O. N., Fouad, K., Wallimann, T., and Schwab, M. E. 2002. Protective effects of oral creatine supplementation on spinal cord injury in rats. Spinal Cord 40:449–456.Google Scholar
  44. 44.
    Zhang, W., Narayanan, M., and Friedlander, R. M. 2003. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann. Neurol. 53:267–270.Google Scholar
  45. 45.
    Ipsiroglu, O. S., Stromberger, C., Ilas, J., Hoger, H., Muhl, A., and Stockler-Ipsiroglu, S. 2001. Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. Life Sci. 69:1805–1815.Google Scholar
  46. 46.
    Guerrero-Ontiveros, M. L. and Wallimann, T. 1998. Creatine supplementation in health and disease: Effects of chronic creatine ingestion in vivo—Down-regulation of the expression of creatine transporter isoforms in skeletal muscle. Mol. Cell Biochem. 184:427–437.Google Scholar
  47. 47.
    Brustovetsky, N., Brustovetsky, T., and Dubinsky, J. M. 2001. On the mechanisms of neuroprotection by creatine and phosphocreatine. J. Neurochem. 76:425–434.Google Scholar
  48. 48.
    Wallimann, T., Wyss, M., Brdiczka, D., Nicolay, K., and Eppenberger, H. M. 1992. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: The ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem. J. 281:21–40.Google Scholar
  49. 49.
    Rabow, L., DeSalles, A. F., Becker, D. P., Yang, M., Kontos, H. A., Ward, J. D., Moulton, R. J., Clifton, G., Gruemer, H. D., Muizelaar, J. P., et al. 1986. CSF brain creatine kinase levels and lactic acidosis in severe head injury. J. Neurosurg. 65:625–629.Google Scholar
  50. 50.
    Marmarou, A. 1992. Intracellular acidosis in human and experimental brain injury. J. Neurotrauma 9 (Suppl 2):S551–S562.Google Scholar
  51. 51.
    McIntosh, T. K., Faden, A. I., Bendall, M. R., and Vink, R. 1987. Traumatic brain injury in the rat: Alterations in brain lactate and pH as characterized by 1H and 31P nuclear magnetic resonance. J. Neurochem. 49:1530–1540.Google Scholar
  52. 52.
    Vink, R., McIntosh, T. K., Weiner, M. W., and Faden, A. I. 1987. Effects of traumatic brain injury on cerebral high-energy phosphates and pH: A 31P magnetic resonance spectroscopy study. J. Cereb. Blood Flow Metab. 7:563–571.Google Scholar
  53. 53.
    McIntosh, T. K., Vink, R., Noble, L., Yamakami, I., Fernyak, S., Soares, H., and Faden, A. L. 1989. Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience 28:233–244.Google Scholar
  54. 54.
    Ishige, N., Pitts, L. H., Berry, I., Nishimura, M. C., and James, T. L. 1988. The effects of hypovolemic hypotension on high-energy phosphate metaboism of traumatized brain in rats. J. Neurosurg. 68:129–136.Google Scholar
  55. 55.
    Dhillon, H. S., Dose, J., and Prasad, M. R. 1998. Amphetamine administration improves neurochemical outcome of lateral fluid percussion injury in the rat. Brain Res. 804:231–237.Google Scholar
  56. 56.
    Prasad, M. R., Laabich, A., Dhillon, H. S., Zhang, L., Maki, A., Clerici, W. J., Hicks, R., Butcher, J., and Barron, S. 1997. Effects of six weeks of chronic ethanol administration on lactic acid accumulatiojn and high energy phosphate levels after experimental brain injury in rats. J. Neurotrauma 14:919–930.Google Scholar
  57. 57.
    Dhillon, H. S. and Prasad, M. R. 1999. Kynurenate attenuates the accumulation of diacylglycerol and free fatty acids after experimental brain injury in the rat. Brain Res. 832:7–12.Google Scholar
  58. 58.
    Gennarelli, T. A. 1994. Animate models of human head injury. J. Neurotrauma 11:357–368.Google Scholar

Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  1. 1.Sanders-Brown Center on AgingUniversity of KentuckyLexington

Personalised recommendations