Neurochemical Research

, Volume 36, Issue 3, pp 467–475 | Cite as

Carnosine Protects Against the Neurotoxic Effects of a Serotonin-Derived Melanoid

  • Tanner D. Brownrigg
  • Christopher S. Theisen
  • Eugene E. Fibuch
  • Norbert W. Seidler
Original Paper

Abstract

Anesthesia-related postoperative cognitive dysfunction (POCD) leads to morbidity in the elderly. Lipid peroxidative byproducts (i.e. acrolein) accumulate in aging and may play a role. Sevoflurane, an inhaled anesthetic, sequesters acrolein and enhances the formation of a serotonin-derived melanoid (SDM). SDM may be a biologically relevant polymeric melanoid that we previously showed exhibits redox activity and disrupts lipid bilayers. In this study, we examined the toxicity of SDM in cell culture and looked at protection using L-carnosine. SDM’s toxic effects were tested on neuronal-like SH-SY5Y cells, causing an exponential decrease in viability, while human dermal fibroblasts were completely resistant to the toxic effects. SDM brought about morphological changes to differentiated SH-SY5Y cells, particularly to neuronal processes. Co- but not pre-treatment with L-carnosine protected differentiated SH-SY5Y cells exposed to SDM. Our mechanism suggests focal sevoflurane-induced sequestration of age-related acrolein leading to SDM synthesis and neuronal impairment, which is prevented by L-carnosine.

Keywords

Postoperative cognitive dysfunction L-Carnosine Serotonin Acrolein Neurotoxicity Inhaled anesthetics 

Notes

Acknowledgments

This study was supported in part by research funds from Kansas City University of Medicine and Biosciences and the Department of Anesthesiology, University of Missouri, Kansas City/Saint Luke’s Hospital, Kansas City, Missouri. The authors acknowledge Jessica Kim and Rachel High for participating in some of the experiments. The authors thank Drs. Asma Zaidi and Alex Shnyra for providing cells and technical advice.

References

  1. 1.
    Steinmetz J, Christensen KB, Lund T et al (2009) Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110:548–555CrossRefPubMedGoogle Scholar
  2. 2.
    Bohnen N, Warner MA, Kokmen E et al (1994) Early and midlife exposure to anesthesia and age of onset of Alzheimer’s disease. Int J Neurosci 77:181–185CrossRefPubMedGoogle Scholar
  3. 3.
    Carnini A, Eckenhoff MF, Eckenhoff RG (2006) Interactions of volatile anesthetics with neurodegenerative-disease-associated proteins. Anesthesiol Clin 24:381–405CrossRefPubMedGoogle Scholar
  4. 4.
    Xie Z, Tanzi RE (2006) Alzheimer’s disease and post-operative cognitive dysfunction. Exp Gerontol 41:346–359CrossRefPubMedGoogle Scholar
  5. 5.
    Baranov D, Bickler PE, Crosby GJ et al (2009) Consensus statement: first international workshop on anesthetics and Alzheimer’s disease. Anesth Analg 108:1627–1630CrossRefPubMedGoogle Scholar
  6. 6.
    Kalenka A, Gross B, Maurer MH et al (2010) Isoflurane anesthesia elicits protein pattern changes in rat hippocampus. J Neurosurg Anesthesiol 22:144–154CrossRefPubMedGoogle Scholar
  7. 7.
    Roberts RD, Fibuch EE, Elisabeth Heal M et al (2007) Production of a novel neuromelanin at the sevoflurane-water interface. Biochem Biophys Res Commun 363:77–81CrossRefPubMedGoogle Scholar
  8. 8.
    Whittington RA, Virag L (2006) Isoflurane decreases extracellular serotonin in the mouse hippocampus. Anesth Analg 103:92–98CrossRefPubMedGoogle Scholar
  9. 9.
    Sambeth A, Riedel WJ, Tillie DE et al (2009) Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink. J Psychopharmacol 23:56–64CrossRefPubMedGoogle Scholar
  10. 10.
    Jones CE, Underwood CK, Coulson EJ et al (2007) Copper induced oxidation of serotonin: analysis of products and toxicity. J Neurochem 102:1035–1043CrossRefPubMedGoogle Scholar
  11. 11.
    Wrona MZ, Goyal RN, Turk DJ et al (1992) 5, 5′-Dihydroxy-4, 4′-bitryptamine: a potentially aberrant, neurotoxic metabolite of serotonin. J Neurochem 59:1392–1398CrossRefPubMedGoogle Scholar
  12. 12.
    Williams TI, Lynn BC, Markesbery WR et al (2006) Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 27:1094–1099CrossRefPubMedGoogle Scholar
  13. 13.
    Shamoto-Nagai M, Maruyama W, Hashizume Y et al (2007) In parkinsonian substantia nigra, alpha-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity. J Neural Transm 114:1559–1567CrossRefPubMedGoogle Scholar
  14. 14.
    Murphy MM, Miller ED, Fibuch EE et al (2010) Redox mechanism of neurotoxicity by a serotonin-acrolein polymeric melanoid. Neurotox Res (in press)Google Scholar
  15. 15.
    Miller ED, Fibuch EE, Seidler NW (2010) Toxicity of a serotonin-derived neuromelanin. Biochem Biophys Res Commun 391:1297–1300CrossRefPubMedGoogle Scholar
  16. 16.
    Hipkiss AR (2009) Carnosine and its possible roles in nutrition and health. Adv Food Nutr Res 57:87–154CrossRefPubMedGoogle Scholar
  17. 17.
    Fields R, Dixon HB (1971) Micro method for determination of reactive carbonyl groups in proteins and peptides, using 2, 4-dinitrophenylhydrazine. Biochem J 121:587–589PubMedGoogle Scholar
  18. 18.
    Cheung YT, Lau WK, Yu MS et al (2009) Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research. Neurotoxicology 30:127–135CrossRefPubMedGoogle Scholar
  19. 19.
    Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA 73:2424–2428CrossRefPubMedGoogle Scholar
  20. 20.
    Nguyen A, Gille G, Moldzio R et al (2002) Synthetic neuromelanin is toxic to dopaminergic cell cultures. J Neural Transm 109:651–661CrossRefPubMedGoogle Scholar
  21. 21.
    Wakamatsu K, Fujikawa K, Zucca FA et al (2003) The structure of neuromelanin as studied by chemical degradative methods. J Neurochem 86:1015–1023CrossRefPubMedGoogle Scholar
  22. 22.
    Volicer L, Chen JC, Crino PB et al (1989) Neurotoxic properties of a serotonin oxidation product: possible role in Alzheimer’s disease. Prog Clin Biol Res 317:453–465PubMedGoogle Scholar
  23. 23.
    Zecca L, Bellei C, Costi P et al (2008) New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals. Proc Natl Acad Sci USA 105:17567–17572CrossRefPubMedGoogle Scholar
  24. 24.
    Seidler NW, Yeargans GS (2004) Albumin-bound polyacrolein: implications for Alzheimer’s disease. Biochem Biophys Res Commun 320:213–217CrossRefPubMedGoogle Scholar
  25. 25.
    Seelig J, Macdonald PM, Scherer PG (1987) Phospholipid head groups as sensors of electric charge in membranes. Biochemistry 26:7535–7541CrossRefPubMedGoogle Scholar
  26. 26.
    Ansell GB, Spanner S (1982) Phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. In: Hawthorne JN (ed) Phospholipids. Elsevier Biomedical Press, Sole distributors for the USA and Canada, Elsevier Science Pub. Co., Amsterdam, New York, NYGoogle Scholar
  27. 27.
    Marcucci H, Paoletti L, Jackowski S et al (2010) Phosphatidylcholine biosynthesis during neuronal differentiation and its role in cell fate determination. J Biol Chem 285:25382–25393CrossRefPubMedGoogle Scholar
  28. 28.
    Kohen R, Yamamoto Y, Cundy KC et al (1988) Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proc Natl Acad Sci USA 85:3175–3179CrossRefPubMedGoogle Scholar
  29. 29.
    Severin ES, Kondratyev AD (1988) Regulation of differentiation of PC12 cells by nerve growth factor. Adv Enzyme Regul 27:357–370CrossRefPubMedGoogle Scholar
  30. 30.
    Hobart LJ, Seibel I, Yeargans GS et al (2004) Anti-crosslinking properties of carnosine: significance of histidine. Life Sci 75:1379–1389CrossRefPubMedGoogle Scholar
  31. 31.
    Carini M, Aldini G, Beretta G et al (2003) Acrolein-sequestering ability of endogenous dipeptides: characterization of carnosine and homocarnosine/acrolein adducts by electrospray ionization tandem mass spectrometry. J Mass Spectrom 38:996–1006CrossRefPubMedGoogle Scholar
  32. 32.
    Seidler NW, Shokry SS, Nauth J (2001) Properties of a glycation product derived from carnosine. J Biochem Mol Biol Biophys 5:153–162Google Scholar
  33. 33.
    Oh YM, Jang EH, Ko JH et al (2009) Inhibition of 6-hydroxydopamine-induced endoplasmic reticulum stress by l-carnosine in SH-SY5Y cells. Neurosci Lett 459:7–10CrossRefPubMedGoogle Scholar
  34. 34.
    Fonteh AN, Harrington RJ, Tsai A et al (2007) Free amino acid and dipeptide changes in the body fluids from Alzheimer’s disease subjects. Amino Acids 32:213–224CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Tanner D. Brownrigg
    • 1
  • Christopher S. Theisen
    • 2
  • Eugene E. Fibuch
    • 1
  • Norbert W. Seidler
    • 2
  1. 1.Department of AnesthesiologyUniversity of Missouri-Kansas City School of MedicineKansas CityUSA
  2. 2.Department of BiochemistryKansas City University of Medicine and BiosciencesKansas CityUSA

Personalised recommendations