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Neurotoxicity Research

, Volume 25, Issue 2, pp 226–234 | Cite as

Neuroprotective Effects of Rosmarinic Acid on Ciguatoxin in Primary Human Neurons

  • N. Braidy
  • A. Matin
  • F. Rossi
  • M. Chinain
  • D. Laurent
  • G. J. Guillemin
Original Article

Abstract

Ciguatoxin (CTX), is a toxic compound produced by microalgae (dinoflagellate) Gambierdiscus spp., and is bio-accumulated and bio-transformed through the marine food chain causing neurological deficits. To determine the mechanism of CTX-mediated cytotoxicity in human neurons, we measured extracellular lactate dehydrogenase (LDH) activity, intracellular levels of nicotinamide adenine dinucleotide (NAD+) and H2AX phosphorylation at serine 139 as a measure for DNA damage in primary cultures of human neurons treated with Pacific (P)-CTX-1B and P-CTX-3C. We found these marine toxins can induce a time and dose-dependent increase in extracellular LDH activity, with a concomitant decline in intracellular NAD+ levels and increased DNA damage at the concentration range of 5–200 nM. We also showed that pre- and post-treatment with rosmarinic acid (RA), the active constituent of the Heliotropium foertherianum (Boraginaceae) can attenuate CTX-mediated neurotoxicity. These results further highlight the potential of RA in the treatment of CTX-induced neurological deficits.

Keywords

Ciguatera Ciguatoxin DNA damage NAD+ Neurotoxicity Rosmarinic acid 

Notes

Acknowledgements

Dr Fanny Rossi was supported by a CIFRE grant from the Pacific Biotech company subsidised by the ANRT (No 1005/2010). Financial support was also insured by Tahiti Fa.’ahotu. Dr Nady Braidy is the recipient of the Alzheimer’s Australia Viertel Foundation and the National Health and Medical Research Early Career Postdoctoral Research Fellowship at the University of New South Wales. The National Health and Medical Research Council and the Australian Research Council also supported this research.

Conflict of interest

There is no conflict of interest in the reported work.

References

  1. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357:593–615PubMedCrossRefGoogle Scholar
  2. Bagnis R, Spiegel A, Boutin JP, Burucoa C, Nguyen L, Cartel JL, Capdevielle P, Imbert P, Prigent D, Gras C et al (1992) Evaluation of the efficacy of mannitol in the treatment of ciguatera in French Polynesia. Medecine tropicale: revue du Corps de sante colonial 52:67–73Google Scholar
  3. Barnett CB, DiPalma JA (2004) Foodborne illness: seafood intoxication. Pract Gastroenterol 4:58–62Google Scholar
  4. Benoit E, Laurent D, Mattei C, Legrand AM, Molgo J (2000) Reversal of Pacific ciguatoxin-1B effects on myelinated axons by agents used in ciguatera treatment. Cybium 24:33–40Google Scholar
  5. Berlin RM, King SL, Blythe DG (1992) Symptomatic improvement of chronic fatigue with fluoxetine in ciguatera fish poisoning. Med J Aust 157:567PubMedGoogle Scholar
  6. Bernofsky C, Swan M (1973) An improved cycling assay for nicotinamide adenine dinucleotide. Anal Biochem 53:452–458PubMedCrossRefGoogle Scholar
  7. Blythe DG, De Sylva DP, Fleming LE, Ayyar RA, Baden DG, Shrank K (1992) Clinical experience with i.v. mannitol in the treatment of ciguatera. Bull Soc Pathol Exot 85:425–426PubMedGoogle Scholar
  8. Bourdy G, Cabalion P, Amade P, Laurent D (1992) Traditional remedies used in the Western Pacific for the treatment of ciguatera poisoning. J Ethnopharmacol 36:163–174PubMedCrossRefGoogle Scholar
  9. Boyarsky LL, Rayner MD (1970) Effect of ciguatera toxin on aplysia neurons. Proc Soc Exp Biol Med 134:332PubMedCrossRefGoogle Scholar
  10. Bradford MM (1976) A rapid and sensitive method for quantitation of microgram quantities of protein utilising the principle of protein-dye binding. Anal Biochem 53:452–458Google Scholar
  11. Braidy N, Guillemin G, Grant R (2008) Promotion of cellular NAD+ anabolism: therapeutic potential for oxidative stress in ageing and Alzheimer’s disease. Neurotox Res 13:173–184PubMedCrossRefGoogle Scholar
  12. Braidy N, Grant R, Adams S, Brew BJ, Guillemin GJ (2009) Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res 16:77–86PubMedCrossRefGoogle Scholar
  13. Braidy N, Guillemin G, Mansour H, Chan-Ling T, Poljak A, Grant R (2011) Age related changes in NAD+ metabolism, oxidative stress and Sirt1 activity in wistar rats. PLOSONE 6:e19194CrossRefGoogle Scholar
  14. Braidy N, Jayasena T, Poljak A, Sachdev PS (2012) Sirtuins in cognitive ageing and Alzheimer’s disease. Curr Opin Psychiatry 25:226–230PubMedCrossRefGoogle Scholar
  15. Braidy N, Gai WP, Xu YH, Sachdev P, Guillemin GJ, Jiang XM, Ballard JW, Horan MP, Fang ZM, Chong BH, Chan DK (2013) Alpha-synuclein transmission and mitochondrial toxicity in primary human foetal enteric neurons in vitro. Neurotox Res. doi: 10.1007/s12640-013-9420-5 Google Scholar
  16. Bult H, Herman AG, Rampart M (1985) Modification of endotoxin-induced haemodynamic and haematological changes in the rabbit by methylprednisolone, F(ab’)2 fragments and rosmarinic acid. Br J Pharmacol 84:317–327PubMedCrossRefGoogle Scholar
  17. Cameron J, Capra MF (1993) The basis of the paradoxical disturbance of temperature perception in ciguatera poisoning. J Toxicol Clin Toxicol 31:571–579PubMedCrossRefGoogle Scholar
  18. Cameron J, Flowers AE, Capra MF (1991) Effects of ciguatoxin on nerve excitability in rats (Part I). J Neurol Sci 101:87–92PubMedCrossRefGoogle Scholar
  19. Chen J, Cohen ML, Lerner AJ, Yang Y, Herrup K (2010) DNA damage and cell cycle events implicate cerebellar dentate nucleus neurons as targets of Alzheimer’s disease. Mol Neurodegener 5:60PubMedCentralPubMedCrossRefGoogle Scholar
  20. Chiu AS, Gehringer MM, Braidy N, Guillemin GJ, Welch JH, Neilan BA (2012) Excitotoxic potential of the cyanotoxin beta-methyl-amino-l-alanine (BMAA) in primary human neurons. Toxicon 60:1159–1165PubMedCrossRefGoogle Scholar
  21. Chiu AS, Gehringer MM, Braidy N, Guillemin GJ, Welch JH, Neilan BA (2013) Gliotoxicity of the cyanotoxin, beta-methyl-amino-l-alanine (BMAA). Sci Rep 3:1482PubMedCentralPubMedGoogle Scholar
  22. de Haro L, Pommier P, Valli M (2003) Emergence of imported ciguatera in Europe: report of 18 cases at the poison control centre of Marseille. J Toxicol Clin Toxicol 41:927–930PubMedCrossRefGoogle Scholar
  23. Dechraoui MY, Naar J, Pauillac S, Legrand AM (1999) Ciguatoxins and brevetoxins, neurotoxic polyether compounds active on sodium channels. Toxicon 37:125–143PubMedCrossRefGoogle Scholar
  24. Fadel O, El Kirat K, Morandat S (2011) The natural antioxidant rosmarinic acid spontaneously penetrates membranes to inhibit lipid peroxidation in situ. Biochim Biophys Acta 1808:2973–2980PubMedCrossRefGoogle Scholar
  25. Fleming LE, Broad K, Clement A, Dewailly E, Elmir S, Knap A, Pomponi SA, Smith S, Gabriele HS, Walsh P (2006) Oceans and human health: emerging public health risks in the marine environment. Mar Pollut Bull 53:545–560PubMedCentralPubMedCrossRefGoogle Scholar
  26. Friedman MA, Fleming LE, Fernandez M, Bienfang P, Schrank K, Dickey R, Bottein MY, Backer L, Ayyar R, Weisman R, Watkins S, Granade R, Reich A (2008) Ciguatera fish poisoning: treatment, prevention and management. Mar Drugs 6:456–479PubMedCentralPubMedCrossRefGoogle Scholar
  27. Garrec RBL, Benoit E, Sauviat MP, Lewis RJ, Molgo J, Laurent D (2005) Ability of some plant extracts, traditionally used to treat ciguatera fish poisoning, to prevent the in vitro neurotoxicity produced by sodium channel activators. Toxicon 46:625–634CrossRefGoogle Scholar
  28. Grant RS, Kapoor V (1998) Murine glial cells regenerate NAD, after peroxide-induced depletion, using either nicotinic acid, nicotinamide, or quinolinic acid as substrates. J Neurochem 70:1759–1763PubMedCrossRefGoogle Scholar
  29. Guillemin GJ, Smythe G, Takikawa O, Brew BJ (2005) Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 49:15–23PubMedCrossRefGoogle Scholar
  30. Guillemin GJ, Cullen KM, Lim CK, Smythe GA, Garner B, Kapoor V, Takikawa O, Brew BJ (2007) Characterization of the kynurenine pathway in human neurons. J Neurosci 27:12884–12892PubMedCrossRefGoogle Scholar
  31. Heales SJ, Barker JE, Stewart VC, Brand MP, Hargreaves IP, Foppa P, Land JM, Clark JB, Bolanos JP (1997) Nitric oxide, energy metabolism and neurological disease. Biochem Soc Trans 25:939–943PubMedGoogle Scholar
  32. Hokama Y, Takenaka WE, Nishimura KL, Ebesu JSM, Bourke R, Sullivan PK (1998) A simple membrane immunobead assay for detecting ciguatoxin and related polyethers from human ciguatera intoxication and natural reef fishes. J AOAC Int 81:727–735PubMedGoogle Scholar
  33. Huang X, Tanaka T, Kurose A, Traganos F, Darzynkiewicz Z (2006) Constitutive histone H2AX phosphorylation on Ser-139 in cells untreated by genotoxic agents is cell-cycle phase specific and attenuated by scavenging reactive oxygen species. Int J Oncol 29:495–501PubMedGoogle Scholar
  34. Koh JY, Choi DW (1987) Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods 20:83–90PubMedCrossRefGoogle Scholar
  35. Kumar-Roine S, Darius HT, Matsui M, Fabre N, Haddad M, Chinain M, Pauillac S, Laurent D (2011) A review of traditional remedies of ciguatera fish poisoning in the Pacific. Phytother Res 25:947–958PubMedCrossRefGoogle Scholar
  36. Kuruuzum-Uz A, Suleyman H, Cadirci E, Guvenalp Z, Demirezer LO (2012) Investigation on anti-inflammatory and antiulcer activities of Anchusa azurea extracts and their major constituent rosmarinic acid. Z Naturforsch C 67:360–366PubMedCrossRefGoogle Scholar
  37. Lange WR, Snyder FR, Fudala PJ (1992) Travel and ciguatera fish poisoning. Arch Intern Med 152:2049–2053PubMedCrossRefGoogle Scholar
  38. LePage KT, Rainier JD, Johnson HW, Baden DG, TF M (2007) Gambierol acts as a functional antagonist of neurotoxin site 5 on voltage-gated sodium channels in cerebellar granule neurons. J Pharmacol Exp Ther 323:174–179PubMedCentralPubMedCrossRefGoogle Scholar
  39. Lewis RJ (2006) Ciguatera: Australian perspectives on a global problem. Toxicon 48:799–809PubMedCrossRefGoogle Scholar
  40. Lewis RJ, Endean R (1984) Ciguatoxin from the flesh and viscera of the barracuda, Sphyraena jello. Toxicon 22:805–810PubMedCrossRefGoogle Scholar
  41. Lewis RJ, Holmes MJ (1993) Origin and transfer of toxins involved in ciguatera. Comp Biochem Physiol C 106:615–628PubMedGoogle Scholar
  42. Lewis RJ, Ruff TA (1993) Ciguatera—ecological, clinical, and socioeconomic perspectives. Crit Rev Environ Sci Technol 23:137–156CrossRefGoogle Scholar
  43. Lewis RJ, Hoy AWW, Sellin M (1993) Ciguatera and mannitol—in-vivo and in-vitro assessment in mice. Toxicon 31:1039–1050PubMedCrossRefGoogle Scholar
  44. Lombet A, Bidard JN, Lazdunski M (1987) Ciguatoxin and brevetoxins share a common receptor-site on the neuronal voltage-dependent Na-(+) channel. FEBS Lett 219:355–359PubMedCrossRefGoogle Scholar
  45. Matsui M, Kumar-Roine S, Darius HT, Chinain M, Laurent D, Pauillac S (2009) Characterisation of the anti-inflammatory potential of Vitex trifolia L. (Labiatae), a multipurpose plant of the Pacific traditional medicine. J Ethnopharmacol 126:427–433PubMedCrossRefGoogle Scholar
  46. Matsui M, Kumar-Roine S, Darius HT, Chinain M, Laurent D, Pauillac S (2010) Pacific ciguatoxin 1B-induced modulation of inflammatory mediators in a murine macrophage cell line. Toxicon 56:776–784PubMedCrossRefGoogle Scholar
  47. Mattei C, Wen PJ, Nguyen-Huu TD, Alvarez M, Benoit E, Bourdelais AJ, Lewis RJ, Baden DG, Molgo J, Meunier FA (2008) Brevenal inhibits pacific ciguatoxin-1B-induced neurosecretion from bovine chromaffin cells. PLoS ONE 3:e3448PubMedCentralPubMedCrossRefGoogle Scholar
  48. Ng S, Gregory J (2000) An outbreak of ciguatera fish poisoning in Victoria. Commun Dis Intell 24:344–346PubMedGoogle Scholar
  49. Oh HA, Park CS, Ahn HJ, Park YS, Kim HM (2011) Effect of Perilla frutescens var. acuta Kudo and rosmarinic acid on allergic inflammatory reactions. Exp Biol Med 236:99–106CrossRefGoogle Scholar
  50. Palafox NA, Jain LG, Pinano AZ, Gulick TM, Williams RK, Schatz IJ (1988) Successful treatment of ciguatera fish poisoning with intravenous mannitol. JAMA 259:2740–2742PubMedCrossRefGoogle Scholar
  51. Pearn JH, Lewis RJ, Ruff T, Tait M, Quinn J, Murtha W, King G, Mallett A, Gillespie NC (1989) Ciguatera and mannitol: experience with a new treatment regimen. Med J Aust 151:77–80PubMedGoogle Scholar
  52. Perez CM, Vasquez PA, Perret CF (2001) Treatment of ciguatera poisoning with gabapentin. N Engl J Med 344:692–693PubMedCrossRefGoogle Scholar
  53. Perez S, Vale C, Alonso E, Fuwa H, Sasaki M, Konno Y, Goto T, Suga Y, Vieytes MR, Botana LM (2012) Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study. Chem Res Toxicol 25:1929–1937PubMedCrossRefGoogle Scholar
  54. Pietsch K, Saul N, Chakrabarti S, Sturzenbaum SR, Menzel R, Steinberg CE (2011) Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology 12:329–347PubMedCrossRefGoogle Scholar
  55. Raikhlin-Eisenkraft B, Bentur Y (2002) Rabbittish (“aras”): an unusual source of ciguatera poisoning. Isr Med Assoc J 4:28–30PubMedGoogle Scholar
  56. Rossi F, Jullian V, Pawlowiez R, Kumar-Roine S, Haddad M, Darius HT, Gaertner-Mazouni N, Chinain M, Laurent D (2012) Protective effect of Heliotropium foertherianum (Boraginaceae) folk remedy and its active compound, rosmarinic acid, against a Pacific ciguatoxin. J Ethnopharmacol 143:33–40PubMedCrossRefGoogle Scholar
  57. Salimei PS, Marfe G, Di Renzo L, Di Stefano C, Giganti MG, Filomeni G, Ciriolo MR (2007) The interference of rosmarinic acid in the DNA fragmentation induced by osmotic shock. Front Biosci 12:1308–1317PubMedCrossRefGoogle Scholar
  58. Sauviat MP, Garrec RBL, Masson JB, Lewis RL, Vernoux JP, Molgo J, Laurent D, Benoit E (2006) Mechanisms involved in the swelling of erythrocytes caused by Pacific and Caribbean ciguatoxins. Blood Cell Mol Dis 36:1–9CrossRefGoogle Scholar
  59. Sayer A, Hu Q, Bourdelais AJ, Baden DG, Gibson JE (2005) The effect of brevenal on brevetoxin-induced DNA damage in human lymphocytes. Arch Toxicol 79:683–688PubMedCentralPubMedCrossRefGoogle Scholar
  60. Schnorf H, Taurarii M, Cundy T (2002) Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy. Neurology 58:873–880PubMedCrossRefGoogle Scholar
  61. Sharmila R, Manoharan S (2012) Anti-tumor activity of rosmarinic acid in 7,12-dimethylbenz(a)anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. Indian J Exp Biol 50:187–194PubMedGoogle Scholar
  62. Shoemaker RC, House D, Ryan JC (2010) Defining the neurotoxin derived illness chronic ciguatera using markers of chronic systemic inflammatory disturbances: a case/control study. Neurotoxicol Teratol 32:633–639PubMedCrossRefGoogle Scholar
  63. Swarup V, Ghosh J, Ghosh S, Saxena A, Basu A (2007) Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis. Antimicrob Agents Chemother 51:3367–3370PubMedCentralPubMedCrossRefGoogle Scholar
  64. Tavafi M, Ahmadvand H (2011) Effect of rosmarinic acid on inhibition of gentamicin induced nephrotoxicity in rats. Tissue Cell 43:392–397PubMedCrossRefGoogle Scholar
  65. Terao K, Ito E, Oarada M, Ishibashi Y, Legrand AM, Yasumoto T (1991) Light and electron microscopic studies of pathologic changes induced in mice by ciguatoxin poisoning. Toxicon 29:633–643PubMedCrossRefGoogle Scholar
  66. Virag L, Salzman AL, Szabo C (1998) Poly(ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death. J Immunol 161:3753–3759PubMedGoogle Scholar
  67. Wang J, Xu H, Jiang H, Du X, Sun P, Xie J (2012) Neurorescue effect of rosmarinic acid on 6-hydroxydopamine-lesioned nigral dopamine neurons in rat model of Parkinson’s disease. J Mol Neurosci 47:113–119PubMedCrossRefGoogle Scholar
  68. Yang JL, Tadokoro T, Keijzers G, Mattson MP, Bohr VA (2010) Neurons efficiently repair glutamate-induced oxidative DNA damage by a process involving CREB-mediated up-regulation of apurinic endonuclease 1. J Biol Chem 285:28191–28199PubMedCrossRefGoogle Scholar
  69. Yasumoto T (2005) Chemistry, etiology, and food chain dynamics of marine toxins. Proc Jpn Acad B 81:43–51CrossRefGoogle Scholar
  70. Yasumoto T, Murata M (1993) Marine toxins. Chem Rev 93:1897–1909CrossRefGoogle Scholar
  71. Yu SW, Wang H, Poitras MF (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–263PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • N. Braidy
    • 1
  • A. Matin
    • 2
  • F. Rossi
    • 3
    • 4
    • 5
    • 6
  • M. Chinain
    • 7
  • D. Laurent
    • 3
    • 4
  • G. J. Guillemin
    • 8
  1. 1.Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of MedicineUniversity of New South WalesSydneyAustralia
  2. 2.Department of Pharmacology, School of Medical Sciences, Faculty of MedicineUniversity of NSWSydneyAustralia
  3. 3.Université de Toulouse, UPS, UMR-152 (Pharma-Dev)Toulouse Cedex 9France
  4. 4.Institut de Recherche pour le Développement (IRD), UMR-152PapeeteFrench Polynesia
  5. 5.Pacific Biotech SASArueFrench Polynesia
  6. 6.Ecosystèmes Insulaires Océaniens, UMR-241Université de la Polynésie françaiseFaa’aFrench Polynesia
  7. 7.Ecosystèmes Insulaires Océaniens, UMR-241, Laboratoire de Recherche sur les Microalgues ToxiquesInstitut Louis MalardéPapeeteFrench Polynesia
  8. 8.Neuroinflammation group, MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced MedicineMacquarie UniversityNorth RydeAustralia

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