Advertisement

Inflammopharmacology

, Volume 20, Issue 1, pp 39–48 | Cite as

Acamprosate modulates experimental autoimmune encephalomyelitis

  • Z. Sternberg
  • A. Cesario
  • K. Rittenhouse-Olson
  • R. A. Sobel
  • O. Pankewycz
  • B. Zhu
  • T. Whitcomb
  • D. S. Sternberg
  • F. E. Munschauer
Research Article

Abstract

Objective

This pilot study aimed to determine the efficacy of acamprosate (N-acetyl homotaurine) in reducing the pathological features of experimental autoimmune encephalomyelitis (EAE) which is an animal model for multiple sclerosis (MS).

Background

The amino acid taurine has multiple biological activities including immunomodulation and neuromodulation. The synthetic acetylated taurine derivative, acamprosate, which crosses the blood–brain barrier more readily compared to taurine, is currently being used for the prevention of alcohol withdrawal symptoms associated with enhanced glutamatergic receptor function and GABA receptor hypofunction.

Methods

EAE was induced in C57BL/6 female mice with myelin oligodendrocyte glyocoprotein, amino acid 35–55. Mice were treated with 20, 100 and 500 mg/kg acamprosate for 21 days.

Results

Neurological scores at disease peak were reduced by 21, 64 and 9% in the 20, 100 and 500 mg/kg groups, respectively. Neurological improvement in the 100 mg/kg group correlated with a reduction in numbers of inflammatory lesions and the extent of CNS demyelination. Blood TNF-α levels were significantly reduced in the 500 mg/kg group.

Discussion

Acamprosate and other taurine analogs have a potential for future MS therapy.

Keywords

Acamprosate Body weight EAE Multiple sclerosis Taurine Tumor necrosis factor-α 

Abbreviations

NMDA

N-Methyl-d-aspartic acid

GABA

Gamma-aminobutyric acid

EAE

Experimental autoimmune encephalomyelitis

MOG

Myelin oligodendrocyte glycoprotein

CFA

Complete Freund’s adjuvant

ELISA

Enzyme-linked immunosorbent assay

LPS

Lipopolysaccharide

PBS

Phosphate buffer saline

TNF-α

Tumor necrosis factor-α

PI

Postimmunization

Notes

Acknowledgments

The study was supported by grants from Jog For The Jake (grant # 9333-521926) and from the National Multiple Sclerosis Society (grant # RG-4278).

References

  1. Barua M, Liu Y, Quinn MR (2001) Taurine chloramine inhibits inducible nitric oxide synthase and TNF-alpha gene expression in activated alveolar macrophages: decreased NF-kappaB activation and IkappaB kinase activity. J Immunol 167:2275–2281PubMedGoogle Scholar
  2. Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, Steinman L (2010) Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci USA 107:2580–2585PubMedCrossRefGoogle Scholar
  3. Bolton C, Paul C (1997) MK-801 limits neurovascular dysfunction during experimental allergic encephalomyelitis. J Pharmacol Exp Ther 282:397–402PubMedGoogle Scholar
  4. Bowers MS, Chen BT, Chou JK, Osborne MP, Gass JT, See RE, Bonci A, Janak PH, Olive MF (2007) Acamprosate attenuates cocaine- and cue-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology (Berl) 195:397–406CrossRefGoogle Scholar
  5. Brasser SM, McCaul ME, Houtsmuller EJ (2004) Alcohol effects during acamprosate treatment: a dose-response study in humans. Alcohol Clin Exp Res 28:1074–1083PubMedCrossRefGoogle Scholar
  6. Burattini C, McGeehan AJ, Griffin WC 3rd, Gass JT, Kinder JR, Janak PH, Olive MF (2008) A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration. Addict Biol 13:70–79PubMedCrossRefGoogle Scholar
  7. Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, D’Amelio M, Cavallucci V, Martorana A, Bergamaschi A, Cencioni MT, Diamantini A, Butti E, Comi G, Bernardi G, Cecconi F, Battistini L, Furlan R, Martino G (2009) Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci 29:3442–3452PubMedCrossRefGoogle Scholar
  8. Centonze D, Muzio L, Rossi S, Furlan R, Bernardi G, Martino G (2010) The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ 17:1083–1091PubMedCrossRefGoogle Scholar
  9. Courtyn J, Cornelissen B, Oltenfreiter R, Vandecapelle M, Slegers G, Strijckmans K (2004) Synthesis and assessment of [11C]acetylhomotaurine as an imaging agent for the study of the pharmacodynamic properties of acamprosate by positron emission tomography. Nucl Med Biol 31:649–654PubMedCrossRefGoogle Scholar
  10. Czachowski CL, Delory MJ (2009) Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats. Psychopharmacology (Berl) 204:335–348CrossRefGoogle Scholar
  11. Dahchour A, De Witte P (2000) Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 60:343–362PubMedCrossRefGoogle Scholar
  12. De Witte P (2004) Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol. Addict Behav 29:1325–1339PubMedCrossRefGoogle Scholar
  13. Engelhard K, Werner C, Lu H, Mollenberg O, Zieglgansberger W, Kochs E (2000) The neuroprotective effect of the glutamate antagonist acamprosate following experimental cerebral ischemia. A study with the lipid peroxidase inhibitor u-101033e. Anaesthesist 49:816–821PubMedCrossRefGoogle Scholar
  14. Gupta RC, Win T, Bittner S (2005) Taurine analogues; a new class of therapeutics: retrospect and prospects. Curr Med Chem 12:2021–2039PubMedCrossRefGoogle Scholar
  15. Kanayama A, Inoue J, Sugita-Konishi Y, Shimizu M, Miyamoto Y (2002) Oxidation of Ikappa Balpha at methionine 45 is one cause of taurine chloramine-induced inhibition of NF-kappa B activation. J Biol Chem 277:24049–24056PubMedCrossRefGoogle Scholar
  16. Kast RE, Altschuler EL (2007) Consideration of acamprosate for treatment of amyotrophic lateral sclerosis. Med Hypotheses 69:836–837PubMedCrossRefGoogle Scholar
  17. Kiefer F, Jahn H, Otte C, Nakovics H, Wiedemann K (2006) Effects of treatment with acamprosate on beta-endorphin plasma concentration in humans with high alcohol preference. Neurosci Lett 404:103–106PubMedCrossRefGoogle Scholar
  18. Kril JJ, Halliday GM (1999) Brain shrinkage in alcoholics: a decade on and what have we learned? Prog Neurobiol 58:381–387PubMedCrossRefGoogle Scholar
  19. Lenzi D, Conte A, Mainero C, Frasca V, Fubelli F, Totaro P, Caramia F, Inghilleri M, Pozzilli C, Pantano P (2007) Effect of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: a functional and anatomical study. Hum Brain Mapp 28:636–644PubMedCrossRefGoogle Scholar
  20. Mann K, Lehert P, Morgan MY (2004) The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: results of a meta-analysis. Alcohol Clin Exp Res 28:51–63PubMedCrossRefGoogle Scholar
  21. Manyam NV, Katz L, Hare TA, Gerber JC 3rd, Grossman MH (1980) Levels of gamma-aminobutyric acid in cerebrospinal fluid in various neurologic disorders. Arch Neurol 37:352–355PubMedCrossRefGoogle Scholar
  22. Mas-Serrano P, Granero L, Martin-Algarra RV, Guerri C, Polache A (2000) Kinetic study of acamprosate absorption in rat small intestine. Alcohol Alcohol 35:324–330PubMedGoogle Scholar
  23. McGeehan AJ, Olive MF (2003) The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine. Br J Pharmacol 138:9–12PubMedCrossRefGoogle Scholar
  24. Mix E, Meyer-Rienecker H, Hartung HP, Zettl UK (2010) Animal models of multiple sclerosis—potentials and limitations. Prog Neurobiol 92:386–404PubMedCrossRefGoogle Scholar
  25. Morgen K, Sammer G, Courtney SM, Wolters T, Melchior H, Blecker CR, Oschmann P, Kaps M, Vaitl D (2007) Distinct mechanisms of altered brain activation in patients with multiple sclerosis. Neuroimage 37:937–946PubMedCrossRefGoogle Scholar
  26. Nalpas B, Dabadie H, Parot P, Paccalin J (1990) Acamprosate. From pharmacology to therapeutics. Encephale 16:175–179PubMedGoogle Scholar
  27. Newcombe J, Uddin A, Dove R, Patel B, Turski L, Nishizawa Y, Smith T (2008) Glutamate receptor expression in multiple sclerosis lesions. Brain Pathol 18:52–61PubMedCrossRefGoogle Scholar
  28. Pierrefiche O, Daoust M, Naassila M (2004) Biphasic effect of acamprosate on NMDA but not on GABAA receptors in spontaneous rhythmic activity from the isolated neonatal rat respiratory network. Neuropharmacology 47:35–45PubMedCrossRefGoogle Scholar
  29. Pitt D, Werner P, Raine CS (2000) Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 6:67–70PubMedCrossRefGoogle Scholar
  30. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661PubMedCrossRefGoogle Scholar
  31. Saivin S, Hulot T, Chabac S, Potgieter A, Durbin P, Houin G (1998) Clinical pharmacokinetics of acamprosate. Clin Pharmacokinet 35:331–345PubMedCrossRefGoogle Scholar
  32. Schaffer S, Azuma J, Takahashi K, Mozaffari M (2003) Why is taurine cytoprotective? Adv Exp Med Biol 526:307–321PubMedCrossRefGoogle Scholar
  33. Simonini MV, Polak PE, Sharp A, McGuire S, Galea E, Feinstein DL (2010) Increasing CNS noradrenaline reduces EAE severity. J Neuroimmune Pharmacol 5:252–259PubMedCrossRefGoogle Scholar
  34. Smith T, Groom A, Zhu B, Turski L (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6:62–66PubMedCrossRefGoogle Scholar
  35. Spanagel R, Zieglgansberger W (1997) Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes. Trends Pharmacol Sci 18:54–59PubMedCrossRefGoogle Scholar
  36. Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D (2005) Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 128:1016–1025PubMedCrossRefGoogle Scholar
  37. Tian J, Lu Y, Zhang H, Chau CH, Dang HN, Kaufman DL (2004) Gamma-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model. J Immunol 173:5298–5304PubMedGoogle Scholar
  38. Wallstrom E, Diener P, Ljungdahl A, Khademi M, Nilsson CG, Olsson T (1996) Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis. J Neurol Sci 137:89–96PubMedCrossRefGoogle Scholar
  39. Wang GH, Jiang ZL, Fan XJ, Zhang L, Li X, Ke KF (2007) Neuroprotective effect of taurine against focal cerebral ischemia in rats possibly mediated by activation of both GABAA and glycine receptors. Neuropharmacology 52:1199–1209PubMedCrossRefGoogle Scholar
  40. Weiner HL (2009) The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol 65:239–248PubMedCrossRefGoogle Scholar
  41. Wu JY, Wu H, Jin Y, Wei J, Sha D, Prentice H, Lee HH, Lin CH, Lee YH, Yang LL (2009) Mechanism of neuroprotective function of taurine. Adv Exp Med Biol 643:169–179PubMedCrossRefGoogle Scholar
  42. Zagon IS, Rahn KA, Turel AP, McLaughlin PJ (2009) Endogenous opioids regulate expression of experimental autoimmune encephalomyelitis: a new paradigm for the treatment of multiple sclerosis. Exp Biol Med (Maywood) 234:1383–1392CrossRefGoogle Scholar
  43. Zalewska-Kaszubska J, Cwiek W, Dyr W, Czarnecka E (2005) Changes in the beta-endorphin plasma level after repeated treatment with acamprosate in rats selectively bred for high and low alcohol preference. Neurosci Lett 388:45–48PubMedCrossRefGoogle Scholar
  44. Zeise ML, Kasparov S, Capogna M, Zieglgansberger W (1993) Acamprosate (calciumacetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol 231:47–52PubMedCrossRefGoogle Scholar
  45. Zornoza T, Cano-Cebrian MJ, Hipolito L, Granero L, Polache A (2006) Evidence of a flip-flop phenomenon in acamprosate pharmacokinetics: an in vivo study in rats. Biopharm Drug Dispos 27:305–311PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Z. Sternberg
    • 1
  • A. Cesario
    • 1
  • K. Rittenhouse-Olson
    • 2
  • R. A. Sobel
    • 3
  • O. Pankewycz
    • 4
  • B. Zhu
    • 5
  • T. Whitcomb
    • 1
  • D. S. Sternberg
    • 1
  • F. E. Munschauer
    • 1
  1. 1.Department of Neurology, Baird MS CenterJacobs Neurological InstituteBuffaloUSA
  2. 2.Department of Biotechnical and Neurological Laboratory SciencesUniversity of BuffaloBuffaloUSA
  3. 3.Department of PathologyVA Health Care SystemPalo AltoUSA
  4. 4.Department of Surgery, Buffalo General HospitalState University of New York, University at BuffaloBuffaloUSA
  5. 5.Center for Neurologic DiseasesBrigham and Women’s HospitalBostonUSA

Personalised recommendations