Advertisement

Journal of Neurology

, Volume 265, Issue 11, pp 2614–2624 | Cite as

Targeting phosphocreatine metabolism in relapsing–remitting multiple sclerosis: evaluation with brain MRI, 1H and 31P MRS, and clinical and cognitive testing

  • Melissa Cambron
  • Tatjana Reynders
  • Jan Debruyne
  • Harmen Reyngoudt
  • Annemie Ribbens
  • Erik Achten
  • Guy Laureys
Original Communication
  • 73 Downloads

Abstract

Background/objectives

Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP–PKA pathway, an interesting target in the neurodegenerative mechanisms of MS.

Methods

We conducted a two-center double-blind, placebo-controlled, randomized trial including 48 relapsing–remitting MS patients. Patients were randomized to receive placebo (n = 13), fluoxetine (n = 15), or prucalopride (n = 14) for 6 weeks. Proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) as well as volumetric and perfusion MR imaging were performed at weeks 0, 2, and 6. Clinical and cognitive testing were evaluated at weeks 0 and 6.

Results

No significant changes were observed for both 31P and 1H MRS indices. We found a significant effect on white matter volume and a trend towards an increase in grey matter and whole brain volume in the fluoxetine group at week 2; however, these effects were not sustained at week 6 for white matter and whole brain volume. Fluoxetine and prucalopride showed a positive effect on 9-HPT, depression, and fatigue scores.

Conclusion

Both fluoxetine and prucalopride had a symptomatic effect on upper limb function, fatigue, and depression, but this should be interpreted with caution. No effect of treatment was found on 31P and 1H MRS parameters, suggesting that these molecules do not influence the PCr metabolism.

Keywords

Multiple sclerosis Fluoxetine Prucalopride Magnetic resonance spectroscopy Phosphocreatine 

Notes

Acknowledgements

We would like to thank our study nurses Karolien Flamée and Reinhilde Goorts for all the help with data input. We would like to thank everyone at icometrix, especially Diana Sima and Thibo Billiet for all their support with the analysis of the data.

Funding

We received funding of the MS Liga Belgium, MS steunfonds Vlaanderen. MC has a PhD fellowship funded by the FWO (Fonds Wetenschappelijk Onderzoek).

Compliance with ethical standards

Conflicts of interest

The authors declare that there is no conflict of interest.

Supplementary material

415_2018_9039_MOESM1_ESM.doc (95 kb)
Supplementary material 1 (DOC 95 KB)

References

  1. 1.
    Leray E, Yaouanq J, Le Page E, Coustans M, Laplaud D, Oger J, Edan G (2010) Evidence for a two-stage disability progression in multiple sclerosis. Brain 133(Pt 7):1900–1913.  https://doi.org/10.1093/brain/awq076 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15(9):545–558.  https://doi.org/10.1038/nri3871 CrossRefPubMedGoogle Scholar
  3. 3.
    Grigoriadis N, van Pesch V, Paradig MSG (2015) A basic overview of multiple sclerosis immunopathology. Eur J Neurol 22(Suppl 2):3–13.  https://doi.org/10.1111/ene.12798 CrossRefPubMedGoogle Scholar
  4. 4.
    Comi G, Radaelli M, Soelberg Sorensen P (2017) Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet 389(10076):1347–1356.  https://doi.org/10.1016/S0140-6736(16)32388-1 CrossRefPubMedGoogle Scholar
  5. 5.
    Liu B, Teschemacher AG, Kasparov S (2017) Neuroprotective potential of astroglia. J Neurosci Res 95(11):2126–2139.  https://doi.org/10.1002/jnr.24140 CrossRefPubMedGoogle Scholar
  6. 6.
    De Keyser J, Wilczak N, Leta R, Streetland C (1999) Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors. Neurology 53(8):1628–1633CrossRefGoogle Scholar
  7. 7.
    Zeinstra E, Wilczak N, De Keyser J (2000) [3H]dihydroalprenolol binding to beta adrenergic receptors in multiple sclerosis brain. Neurosci Lett 289(1):75–77CrossRefGoogle Scholar
  8. 8.
    Laureys G, Gerlo S, Spooren A, Demol F, De Keyser J, Aerts JL (2014) beta(2)-adrenergic agonists modulate TNF-alpha induced astrocytic inflammatory gene expression and brain inflammatory cell populations. J Neuroinflamm 11:21.  https://doi.org/10.1186/1742-2094-11-21 CrossRefGoogle Scholar
  9. 9.
    Laureys G, Valentino M, Demol F, Zammit C, Muscat R, Cambron M, Kooijman R, De Keyser J (2014) beta(2)-adrenergic receptors protect axons during energetic stress but do not influence basal glio-axonal lactate shuttling in mouse white matter. Neuroscience 277:367–374.  https://doi.org/10.1016/j.neuroscience.2014.07.022 CrossRefPubMedGoogle Scholar
  10. 10.
    Kuzhikandathil EV, Molloy GR (1994) Transcription of the brain creatine kinase gene in glial cells is modulated by cyclic AMP-dependent protein kinase. J Neurosci Res 39(1):70–82.  https://doi.org/10.1002/jnr.490390110 CrossRefPubMedGoogle Scholar
  11. 11.
    Kuzhikandathil EV, Molloy GR (1999) Proximal promoter of the rat brain creatine kinase gene lacks a consensus CRE element but is essential for the cAMP-mediated increased transcription in glioblastoma cells. J Neurosci Res 56(4):371–385CrossRefGoogle Scholar
  12. 12.
    Cambron M, D’Haeseleer M, Laureys G, Clinckers R, Debruyne J, De Keyser J (2012) White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis. J Cereb Blood Flow Metab 32(3):413–424.  https://doi.org/10.1038/jcbfm.2011.193 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Obert D, Helms G, Sattler MB, Jung K, Kretzschmar B, Bahr M, Dechent P, Diem R, Hein K (2016) Brain metabolite changes in patients with relapsing-remitting and secondary progressive multiple sclerosis: a two-year follow-up study. PloS One 11(9):e0162583.  https://doi.org/10.1371/journal.pone.0162583 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Steen C, Wilczak N, Hoogduin JM, Koch M, De Keyser J (2010) Reduced creatine kinase B activity in multiple sclerosis normal appearing white matter. PloS One 5(5):e10811.  https://doi.org/10.1371/journal.pone.0010811 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kauv P, Ayache SS, Creange A, Chalah MA, Lefaucheur JP, Hodel J, Brugieres P (2017) Adenosine triphosphate metabolism measured by phosphorus magnetic resonance spectroscopy: a potential biomarker for multiple sclerosis severity. Eur Neurol 77(5–6):316–321.  https://doi.org/10.1159/000475496 CrossRefPubMedGoogle Scholar
  16. 16.
    Spencer JP, Brown JT, Richardson JC, Medhurst AD, Sehmi SS, Calver AR, Randall AD (2004) Modulation of hippocampal excitability by 5-HT4 receptor agonists persists in a transgenic model of Alzheimer’s disease. Neuroscience 129(1):49–54.  https://doi.org/10.1016/j.neuroscience.2004.06.070 CrossRefPubMedGoogle Scholar
  17. 17.
    Tramontina AC, Tramontina F, Bobermin LD, Zanotto C, Souza DF, Leite MC, Nardin P, Gottfried C, Goncalves CA (2008) Secretion of S100B, an astrocyte-derived neurotrophic protein, is stimulated by fluoxetine via a mechanism independent of serotonin. Prog Neuro-psychopharmacol Biol Psychiatry 32(6):1580–1583.  https://doi.org/10.1016/j.pnpbp.2008.06.001 CrossRefGoogle Scholar
  18. 18.
    Mostert JP, Sijens PE, Oudkerk M, De Keyser J (2006) Fluoxetine increases cerebral white matter NAA/Cr ratio in patients with multiple sclerosis. Neurosci Lett 402(1–2):22–24.  https://doi.org/10.1016/j.neulet.2006.03.042 CrossRefPubMedGoogle Scholar
  19. 19.
    Allaman I, Fiumelli H, Magistretti PJ, Martin JL (2011) Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes. Psychopharmacology 216(1):75–84.  https://doi.org/10.1007/s00213-011-2190-y CrossRefPubMedGoogle Scholar
  20. 20.
    Cellek S, John AK, Thangiah R, Dass NB, Bassil AK, Jarvie EM, Lalude O, Vivekanandan S, Sanger GJ (2006) 5-HT4 receptor agonists enhance both cholinergic and nitrergic activities in human isolated colon circular muscle. Neurogastroenterol Motil 18(9):853–861.  https://doi.org/10.1111/j.1365-2982.2006.00810.x CrossRefPubMedGoogle Scholar
  21. 21.
    Dhami KS, Churchward MA, Baker GB, Todd KG (2013) Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult. Mol Cell Neurosci 56:365–374.  https://doi.org/10.1016/j.mcn.2013.07.006 CrossRefPubMedGoogle Scholar
  22. 22.
    Su F, Yi H, Xu L, Zhang Z (2015) Fluoxetine and S-citalopram inhibit M1 activation and promote M2 activation of microglia in vitro. Neuroscience 294:60–68.  https://doi.org/10.1016/j.neuroscience.2015.02.028 CrossRefPubMedGoogle Scholar
  23. 23.
    Zeinstra EM, Wilczak N, Wilschut JC, Glazenburg L, Chesik D, Kroese FG, De Keyser J (2006) 5HT4 agonists inhibit interferon-gamma-induced MHC class II and B7 costimulatory molecules expression on cultured astrocytes. J Neuroimmunol 179(1–2):191–195.  https://doi.org/10.1016/j.jneuroim.2006.06.012 CrossRefPubMedGoogle Scholar
  24. 24.
    World Medical A (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310(20):2191–2194.  https://doi.org/10.1001/jama.2013.281053 CrossRefGoogle Scholar
  25. 25.
    Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302.  https://doi.org/10.1002/ana.22366 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Poullet JB, Sima DM, Simonetti AW, De Neuter B, Vanhamme L, Lemmerling P, Van Huffel S (2007) An automated quantitation of short echo time MRS spectra in an open source software environment: AQSES. NMR Biomed 20(5):493–504.  https://doi.org/10.1002/nbm.1112 CrossRefPubMedGoogle Scholar
  27. 27.
    Buxton RB, Frank LR, Wong EC, Siewert B, Warach S, Edelman RR (1998) A general kinetic model for quantitative perfusion imaging with arterial spin labeling. Magn Reson Med 40(3):383–396CrossRefGoogle Scholar
  28. 28.
    Thompson C (2002) Onset of action of antidepressants: results of different analyses. Hum Psychopharmacol 17(Suppl 1):S27–S32.  https://doi.org/10.1002/hup.386 CrossRefPubMedGoogle Scholar
  29. 29.
    Smart CM, Segalowitz SJ, Mulligan BP, Koudys J, Gawryluk JR (2016) Mindfulness training for older adults with subjective cognitive decline: results from a pilot randomized controlled trial. J Alzheimers Dis 52(2):757–774.  https://doi.org/10.3233/JAD-150992 CrossRefPubMedGoogle Scholar
  30. 30.
    Han F, Xiao B, Wen L, Shi Y (2015) Effects of fluoxetine on the amygdala and the hippocampus after administration of a single prolonged stress to male Wistar rates: in vivo proton magnetic resonance spectroscopy findings. Psychiatry Res 232(2):154–161.  https://doi.org/10.1016/j.pscychresns.2015.02.011 CrossRefPubMedGoogle Scholar
  31. 31.
    Zhao L, Xiong Z, Lu X, Zheng S, Wang F, Ge L, Su G, Yang J, Wu C (2015) Metabonomic evaluation of chronic unpredictable mild stress-induced changes in rats by intervention of fluoxetine by HILIC-UHPLC/MS. PloS One 10(6):e0129146.  https://doi.org/10.1371/journal.pone.0129146 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bai S, Zhou C, Cheng P, Fu Y, Fang L, Huang W, Yu J, Shao W, Wang X, Liu M, Zhou J, Xie P (2015) 1H NMR-based metabolic profiling reveals the effects of fluoxetine on lipid and amino acid metabolism in astrocytes. Int J Mol Sci 16(4):8490–8504.  https://doi.org/10.3390/ijms16048490 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sijens PE, Mostert JP, Irwan R, Potze JH, Oudkerk M, De Keyser J (2008) Impact of fluoxetine on the human brain in multiple sclerosis as quantified by proton magnetic resonance spectroscopy and diffusion tensor imaging. Psychiatry Res 164(3):274–282.  https://doi.org/10.1016/j.pscychresns.2007.12.014 CrossRefPubMedGoogle Scholar
  34. 34.
    Duan DM, Tu Y, Jiao S, Qin W (2011) The relevance between symptoms and magnetic resonance imaging analysis of the hippocampus of depressed patients given electro-acupuncture combined with fluoxetine intervention—a randomized, controlled trial. Chin J Integr Med 17(3):190–199.  https://doi.org/10.1007/s11655-011-0666-6 CrossRefPubMedGoogle Scholar
  35. 35.
    Maclaren J, Han Z, Vos SB, Fischbein N, Bammer R (2014) Reliability of brain volume measurements: a test-retest dataset. Sci Data 1:140037.  https://doi.org/10.1038/sdata.2014.37 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hedman AM, van Haren NE, Schnack HG, Kahn RS, Hulshoff Pol HE (2012) Human brain changes across the life span: a review of 56 longitudinal magnetic resonance imaging studies. Hum Brain Mapp 33(8):1987–2002.  https://doi.org/10.1002/hbm.21334 CrossRefPubMedGoogle Scholar
  37. 37.
    Ontaneda D, Fox RJ, Chataway J (2015) Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol 14(2):208–223.  https://doi.org/10.1016/S1474-4422(14)70264-9 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lucas G, Du J, Romeas T, Mnie-Filali O, Haddjeri N, Pineyro G, Debonnel G (2010) Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat. PloS One 5(2):e9253.  https://doi.org/10.1371/journal.pone.0009253 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Melissa Cambron
    • 1
    • 2
  • Tatjana Reynders
    • 1
    • 3
  • Jan Debruyne
    • 4
  • Harmen Reyngoudt
    • 5
  • Annemie Ribbens
    • 6
  • Erik Achten
    • 5
  • Guy Laureys
    • 4
  1. 1.Department of NeurologyUniversitair Ziekenhuis BrusselJetteBelgium
  2. 2.Department of NeurologyAZ Sint-Jan HospitalBruggeBelgium
  3. 3.Department of NeurologyUniversity Hospital AntwerpAntwerpBelgium
  4. 4.Department of NeurologyUniversity Hospital GhentGhentBelgium
  5. 5.Department of Radiology and Nuclear MedicineGhent UniversityGhentBelgium
  6. 6.IcometrixLeuvenBelgium

Personalised recommendations