Targeting phosphocreatine metabolism in relapsing–remitting multiple sclerosis: evaluation with brain MRI, 1H and 31P MRS, and clinical and cognitive testing
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Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP–PKA pathway, an interesting target in the neurodegenerative mechanisms of MS.
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.
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.
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.
KeywordsMultiple sclerosis Fluoxetine Prucalopride Magnetic resonance spectroscopy Phosphocreatine
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.
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.
- 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
- 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
- 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.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.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
- 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
- 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.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
- 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
- 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.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.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.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.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
- 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