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Translocator Protein Ligand PIGA1138 Reduces Disease Symptoms and Severity in Experimental Autoimmune Encephalomyelitis Model of Primary Progressive Multiple Sclerosis

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Abstract

Multiple sclerosis (MS) is an autoimmune and demyelinating disease of the central nervous system (CNS) caused by CNS infiltration of peripheral immune cells, immune-mediated attack of the myelin sheath, neuroinflammation, and/or axonal/neuronal dysfunctions. Some drugs are available to cope with relapsing–remitting MS (RRMS) but there is no therapy for the primary progressive MS (PPMS). Because growing evidence supports a regulatory role of the translocator protein (TSPO) in neuroinflammatory, demyelinating, and neurodegenerative processes, we investigated the therapeutic potential of phenylindolyilglyoxylamydes (PIGAs) TSPO ligands in myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE) mice mimicking the human PPMS. MOG-EAE C57Bl/6-mice were treated by TSPO ligands PIGA839, PIGA1138, or the vehicle. Several methods were combined to evaluate PIGAs-TSPO ligand effects on MOG-EAE symptoms, CNS infiltration by immune cells, demyelination, and axonal damages. PIGA1138 (15 mg/kg) drastically reduced MOG-EAE mice clinical scores, ameliorated motor dysfunctions assessed with the Catwalk device, and counteracted MOG-EAE-induced demyelination by preserving Myelin basic protein (MBP) expression in the CNS. Furthermore, PIGA1138-treatment prevented EAE-evoked decreased neurofilament-200 expression in spinal and cerebellar axons. Moreover, PIGA1138 inhibited peripheral immune-CD45 + cell infiltration in the CNS, suggesting that it may control inflammatory mechanisms involved in PPMS. Concordantly, PIGA1138 enhanced anti-inflammatory interleukin-10 serum level in MOG-EAE mice. PIGA1138-treatment, which increased neurosteroid allopregnanolone production, ameliorated all pathological biomarkers, while PIGA839, unable to activate neurosteroidogenesis in vivo, exerted only moderate/partial effects in MOG-EAE mice. Altogether, our results suggest that PIGA1138-based treatment may represent an interesting possibility to be explored for the innovation of effective therapies against PPMS.

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Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Change history

  • 24 January 2022

    "Christine Patte-Mensah and Ayikoé-Guy Mensah-Nyagan are co-seniors." was added in print proofs.

Abbreviations

MS:

Multiple sclerosis

CNS:

Central nervous system

PPMS:

Primary progressive multiple sclerosis

RRMS:

Relapsing-remitting multiple sclerosis

TSPO:

Translocator protein

PIGAs:

Phenylindolyilglyoxylamydes

MOG:

Myelin oligodendrocyte glycoprotein

EAE:

Experimental autoimmune encephalomyelitis

MBP:

Myelin basic protein

PLP:

Proteolipid protein

RT:

Residence time

PBS:

Phosphate-buffered saline

i.p. :

Intraperitoneally

CS:

Clinical score

HPC:

Hydroxypropyl cellulose

PFA:

Paraformaldehyde

BSA:

Bovine serum albumin

NF:

Neurofilament

DAPI:

4′,6′-Diamidino-2-phenylindole

ROIs:

Regions of interest

AU:

Arbitrary unit

IL-10:

Interleukin 10

ELISA:

Enzyme-linked immunosorbent assay

LC/HR-MS:

Liquid chromatography/high-resolution-mass spectrometry

LFB/CV:

Luxol fast blue/cresyl violet

H-ESI:

Heated electrospray ionization

SEM:

Standard error mean

Cer:

Cerebellum

CC:

Corpus callosum

CTX:

Cortex

References

  1. Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747. https://doi.org/10.1146/annurev.immunol.23.021704.115707

    Article  CAS  PubMed  Google Scholar 

  2. Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517. https://doi.org/10.1016/S0140-6736(08)61620-7

    Article  CAS  PubMed  Google Scholar 

  3. Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA (2018) Multiple sclerosis Nat Rev Dis Primers 4(1):43. https://doi.org/10.1038/s41572-018-0041-4

    Article  PubMed  Google Scholar 

  4. Milo R, Kahana E (2010) Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun Rev 9(5):A387–A394. https://doi.org/10.1016/j.autrev.2009.11.010

    Article  CAS  PubMed  Google Scholar 

  5. McNamara C, Sugrue G, Murray B, MacMahon PJ (2017) Current and Emerging Therapies in Multiple Sclerosis: Implications for the Radiologist, Part 2-Surveillance for Treatment Complications and Disease Progression. AJNR Am J Neuroradiol 38(9):1672–1680. https://doi.org/10.3174/ajnr.A5148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rocca MA, Filippi M (2019) Targeting progression in multiple sclerosis - an update. Nat Rev Neurol 15(2):62–64. https://doi.org/10.1038/s41582-018-0127-3

    Article  PubMed  Google Scholar 

  7. Feinstein A, Freeman J, Lo AC (2015) Treatment of progressive multiple sclerosis: what works, what does not, and what is needed. Lancet Neurol 14(2):194–207. https://doi.org/10.1016/S1474-4422(14)70231-5

    Article  PubMed  Google Scholar 

  8. Faissner S, Plemel JR, Gold R, Yong VW (2019) Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov 18(12):905–922. https://doi.org/10.1038/s41573-019-0035-2

    Article  CAS  PubMed  Google Scholar 

  9. Mendel I, Kerlero de Rosbo N, Ben-Nun A (1995) A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells. Eur J Immunol 25(7):1951–1959. https://doi.org/10.1002/eji.1830250723

    Article  CAS  PubMed  Google Scholar 

  10. Crawford DK, Mangiardi M, Song B, Patel R, Du S, Sofroniew MV, Voskuhl RR, Tiwari-Woodruff SK (2010) Oestrogen receptor beta ligand: a novel treatment to enhance endogenous functional remyelination. Brain 133(10):2999–3016. https://doi.org/10.1093/brain/awq237

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mangiardi M, Crawford DK, Xia X, Du S, Simon-Freeman R, Voskuhl RR, Tiwari-Woodruff SK (2011) An animal model of cortical and callosal pathology in multiple sclerosis. Brain Pathol 21(3):263–278. https://doi.org/10.1111/j.1750-3639.2010.00444.x

    Article  PubMed  Google Scholar 

  12. Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc 1(4):1810–1819. https://doi.org/10.1038/nprot.2006.285

    Article  CAS  PubMed  Google Scholar 

  13. Tompkins SM, Fuller KG, Miller SD (2002) Theiler’s virus-mediated autoimmunity: local presentation of CNS antigens and epitope spreading. Ann N Y Acad Sci 958:26–38

    Article  CAS  Google Scholar 

  14. Lassmann H (2010) Axonal and neuronal pathology in multiple sclerosis: what have we learnt from animal models. Exp Neurol 225(1):2–8. https://doi.org/10.1016/j.expneurol.2009.10.009

    Article  PubMed  Google Scholar 

  15. Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15(8):1074–1077. https://doi.org/10.1038/nn.3168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hasselmann JPC, Karim H, Khalaj AJ, Ghosh S, Tiwari-Woodruff SK (2017) Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair. J Neurosci Methods 284:71–84. https://doi.org/10.1016/j.jneumeth.2017.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lassmann H (2007) Experimental models of multiple sclerosis. Rev Neurol (Paris) 163(6–7):651–655. https://doi.org/10.1016/s0035-3787(07)90474-9

    Article  CAS  Google Scholar 

  18. Robinson AP, Harp CT, Noronha A, Miller SD (2014) The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment. Handb Clin Neurol 122:173–189. https://doi.org/10.1016/B978-0-444-52001-2.00008-X

    Article  PubMed  PubMed Central  Google Scholar 

  19. Leva G, Klein C, Benyounes J, Halle F, Bihel F, Collongues N, De Seze J (1863) Mensah-Nyagan AG and Patte-Mensah C (2017) The translocator protein ligand XBD173 improves clinical symptoms and neuropathological markers in the SJL/J mouse model of multiple sclerosis. Biochim Biophys Acta Mol Basis Dis 12:3016–3027. https://doi.org/10.1016/j.bbadis.2017.09.007

    Article  CAS  Google Scholar 

  20. Daugherty DJ, Selvaraj V, Chechneva OV, Liu XB, Pleasure DE, Deng W (2013) A TSPO ligand is protective in a mouse model of multiple sclerosis. EMBO Mol Med 5(6):891–903. https://doi.org/10.1002/emmm.201202124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Scholz R, Caramoy A, Bhuckory MB, Rashid K, Chen M, Xu H, Grimm C, Langmann T (2015) Targeting translocator protein (18 kDa) (TSPO) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration. J Neuroinflammation 12:201. https://doi.org/10.1186/s12974-015-0422-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ravikumar B, Crawford D, Dellovade T, Savinainen A, Graham D, Liere P, Oudinet JP, Webb M, Hering H (2016) Differential efficacy of the TSPO ligands etifoxine and XBD-173 in two rodent models of Multiple Sclerosis. Neuropharmacology 108:229–237. https://doi.org/10.1016/j.neuropharm.2016.03.053

    Article  CAS  PubMed  Google Scholar 

  23. Betlazar C, Middleton RJ, Banati R, Liu GJ (2020) The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes. Cells 9(2):512. https://doi.org/10.3390/cells9020512

    Article  CAS  PubMed Central  Google Scholar 

  24. Costa E, Auta J, Guidotti A, Korneyev A, Romeo E (1994) The pharmacology of neurosteroidogenesis. J Steroid Biochem Mol Biol 49(4–6):385–389. https://doi.org/10.1016/0960-0760(94)90284-4

    Article  CAS  PubMed  Google Scholar 

  25. Mensah-Nyagan AG, Do-Rego JL, Beaujean D, Luu-The V, Pelletier G, Vaudry H (1999) Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol Rev 51(1):63–81. https://doi.org/10.1111/j.1365-2826.2004.01226.x

    Article  CAS  PubMed  Google Scholar 

  26. Ghoumari AM, Ibanez C, El-Etr M, Leclerc P, Eychenne B, O’Malley BW, Baulieu EE, Schumacher M (2003) Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem 86(4):848–859. https://doi.org/10.1046/j.1471-4159.2003.01881.x

    Article  CAS  PubMed  Google Scholar 

  27. Melcangi RC, Panzica GC (2014) Allopregnanolone: state of the art. Prog Neurobiol 113:1–5. https://doi.org/10.1016/j.pneurobio.2013.09.005

    Article  CAS  PubMed  Google Scholar 

  28. Noorbakhsh F, Baker GB, Power C (2014) Allopregnanolone and neuroinflammation: a focus on multiple sclerosis. Front Cell Neurosci 8(134):1–6. https://doi.org/10.3389/fncel.2014.00134

    Article  CAS  Google Scholar 

  29. De Nicola AF, Meyer M, Garay L, Kruse MS, Schumacher M, Guennoun R, Gonzalez Deniselle MC (2021) Progesterone and Allopregnanolone Neuroprotective Effects in the Wobbler Mouse Model of Amyotrophic Lateral Sclerosis. Cell Mol Neurobiol. https://doi.org/10.1007/s10571-021-01118-y

    Article  PubMed  Google Scholar 

  30. Jolivel V, Brun S, Biname F, Benyounes J, Taleb O, Bagnard D, De Seze J, Patte-Mensah C, Mensah-Nyagan AG (2021) Microglial Cell Morphology and Phagocytic Activity Are Critically Regulated by the Neurosteroid Allopregnanolone: A Possible Role in Neuroprotection. Cells 10(3):698. https://doi.org/10.3390/cells10030698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Da Pozzo ED, Tremolanti C, Costa B, Giacomelli C, Milenkovic VM, Bader S, Wetzel CH, Rupprecht R, Taliani S, Settimo FD, Martini C (2019) Microglial Pro-Inflammatory and Anti-Inflammatory Phenotypes Are Modulated by Translocator Protein Activation. Int J Mol Sci 20(18):4467. https://doi.org/10.3390/ijms20184467

    Article  CAS  PubMed Central  Google Scholar 

  32. Barresi E, Bruno A, Taliani S, Cosconati S, Da Pozzo E, Salerno S, Simorini F, Daniele S, Giacomelli C, Marini AM, La Motta C, Marinelli L, Cosimelli B, Novellino E, Greco G, Da Settimo F, Martini C (2015) Deepening the Topology of the Translocator Protein Binding Site by Novel N, N-Dialkyl-2-arylindol-3-ylglyoxylamides. J Med Chem 58(15):6081–6092. https://doi.org/10.1021/acs.jmedchem.5b00689

    Article  CAS  PubMed  Google Scholar 

  33. Milenkovic VM, Slim D, Bader S, Koch V, Heinl ES, Alvarez-Carbonell D, Nothdurfter C, Rupprecht R, Wetzel CH (2019) CRISPR-Cas9 Mediated TSPO Gene Knockout alters Respiration and Cellular Metabolism in Human Primary Microglia Cells. Int J Mol Sci 20(13):3359. https://doi.org/10.3390/ijms20133359

    Article  CAS  PubMed Central  Google Scholar 

  34. Da Pozzo E, Giacomelli C, Costa B, Cavallini C, Taliani S, Barresi E, Da Settimo F, Martini C (2016) TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being. Int J Mol Sci 17(7):1028. https://doi.org/10.3390/ijms17071028

    Article  CAS  PubMed Central  Google Scholar 

  35. Germelli L, Da Pozzo E, Giacomelli C, Tremolanti C, Marchetti L, Wetzel CH, Barresi E, Taliani S, Da Settimo F, Martini C, Costa B (2021) De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein. Int J Mol Sci 22(6):3115. https://doi.org/10.3390/ijms22063115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Costa B, Da Pozzo E, Giacomelli C, Barresi E, Taliani S, Da Settimo F, Martini C (2016) TSPO ligand residence time: a new parameter to predict compound neurosteroidogenic efficacy. Sci Rep 6:18164. https://doi.org/10.1038/srep18164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Costa B, Taliani S, Da Pozzo E, Barresi E, Robello M, Cavallini C, Cosconati S, Da Settimo F, Novellino E, Martini C (2017) Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N, N-Dialkyl-2-arylindol-3-ylglyoxylamides. ChemMedChem 12(16):1275–1278. https://doi.org/10.1002/cmdc.201700220

    Article  CAS  PubMed  Google Scholar 

  38. Da Settimo F, Simorini F, Taliani S, La Motta C, Marini AM, Salerno S, Bellandi M, Novellino E, Greco G, Cosimelli B, Da Pozzo E, Costa B, Simola N, Morelli M, Martini C (2008) Anxiolytic-like effects of N, N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis. J Med Chem 51(18):5798–5806. https://doi.org/10.1021/jm8003224

    Article  CAS  PubMed  Google Scholar 

  39. Rueden CT, Schindelin J, Hiner MC, DeZonia BE, Walter AE, Arena ET, Eliceiri KW (2017) Image J2: ImageJ for the next generation of scientific image data. BMC Bioinformatics 18(1):529. https://doi.org/10.1186/s12859-017-1934-z

    Article  PubMed  PubMed Central  Google Scholar 

  40. Giatti S, Caruso D, Boraso M, Abbiati F, Ballarini E, Calabrese D, Pesaresi M, Rigolio R, Santos-Galindo M, Viviani B, Cavaletti G, Garcia-Segura LM, Melcangi RC (2012) Neuroprotective effects of progesterone in chronic experimental autoimmune encephalomyelitis. J Neuroendocrinol 24(6):851–861. https://doi.org/10.1111/j.1365-2826.2012.02284.x

    Article  CAS  PubMed  Google Scholar 

  41. Liu Q, Chi Q, Fan RT, Tian HD, Wang X (2019) Quantitative-Profiling Method of Serum Steroid Hormones by Hydroxylamine-Derivatization HPLC-MS. Nat Prod Bioprospect 9(3):201–208. https://doi.org/10.1007/s13659-019-0204-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kriszta G, Nemes B, Sandor Z, Acs P, Komoly S, Berente Z, Bolcskei K and Pinter E (2019) Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice. Cells 9(1):https://doi.org/10.3390/cells9010081.

  43. Saghy E, Sipos E, Acs P, Bolcskei K, Pohoczky K, Kemeny A, Sandor Z, Szoke E, Setalo G Jr, Komoly S, Pinter E (2016) TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis. Glia 64(12):2166–2180. https://doi.org/10.1002/glia.23051

    Article  PubMed  Google Scholar 

  44. Martin R, McFarland HF, McFarlin DE (1992) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10:153–187. https://doi.org/10.1146/annurev.iy.10.040192.001101

    Article  CAS  PubMed  Google Scholar 

  45. Weil MT, Mobius W, Winkler A, Ruhwedel T, Wrzos C, Romanelli E, Bennett JL, Enz L, Goebels N, Nave KA, Kerschensteiner M, Schaeren-Wiemers N, Stadelmann C, Simons M (2016) Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases. Cell Rep 16(2):314–322. https://doi.org/10.1016/j.celrep.2016.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tallantyre EC, Bo L, Al-Rawashdeh O, Owens T, Polman CH, Lowe J, Evangelou N (2009) Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease. Brain 132(Pt 5):1190–1199. https://doi.org/10.1093/brain/awp106

    Article  CAS  PubMed  Google Scholar 

  47. Wang H, Wu M, Zhan C, Ma E, Yang M, Yang X, Li Y (2012) Neurofilament proteins in axonal regeneration and neurodegenerative diseases. Neural Regen Res 7(8):620–626. https://doi.org/10.3969/j.issn.1673-5374.2012.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wilkins A (2017) Cerebellar Dysfunction in Multiple Sclerosis. Front Neurol 8:312. https://doi.org/10.3389/fneur.2017.00312

    Article  PubMed  PubMed Central  Google Scholar 

  49. Nyland H, Mork S, Matre R (1982) In-situ characterization of mononuclear cell infiltrates in lesions of multiple sclerosis. Neuropathol Appl Neurobiol 8(5):403–411. https://doi.org/10.1111/j.1365-2990.1982.tb00308.x

    Article  CAS  PubMed  Google Scholar 

  50. Hemmer B, Archelos JJ, Hartung HP (2002) New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 3(4):291–301. https://doi.org/10.1038/nrn784

    Article  CAS  PubMed  Google Scholar 

  51. Hoglund RA, Maghazachi AA (2014) Multiple sclerosis and the role of immune cells. World J Exp Med 4(3):27–37. https://doi.org/10.5493/wjem.v4.i3.27

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK (1998) IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol 161(7):3299–3306

    CAS  PubMed  Google Scholar 

  53. Kwilasz AJ, Grace PM, Serbedzija P, Maier SF, Watkins LR (2015) The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology 96(Pt A):55–69. https://doi.org/10.1016/j.neuropharm.2014.10.020

    Article  CAS  PubMed  Google Scholar 

  54. Gobel K, Ruck T, Meuth SG (2018) Cytokine signaling in multiple sclerosis: Lost in translation. Mult Scler 24(4):432–439. https://doi.org/10.1177/1352458518763094

    Article  CAS  PubMed  Google Scholar 

  55. Constantinescu CS, Farooqi N, O’Brien K, Gran B (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164(4):1079–1106. https://doi.org/10.1111/j.1476-5381.2011.01302.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kipp M, Nyamoya S, Hochstrasser T, Amor S (2017) Multiple sclerosis animal models: a clinical and histopathological perspective. Brain Pathol 27(2):123–137. https://doi.org/10.1111/bpa.12454

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hamers FP, Koopmans GC, Joosten EA (2006) CatWalk-assisted gait analysis in the assessment of spinal cord injury. J Neurotrauma 23(3–4):537–548. https://doi.org/10.1089/neu.2006.23.537

    Article  PubMed  Google Scholar 

  58. Crowley ST, Kataoka K, Itaka K (2018) Combined CatWalk Index: an improved method to measure mouse motor function using the automated gait analysis system. BMC Res Notes 11(1):263. https://doi.org/10.1186/s13104-018-3374-x

    Article  PubMed  PubMed Central  Google Scholar 

  59. Hoffman PN, Cleveland DW, Griffin JW, Landes PW, Cowan NJ, Price DL (1987) Neurofilament gene expression: a major determinant of axonal caliber. Proc Natl Acad Sci U S A 84(10):3472–3476. https://doi.org/10.1073/pnas.84.10.3472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Marmarou CR, Walker SA, Davis CL, Povlishock JT (2005) Quantitative analysis of the relationship between intra- axonal neurofilament compaction and impaired axonal transport following diffuse traumatic brain injury. J Neurotrauma 22(10):1066–1080. https://doi.org/10.1089/neu.2005.22.1066

    Article  PubMed  Google Scholar 

  61. Petzold A, Eikelenboom MJ, Keir G, Grant D, Lazeron RH, Polman CH, Uitdehaag BM, Thompson EJ, Giovannoni G (2005) Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study. J Neurol Neurosurg Psychiatry 76(2):206–211. https://doi.org/10.1136/jnnp.2004.043315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Correale J, Marrodan M, Ysrraelit MC (2019) Mechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis. Biomedicines 7(1):14. https://doi.org/10.3390/biomedicines7010014

    Article  CAS  PubMed Central  Google Scholar 

  63. Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15(9):545–558. https://doi.org/10.1038/nri3871

    Article  CAS  PubMed  Google Scholar 

  64. Lopes Pinheiro MA, Kooij G, Mizee MR, Kamermans A, Enzmann G, Lyck R, Schwaninger M (1862) Engelhardt B and de Vries HE (2016) Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim Biophys Acta 3:461–471. https://doi.org/10.1016/j.bbadis.2015.10.018

    Article  CAS  Google Scholar 

  65. Sen MK, Almuslehi MSM, Gyengesi E, Myers SJ, Shortland PJ, Mahns DA, Coorssen JR (2019) Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis. Cells 8(11):1314. https://doi.org/10.3390/cells8111314

    Article  CAS  PubMed Central  Google Scholar 

  66. Ran Z, Yue-Bei L, Qiu-Ming Z, Huan Y (2020) Regulatory B Cells and Its Role in Central Nervous System Inflammatory Demyelinating Diseases. Front Immunol 11:1884. https://doi.org/10.3389/fimmu.2020.01884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Melcangi RC, Mensah-Nyagan AG (2008) Neurosteroids: measurement and pathophysiologic relevance. Neurochem Int 52(4–5):503–505. https://doi.org/10.1016/j.neuint.2007.09.010

    Article  CAS  PubMed  Google Scholar 

  68. Costa B, Da Pozzo E, Chelli B, Simola N, Morelli M, Luisi M, Maccheroni M, Taliani S, Simorini F, Da Settimo F, Martini C (2011) Anxiolytic properties of a 2-phenylindolglyoxylamide TSPO ligand: Stimulation of in vitro neurosteroid production affecting GABAA receptor activity. Psychoneuroendocrinology 36(4):463–472. https://doi.org/10.1016/j.psyneuen.2010.07.021

    Article  CAS  PubMed  Google Scholar 

  69. Mancino DN, Leicaj ML, Lima A, Roig P, Guennoun R, Schumacher M, De Nicola AF and Garay LI (2021) Developmental expression of genes involved in progesterone synthesis, metabolism and action during the post-natal cerebellar myelination. J Steroid Biochem Mol Biol 207(105820):https://doi.org/10.1016/j.jsbmb.2021.105820.

  70. Girard C, Liu S, Adams D, Lacroix C, Sineus M, Boucher C, Papadopoulos V, Rupprecht R, Schumacher M, Groyer G (2012) Axonal regeneration and neuroinflammation: roles for the translocator protein 18 kDa. J Neuroendocrinol 24(1):71–81. https://doi.org/10.1111/j.1365-2826.2011.02215.x

    Article  CAS  PubMed  Google Scholar 

  71. Pawlikowski M, Immunomodulating effects of peripherally acting benzodiazepines, In: Giesen-Crouse E, Editor. Peripheral benzodiazepine receptors. Academic Press; 1993. London. p. 125–35.

  72. Qi X, Xu J, Wang F and Xiao J (2012) Translocator protein (18 kDa): a promising therapeutic target and diagnostic tool for cardiovascular diseases. Oxid Med Cell Longev 2012(162934):https://doi.org/10.1155/2012/162934.

  73. Fan J, Lindemann P, Feuilloley MG, Papadopoulos V (2012) Structural and functional evolution of the translocator protein (18 kDa). Curr Mol Med 12(4):369–386. https://doi.org/10.2174/1566524011207040369

    Article  CAS  PubMed  Google Scholar 

  74. Costa B, Da Pozzo E and Martini C (2020) 18-kDa translocator protein association complexes in the brain: From structure to function. Biochem Pharmacol 177(114015):https://doi.org/10.1016/j.bcp.2020.114015.

  75. Bonsack F, Sukumari-Ramesh S (2018) TSPO: An Evolutionarily Conserved Protein with Elusive Functions. Int J Mol Sci 19(6):1694. https://doi.org/10.3390/ijms19061694

    Article  CAS  PubMed Central  Google Scholar 

  76. Papadopoulos V, Fan J and Zirkin B (2018) Translocator protein (18 kDa): an update on its function in steroidogenesis. J Neuroendocrinol 30(2):https://doi.org/10.1111/jne.12500.

  77. Scarf AM, Auman KM, Kassiou M (2012) Is there any correlation between binding and functional effects at the translocator protein (TSPO) (18 kDa)? Curr Mol Med 12(4):387–397. https://doi.org/10.2174/1566524011207040387

    Article  CAS  PubMed  Google Scholar 

  78. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M (2010) Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 9(12):971–988. https://doi.org/10.1038/nrd3295

    Article  CAS  PubMed  Google Scholar 

  79. Gilgun-Sherki Y, Melamed E, Offen D (2004) The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 251(3):261–268. https://doi.org/10.1007/s00415-004-0348-9

    Article  CAS  PubMed  Google Scholar 

  80. Choi IY, Lee P, Adany P, Hughes AJ, Belliston S, Denney DR, Lynch SG (2018) In vivo evidence of oxidative stress in brains of patients with progressive multiple sclerosis. Mult Scler 24(8):1029–1038. https://doi.org/10.1177/1352458517711568

    Article  CAS  PubMed  Google Scholar 

  81. Guilarte TR, Loth MK, Guariglia SR (2016) TSPO Finds NOX2 in Microglia for Redox Homeostasis. Trends Pharmacol Sci 37(5):334–343. https://doi.org/10.1016/j.tips.2016.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Baez E, Guio-Vega GP, Echeverria V, Sandoval-Rueda DA, Barreto GE (2017) 4’-Chlorodiazepam Protects Mitochondria in T98G Astrocyte Cell Line from Glucose Deprivation. Neurotox Res 32(2):163–171. https://doi.org/10.1007/s12640-017-9733-x

    Article  CAS  PubMed  Google Scholar 

  83. Lejri I, Grimm A, Halle F, Abarghaz M, Klein C, Maitre M, Schmitt M, Bourguignon JJ, Mensah-Nyagan AG, Bihel F, Eckert A (2019) TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis. J Alzheimers Dis 72(4):1045–1058. https://doi.org/10.3233/JAD-190127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Allender E, Deol H, Schram S, Maheras KJ, Gow A, Simpson EH, Song F (2018) Neuregulin1 modulation of experimental autoimmune encephalomyelitis (EAE). J Neuroimmunol 318:56–64. https://doi.org/10.1016/j.jneuroim.2018.02.008

    Article  CAS  PubMed  Google Scholar 

  85. Papenfuss TL, Rogers CJ, Gienapp I, Yurrita M, McClain M, Damico N, Valo J, Song F, Whitacre CC (2004) Sex differences in experimental autoimmune encephalomyelitis in multiple murine strains. J Neuroimmunol 150(1–2):59–69. https://doi.org/10.1016/j.jneuroim.2004.01.018

    Article  CAS  PubMed  Google Scholar 

  86. Aharoni R, Globerman R, Eilam R, Brenner O, Arnon R (2021) Titration of myelin oligodendrocyte glycoprotein (MOG) - Induced experimental autoimmune encephalomyelitis (EAE) model. J Neurosci Methods 351:108999. https://doi.org/10.1016/j.jneumeth.2020.108999

    Article  CAS  PubMed  Google Scholar 

  87. Fjaer S, Bo L, Myhr KM, Torkildsen O and Wergeland S (2015) Magnetization transfer ratio does not correlate to myelin content in the brain in the MOG-EAE mouse model. Neurochem Int 83–84(28–40. https://doi.org/10.1016/j.neuint.2015.02.006.

  88. Ludwig MD, Zagon IS, McLaughlin PJ (2017) Featured Article: Serum [Met(5)]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone. Exp Biol Med (Maywood) 242(15):1524–1533. https://doi.org/10.1177/1535370217724791

    Article  CAS  Google Scholar 

  89. Teixeira NB, Picolo G, Giardini AC, Boumezbeur F, Pottier G, Kuhnast B, Servent D, Benoit E (2020) Alterations of peripheral nerve excitability in an experimental autoimmune encephalomyelitis mouse model for multiple sclerosis. J Neuroinflammation 17(1):266. https://doi.org/10.1186/s12974-020-01936-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yousuf MS, Noh MC, Friedman TN, Zubkow K, Johnson JC, Tenorio G, Kurata HT, Smith PA and Kerr BJ (2019) Sensory Neurons of the Dorsal Root Ganglia Become Hyperexcitable in a T-Cell-Mediated MOG-EAE Model of Multiple Sclerosis. eNeuro 6(2):https://doi.org/10.1523/ENEURO.0024-19.2019.

  91. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133. https://doi.org/10.1016/j.cell.2006.07.035

    Article  CAS  PubMed  Google Scholar 

  92. Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348(1):15–23. https://doi.org/10.1056/NEJMoa020696

    Article  CAS  PubMed  Google Scholar 

  93. Teitelbaum D, Arnon R, Sela M (1999) Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1. Proc Natl Acad Sci U S A 96(7):3842–3847. https://doi.org/10.1073/pnas.96.7.3842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109. https://doi.org/10.1038/nature06881

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors want to thank Beatrice Muscatello, CISUP (Centre for Instrumentation Sharing—University of Pisa), for her technical assistance during LC/HR-MS investigations.

Funding

This work was supported by recurring grants from the Institut National de la Santé et de la Recherche Médicale (INSERM, France, grant #U1119) and Université de Strasbourg (France, grant #UMR_S 1119). Partial support was provided by the Italian Ministry of Education, Universities and Research (MIUR), grant number 2017MT3993.

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  1. Chiara Tremolanti and Chiara Cavallini Contributed equally to this work

Authors and Affiliations

  1. Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, 67 000, Strasbourg, France

    Chiara Tremolanti, Chiara Cavallini, Laurence Meyer, Christian Klein, Christine Patte-Mensah & Ayikoé-Guy Mensah-Nyagan

  2. Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy

    Chiara Tremolanti, Chiara Cavallini, Eleonora Da Pozzo, Barbara Costa, Lorenzo Germelli & Sabrina Taliani

  3. CISUP - Centre for Instrumentation Sharing - University of Pisa, Lungarno Pacinotti 43, 56126, Pisa, Italy

    Eleonora Da Pozzo, Barbara Costa & Sabrina Taliani

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  1. Chiara Tremolanti
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Contributions

Immunohistochemical experiments, ELISA, data analysis, and contribution to the manuscript draft: CT, CK, LM. Behavioral experiments, clinical scoring, data analysis, and interpretation: CC, CK, LM. TSPO ligand production and critical reading of manuscript: BC, EDP, ST. LC/HR-MS analysis: LG, CT. Study design, supervision, analysis and interpretation of data, manuscript writing, and editing: AGMN and CPM. All authors read and approved the submitted version.

Corresponding author

Correspondence to Ayikoé-Guy Mensah-Nyagan.

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Ethics Approval and Consent to Participate

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed: Ministry of Higher Education and Research, France and CREMEAS ethical committee authorization number 9374–201605111128746-v2. This study does not contain any experiments with human participants performed by any of the authors.

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The authors declare no competing interests.

Author details

1 Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, 67 000 Strasbourg, France.

2 Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.

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Christine Patte-Mensah and Ayikoé-Guy Mensah-Nyagan are co-seniors.

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Tremolanti, C., Cavallini, C., Meyer, L. et al. Translocator Protein Ligand PIGA1138 Reduces Disease Symptoms and Severity in Experimental Autoimmune Encephalomyelitis Model of Primary Progressive Multiple Sclerosis. Mol Neurobiol 59, 1744–1765 (2022). https://doi.org/10.1007/s12035-022-02737-2

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