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Significance of serum VIP and PACAP in multiple sclerosis: an exploratory case–control study

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Abstract

Background

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. Vasoactive and intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are neuropeptides that play roles in anti-inflammation and neuroprotection in MS. In this study, we aimed to determine the serum levels of VIP and PACAP in MS patients versus healthy controls and to correlate them with demographics and clinical characteristics.

Methods

Serum samples were collected from MS patients (n = 145) and healthy controls (n = 73) to measure serum levels VIP and PACAP.

Results

VIP serum levels were lower in MS patients than healthy controls (p < 0.001). Serum PACAP levels were the same among the two groups. Gender-based analysis showed that VIP levels were lower in healthy females (1238.840 pg/ml) than healthy males (3300.105 pg/ml; p < 0.001), and PACAP serum levels were significantly lower in male MS patients (48,516.214 fg/ml) than female MS patients (62,466.400 fg/ml; p = 0.029). ROC curve suggested that serum VIP level can discriminate patients with MS from healthy controls. Relapsing–remitting MS, progressive-MS, and clinically isolated syndrome groups were different in age, MS disease duration, EDSS score, and VIP levels (p < 0.05). MS disease type and history of previous relapses in the preceding 24 months predicted serum VIP levels, while gender predicted PACAP levels.

Conclusion

VIP serum levels are decreased in MS patients and can be used to differentiate between MS patients and healthy controls. Further studies with larger sample sizes are required to investigate VIP as a marker to reflect MS disease progression.

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Data availability

The data may be provided by the corresponding author upon request.

Abbreviations

MS:

Multiple sclerosis

CNS:

Central nervous system

Th:

T-helper

VIP:

Vasoactive intestinal peptide

PACAP:

Pituitary adenylate cyclase-activating peptide

VPAC1:

Vasoactive intestinal peptide type 1

VPAC2:

Vasoactive intestinal peptide type 2

PAC1:

Pituitary adenylate cyclase-activating polypeptide type 1 receptor

EDSS:

Expanded Disability Status Scale

RR-MS:

Relapsing–remitting multiple sclerosis

PR-MS:

Progressive multiple sclerosis

CIS:

Clinically isolated syndrome

ROC:

Receiver operating characteristic

References

  1. Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA et al (2020) Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS. Mult Scler 26(14):1816–1821. https://doi.org/10.1177/1352458520970841

  2. Baecher-Allan C, Kaskow BJ, Weiner HL (2018) Multiple sclerosis: mechanisms and immunotherapy. Neuron 97(4):742–768. https://doi.org/10.1016/j.neuron.2018.01.021

  3. Comi G, Bar-Or A, Lassmann H, Uccelli A, Hartung HP, Montalban X et al (2021) Role of B cells in multiple sclerosis and related disorders. Ann Neurol 89(1):13–23. https://doi.org/10.1002/ana.25927

  4. Kerschensteiner M, Meinl E, Hohlfeld R (2009) Neuro-immune crosstalk in CNS diseases. Neuroscience 158(3):1122–1132. https://doi.org/10.1016/j.neuroscience.2008.09.009

  5. Lassmann H, Brück W, Lucchinetti C (2001) Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 7(3):115–121. https://doi.org/10.1016/s1471-4914(00)01909-2

  6. Baranowska-Bik A, Kochanowski J, Uchman D, Wolinska-Witort E, Kalisz M, Martynska L et al (2013) Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) in humans with multiple sclerosis. J Neuroimmunol 263(1–2):159–161. https://doi.org/10.1016/j.jneuroim.2013.08.012

  7. Schwartz M, Deczkowska A (2016) Neurological disease as a failure of brain–immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol 37(10):668–679. https://doi.org/10.1016/j.it.2016.08.001

  8. Wrona D (2006) Neural–immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J Neuroimmunol 172(1–2):38–58. https://doi.org/10.1016/j.jneuroim.2005.10.017

  9. Carniglia L, Ramírez D, Durand D, Saba J, Turati J, Caruso C et al (2017) Neuropeptides and microglial activation in inflammation, pain, and neurodegenerative diseases. Mediators Inflamm 2017:5048616. https://doi.org/10.1155/2017/5048616

  10. Souza-Moreira L, Campos-Salinas J, Caro M, Gonzalez-Rey E (2011) Neuropeptides as pleiotropic modulators of the immune response. Neuroendocrinology 94(2):89–100. https://doi.org/10.1159/000328636

  11. Tan Y-V, Abad C, Wang Y, Lopez R, Waschek J (2015) VPAC2 (vasoactive intestinal peptide receptor type 2) receptor deficient mice develop exacerbated experimental autoimmune encephalomyelitis with increased Th1/Th17 and reduced Th2/Treg responses. Brain Behav Immun 44:167–175. https://doi.org/10.1016/j.bbi.2014.09.020

  12. Gonzalez-Rey E, Fernandez-Martin A, Chorny A, Martin J, Pozo D, Ganea D et al (2006) Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses. Am J Pathol 168(4):1179–1188. https://doi.org/10.2353/ajpath.2006.051081

  13. Kato H, Ito A, Kawanokuchi J, Jin S, Mizuno T, Ojika K et al (2004) Pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorates experimental autoimmune encephalomyelitis by suppressing the functions of antigen presenting cells. Mult Scler 10(6):651–659. https://doi.org/10.1191/1352458504ms1096oa

  14. Kochanowski J, Uchman D, Litwiniuk A, Kalisz M, Wolinska-Witort E, Martynska L, et al (2015) Assessment of plasma brain-derived neurotrophic factor (BDNF), activity-dependent neurotrophin protein (ADNP) and vasoactive intestinal peptide (VIP) concentrations in treatment-naive humans with multiple sclerosis. Neuro Endocrinol Lett 36(2)

  15. Sun W, Hong J, Zang YC, Liu X, Zhang JZ (2006) Altered expression of vasoactive intestinal peptide receptors in T lymphocytes and aberrant Th1 immunity in multiple sclerosis. Int Immunol 18(12):1691–1700. https://doi.org/10.1093/intimm/dxl103

  16. Martínez C, Ortiz AM, Juarranz Y, Lamana A, Seoane IV, Leceta J, et al (2014) Serum levels of vasoactive intestinal peptide as a prognostic marker in early arthritis. Plos One 9(1):e85248. https://doi.org/10.1371/journal.pone.0085248

  17. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G et al (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17(2):162–173. https://doi.org/10.1016/S1474-4422(17)30470-2

  18. Goldman MD, Motl RW, Rudick RA (2010) Possible clinical outcome measures for clinical trials in patients with multiple sclerosis. Neurol Disord 3(4):229–239. https://doi.org/10.1177/1756285610374117

  19. Sevim S (2016) Relapses in multiple sclerosis: definition, pathophysiology, features, imitators, and treatment. Turk Noroloji Dergisi 22(3). https://doi.org/10.4274/TND.75318

  20. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ et al (2014) Defining the clinical course of multiple sclerosis,” The 2013 revisions. Neurology 83(3):278–286. https://doi.org/10.1212/WNL.0000000000000560

  21. Unal I (2017) Defining an optimal cut-point value in ROC analysis: an alternative approach. Comput Math Methods Med 2017:3762651. https://doi.org/10.1155/2017/3762651

  22. Waschek JA (2013) VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair. Br J Pharmacol 169(3):512–523. https://doi.org/10.1111/bph.12181

  23. Bosca I, Coret F, Valero C, Pascual AM, Magraner MJ, Landete L, Casanova B (2008) Effect of relapses over early progression of disability in multiple sclerosis patients treated with beta-interferon. Mult Scler 14(5):636–639. https://doi.org/10.1177/1352458507086666

  24. Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y (2009) Impact of multiple sclerosis relapses on progression diminishes with time. Neurology 73(20):1616–1623. https://doi.org/10.1212/WNL.0b013e3181c1e44f

  25. Andersen O, Fahrenkrug J, Wikkelsø C, Johansson BB (1984) VIP in cerebrospinal fluid of patients with multiple sclerosis. Acta Neurol Scand 5(2):435–437. https://doi.org/10.1111/j.1600-0404.1984.tb00830.x

  26. Abad C, Jayaram B, Becquet L, Wang Y, O’Dorisio MS, Waschek JA, Tan YV (2016) VPAC1 receptor (Vipr1)-deficient mice exhibit ameliorated experimental autoimmune encephalomyelitis, with specific deficits in the effector stage. J Neuroinflammation 13(1):1–14. https://doi.org/10.1186/s12974-016-0626-3

  27. Caughey GH, Leidig F, Viro NF, Nadel JA (1988) Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. J Pharmacol Exp Ther 244(1):133–137

  28. Rozniecki J, Hauser S, Stein M, Lincoln R, Theoharides TC (1995) Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol 37(1):63–66. https://doi.org/10.1002/ana.410370112

  29. Ganea D, Hooper KM, Kong W (2015) The neuropeptide vasoactive intestinal peptide: direct effects on immune cells and involvement in inflammatory and autoimmune diseases. Acta Physiol (Oxf) 213(2):442–452. https://doi.org/10.1111/apha.12427

  30. Reglodi D, Helyes Z, Nemeth J, Vass RA, Tamas A (2016) PACAP as a potential biomarker: alterations of PACAP levels in human physiological and pathological conditions. (11):815–832. https://doi.org/10.1007/978-3-319-35135-3_48

  31. Mosca E, Rousseau J, Gulemetova R, Kinkead R, Wilson RJA (2015) The effects of sex and neonatal stress on pituitary adenylate cyclase‐activating peptide expression. Exp Physiol 100(2):203–215. https://doi.org/10.1113/expphysiol.2014.082180

  32. Laszlo E, Tamas J, Adam V, Bernadett C, Krisztina K, Peter D et al (2019) Protective effect of PACAP on ischemia/reperfusion-induced kidney injury of male and female rats: gender differences. J Mol Neurosci 68(3):408–419. https://doi.org/10.1007/s12031-018-1207-y

  33. Hou L, Wan D, Dong Z, Tang W, Han X, Li L, Yang F, Yu S (2016) Pituitary adenylate cyclase-activating polypeptide expression in peripheral blood mononuclear cells of migraineurs. Cell Biosci 6(1):1–6. https://doi.org/10.1186/s13578-016-0106-6

  34. Dow RC, Bennie J, Fink G (1994) Pituitary adenylate cyclase-activating peptide-38 (PACAP)-38 is released into hypophysial portal blood in the normal male and female rat. J Endocrinol 142(1):R1-R4. https://doi.org/10.1677/joe.0.142r001

  35. Winters SJ, King JC, Brees CK, Moore Jr JP (2014) Pituitary adenylate cyclase-activating polypeptide (PACAP) in fetal cord blood. Early Hum Dev 90(9):451–453. https://doi.org/10.1016/j.earlhumdev.2014.06.001

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Acknowledgements

The authors thank Doctor Waleed Batiha, a neurologist at PBTH, for his helpful advices and cooperation with the research team.

Funding

This study was funded by Scientific Research Support, Ministry of Higher Education and Scientific Research, Amman, Jordan. Research Grant No: 2018126.

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Authors and Affiliations

Authors

Contributions

MSA generated the idea, designed and supervised the study, and prepared the original draft. BAA contributed to data entry into SPSS, analysis, and interpretation. NAA supervised serum sample analysis and participated in interpreting the data and preparing the figures. MA participated in the recruitment of patients. SAJ contributed to the analysis and interpretation of the data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Maha S. Al-Keilani.

Ethics declarations

Ethical approval

The study was approved by the Research and Ethics Committee at Jordan University of Science and Technology (registration number 17/115/2018).

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All subjects signed a written informed consent in accordance with the Declaration of Helsinki.

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Not applicable.

Conflict of interest

The authors declare no competing interests.

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Al-Keilani, M.S., Almomani, B.A., Al-Sawalha, N.A. et al. Significance of serum VIP and PACAP in multiple sclerosis: an exploratory case–control study. Neurol Sci 43, 2621–2630 (2022). https://doi.org/10.1007/s10072-021-05682-5

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  • DOI: https://doi.org/10.1007/s10072-021-05682-5

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