Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Alpha Calcitonin Gene-related Peptide, Neuropeptide Y, and Substance P as Biomarkers for Diagnosis and Disease Activity and Severity in Multiple Sclerosis

Author(s): Maha S. Al-Keilani*, Basima A. Almomani, Saied A. Jaradat, Nour A. Al-Sawalha and Majdi Al Qawasmeh

Volume 23, Issue 4, 2024

Published on: 11 May, 2023

Page: [512 - 524] Pages: 13

DOI: 10.2174/1871527322666230403130540

Price: $65

Abstract

Background: Alpha calcitonin gene-related peptide (aCGRP), neuropeptide Y (NPY), and substance P (SP) are neuropeptides that have emerged recently as potent immunomodulatory factors with potential as novel biomarkers and therapeutic targets in multiple sclerosis (MS).

Objective: The study aimed to detect serum levels of aCGRP, NPY, and SP in MS patients versus healthy controls and their association with disease activity and severity.

Methods: Serum levels were measured in MS patients and age and sex-matched healthy controls using ELISA.

Results: We included 67 MS patients: 61 relapsing-remitting MS (RR-MS) and 6 progressive MS (PR-MS), and 67 healthy controls. Serum NPY level was found to be lower in MS patients than in healthy controls (p < 0.001). Serum aCGRP level was higher in PR-MS compared to RR-MS (p = 0.007) and healthy controls (p = 0.001), and it positively correlated with EDSS (r = 0.270, p = 0.028). Serum NPY level was significantly higher in RR-MS and PR-MS than in healthy controls (p < 0.001 and p = 0.001, respectively), and it was lower in patients with mild or moderate/severe disease than in healthy controls (p < 0.001). Significant inverse correlations were found between SP level and MS disease duration (r = -0.279, p = 0.022) and duration of current DMT (r = -0.315, p = 0.042).

Conclusion: Lower serum levels of NPY were revealed in MS patients compared to healthy controls. Since serum levels of aCGRP are significantly associated with disease activity and severity, it is a potential disease progression marker.

« Previous Next »
Graphical Abstract

[1]
Matute-Blanch C, Montalban X, Comabella M. Multiple sclerosis, and other demyelinating and autoimmune inflammatory diseases of the central nervous system. Handb Clin Neurol 2018; 146: 67-84.
[http://dx.doi.org/10.1016/B978-0-12-804279-3.00005-8] [PMID: 29110780]
[2]
Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler 2020; 26(14): 1816-21.
[http://dx.doi.org/10.1177/1352458520970841] [PMID: 33174475]
[3]
Waubant E, Lucas R, Mowry E, et al. Environmental and genetic risk factors for MS: An integrated review. Ann Clin Transl Neurol 2019; 6(9): 1905-22.
[http://dx.doi.org/10.1002/acn3.50862] [PMID: 31392849]
[4]
Stys PK, Tsutsui S. Recent advances in understanding multiple sclerosis. F1000 Res 2019; 8: 2100.
[http://dx.doi.org/10.12688/f1000research.20906.1] [PMID: 31885862]
[5]
Assas BM, Pennock JI, Miyan JA. Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis. Front Neurosci 2014; 8: 23.
[http://dx.doi.org/10.3389/fnins.2014.00023] [PMID: 24592205]
[6]
Johnson MB, Young AD, Marriott I. The therapeutic potential of targeting substance P/NK-1R interactions in inflammatory CNS disorders. Front Cell Neurosci 2017; 10: 296.
[http://dx.doi.org/10.3389/fncel.2016.00296] [PMID: 28101005]
[7]
Brain SD, Cox HM. Neuropeptides and their receptors: Innovative science providing novel therapeutic targets. Br J Pharmacol 2006; 147(S1) (Suppl. 1): S202-11.
[http://dx.doi.org/10.1038/sj.bjp.0706461] [PMID: 16402106]
[8]
Douglas SD, Leeman SE. Neurokinin-1 receptor: Functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci 2011; 1217(1): 83-95.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05826.x] [PMID: 21091716]
[9]
Chen W, Liu Y, Liu W, Zhou Y, He H, Lin S. Neuropeptide Y is an immunomodulatory factor: Direct and indirect. Front Immunol 2020; 11: 580378.
[http://dx.doi.org/10.3389/fimmu.2020.580378] [PMID: 33123166]
[10]
Mikami N, Matsushita H, Kato T, et al. Calcitonin gene-related peptide is an important regulator of cutaneous immunity: Effect on dendritic cell and T cell functions. J Immunol 2011; 186(12): 6886-93.
[http://dx.doi.org/10.4049/jimmunol.1100028] [PMID: 21551361]
[11]
Glaser SS, Ueno Y, DeMorrow S, et al. Knockout of α-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice. Lab Invest 2007; 87(9): 914-26.
[http://dx.doi.org/10.1038/labinvest.3700602] [PMID: 17618297]
[12]
Ebbinghaus M, Natura G, Segond von Banchet G, et al. Interleukin-17A is involved in mechanical hyperalgesia but not in the severity of murine antigen-induced arthritis. Sci Rep 2017; 7(1): 10334.
[http://dx.doi.org/10.1038/s41598-017-10509-5] [PMID: 28871176]
[13]
Cameron ND, McCullough E, Troup K, Penman JC. Serum neuropeptide Y (NPY) and leptin concentrations in pigs selected for components of efficient lean growth. Domest Anim Endocrinol 2003; 24(1): 15-29.
[http://dx.doi.org/10.1016/S0739-7240(02)00184-4] [PMID: 12450622]
[14]
Ding WG, Zhang ZM, Zhang YH, Jiang SD, Jiang LS, Dai LY. Changes of substance P during fracture healing in ovariectomized mice. Regul Pept 2010; 159(1-3): 28-34.
[http://dx.doi.org/10.1016/j.regpep.2009.11.004] [PMID: 19903498]
[15]
Sardi C, Zambusi L, Finardi A, et al. Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis. J Neuroimmunol 2014; 271(1-2): 18-29.
[http://dx.doi.org/10.1016/j.jneuroim.2014.03.008] [PMID: 24746422]
[16]
Pérez-Pereda S, Toriello-Suárez M, Ocejo-Vinyals G, et al. Serum CGRP, VIP, and PACAP usefulness in migraine: A case–control study in chronic migraine patients in real clinical practice. Mol Biol Rep 2020; 47(9): 7125-38.
[http://dx.doi.org/10.1007/s11033-020-05781-0] [PMID: 32951099]
[17]
Takkar A, Kumar KVA, Katoch D, et al. Serum calcitonin generelated peptide is elevated in patients with migraine and ophthalmoplegia. J Neuroophthalmol 2022. Publish Ahead of Print: 10-97.
[http://dx.doi.org/10.1097/WNO.0000000000001695] [PMID: 6255114]
[18]
Brod SA, Bauer VL. Ingested (oral) neuropeptide Y inhibits EAE. J Neuroimmunol 2012; 250(1-2): 44-9.
[http://dx.doi.org/10.1016/j.jneuroim.2012.05.015] [PMID: 22703767]
[19]
Koide S, Onishi H, Hashimoto H, Kai T, Yamagami S. Plasma neuropeptide Y is reduced in patients with Alzheimer’s disease. Neurosci Lett 1995; 198(2): 149-51.
[http://dx.doi.org/10.1016/0304-3940(95)11973-Z] [PMID: 8592643]
[20]
Ramirez-Villafaña M, Saldaña-Cruz AM, Aceves-Aceves JA, et al. Serum neuropeptide Y levels are associated with TNF-α levels and disease activity in rheumatoid arthritis. J Immunol Res 2020; 2020: 1-7.
[http://dx.doi.org/10.1155/2020/8982163] [PMID: 32377539]
[21]
Reinke EK, Johnson MJ, Ling C, et al. Substance P receptor mediated maintenance of chronic inflammation in EAE. J Neuroimmunol 2006; 180(1-2): 117-25.
[http://dx.doi.org/10.1016/j.jneuroim.2006.07.010] [PMID: 16942803]
[22]
Barbosa-Cobos RE, Lugo-Zamudio G, Flores-Estrada J, et al. Serum substance P: An indicator of disease activity and subclinical inflammation in rheumatoid arthritis. Clin Rheumatol 2018; 37(4): 901-8.
[http://dx.doi.org/10.1007/s10067-017-3929-6] [PMID: 29256110]
[23]
Lorente L, Martín MM, Almeida T, et al. Serum substance P levels are associated with severity and mortality in patients with severe traumatic brain injury. Crit Care 2015; 19(1): 192.
[http://dx.doi.org/10.1186/s13054-015-0911-z] [PMID: 25928056]
[24]
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17(2): 162-73.
[http://dx.doi.org/10.1016/S1474-4422(17)30470-2] [PMID: 29275977]
[25]
Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014; 83(3): 278-86.
[http://dx.doi.org/10.1212/WNL.0000000000000560] [PMID: 24871874]
[26]
Sevim S. Relapses in multiple sclerosis: Definition, pathophysiology, features, imitators, and treatment. Turk Noroloji Dergisi 2016; 22(3): 99-108.
[http://dx.doi.org/10.4274/tnd.75318]
[27]
Goldman MD, Motl RW, Rudick RA. Possible clinical outcome measures for clinical trials in patients with multiple sclerosis. Ther Adv Neurol Disord 2010; 3(4): 229-39.
[http://dx.doi.org/10.1177/1756285610374117] [PMID: 21179614]
[28]
Unal I. Defining an optimal cut-point value in ROC analysis: An alternative approach. Comput Math Methods Med 2017; 2017: 1-14.
[http://dx.doi.org/10.1155/2017/3762651] [PMID: 28642804]
[29]
Abdelhak A, Huss A, Kassubek J, Tumani H, Otto M. Serum GFAP as a biomarker for disease severity in multiple sclerosis. Sci Rep 2018; 8(1): 14798.
[http://dx.doi.org/10.1038/s41598-018-33158-8] [PMID: 30287870]
[30]
Keane RW, Dietrich WD, de Rivero Vaccari JP. Inflammasome proteins as biomarkers of multiple sclerosis. Front Neurol 2018; 9: 135.
[http://dx.doi.org/10.3389/fneur.2018.00135] [PMID: 29615953]
[31]
abdel Naseer M, Rabah AM, Rashed LA, Hassan A, Fouad AM. Glutamate and nitric oxide as biomarkers for disease activity in patients with multiple sclerosis. Mult Scler Relat Disord 2020; 38: 101873.
[http://dx.doi.org/10.1016/j.msard.2019.101873] [PMID: 31816505]
[32]
Mikami N, Watanabe K, Hashimoto N, et al. Calcitonin gene-related peptide enhances experimental autoimmune encephalomyelitis by promoting Th17-cell functions. Int Immunol 2012; 24(11): 681-91.
[http://dx.doi.org/10.1093/intimm/dxs075] [PMID: 22843730]
[33]
Bedoui S, Miyake S, Lin Y, et al. Neuropeptide Y (NPY) suppresses experimental autoimmune encephalomyelitis: NPY1 receptor-specific inhibition of autoreactive Th1 responses in vivo. J Immunol 2003; 171(7): 3451-8.
[http://dx.doi.org/10.4049/jimmunol.171.7.3451] [PMID: 14500640]
[34]
Constantinescu CS, Farooqi N, O’Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 2011; 164(4): 1079-106.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01302.x] [PMID: 21371012]
[35]
Matsuda R, Kezuka T, Nishiyama C, et al. Suppression of murine experimental autoimmune optic neuritis by mature dendritic cells transfected with calcitonin gene-related Peptide gene. Invest Ophthalmol Vis Sci 2012; 53(9): 5475-85.
[http://dx.doi.org/10.1167/iovs.12-9935] [PMID: 22807299]
[36]
Donnerer J, Stein C. Evidence for an increase in the release of CGRP from sensory nerves during inflammation Ann N Y Acad Sci 657(1 Calcitonin Ge): 505-6.1992;
[http://dx.doi.org/10.1111/j.1749-6632.1992.tb22814.x] [PMID: 1379022]
[37]
Bründl E, Proescholdt M, Störr EM, et al. The endogenous neuropeptide calcitonin gene-related peptide after spontaneous subarachnoid hemorrhage–A potential psychoactive prognostic serum biomarker of pain-associated neuropsychological symptoms. Front Neurol 2022; 13: 889213.
[http://dx.doi.org/10.3389/fneur.2022.889213] [PMID: 35968282]
[38]
Juul R, Hara H, Gisvold SE, et al. Alterations in perivascular dilatory neuropeptides (CGRP, SP, VIP) in the external jugular vein and in the cerebrospinal fluid following subarachnoid haemorrhage in man. Acta Neurochir 1995; 132(1-3): 32-41.
[http://dx.doi.org/10.1007/BF01404845] [PMID: 7538726]
[39]
Schebesch KM, Bründl E, Hochreiter A, et al. Calcitonin gene-related peptide in serum after spontaneous subarachnoid hemorrhage. Am J Neurosci 2014; 5(1): 10-7.
[http://dx.doi.org/10.3844/amjnsp.2014.10.17]
[40]
Dötsch J, Adelmann M, Englaro P, et al. Relation of leptin and neuropeptide Y in human blood and cerebrospinal fluid. J Neurol Sci 1997; 151(2): 185-8.
[http://dx.doi.org/10.1016/S0022-510X(97)00116-0] [PMID: 9349674]
[41]
Maeda K, Yasuda M, Kaneda H, Maeda S, Yamadori A. Cerebrospinal fluid (CSF) neuropeptide Y- and somatostatin-like immunoreactivities in man. Neuropeptides 1994; 27(6): 323-32.
[http://dx.doi.org/10.1016/0143-4179(94)90058-2] [PMID: 7898640]
[42]
dos Santos VV, Santos DB, Lach G, et al. Neuropeptide Y (NPY) prevents depressive-like behavior, spatial memory deficits and oxidative stress following amyloid-β (Aβ1–40) administration in mice. Behav Brain Res 2013; 244: 107-15.
[http://dx.doi.org/10.1016/j.bbr.2013.01.039] [PMID: 23396168]
[43]
Spencer B, Potkar R, Metcalf J, et al. Systemic central nervous system (CNS)-targeted delivery of neuropeptide Y (NPY) reduces neurodegeneration and increases neural precursor cell proliferation in a mouse model of Alzheimer disease. J Biol Chem 2016; 291(4): 1905-20.
[http://dx.doi.org/10.1074/jbc.M115.678185] [PMID: 26620558]
[44]
Clark CM, Clark RM, Hoyle JA, Dickson TC. Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis. J Neurochem 2021; 156(3): 273-89.
[http://dx.doi.org/10.1111/jnc.15125] [PMID: 32654149]
[45]
Coppin H, Ribouchon M-T, Fontaine B, Edan G, Clanet M, Roth M-P. A vulnerability locus to multiple sclerosis maps to 7p15 in a region syntenic to an EAE locus in the rat. Genes Immun 2004; 5(1): 72-5.
[http://dx.doi.org/10.1038/sj.gene.6364038] [PMID: 14735153]
[46]
Mohammadi SM, Shirvani Farsani Z, Dosti R, Sahraian MA, Behmanesh M. Association study of two functional single nucleotide polymorphisms of neuropeptide y gene with multiple sclerosis. Neuropeptides 2016; 60: 45-50.
[http://dx.doi.org/10.1016/j.npep.2016.08.004] [PMID: 27559040]
[47]
Barker R, Larner A. Substance P and multiple sclerosis. Med Hypotheses 1992; 37(1): 40-3.
[http://dx.doi.org/10.1016/0306-9877(92)90011-Z] [PMID: 1373793]
[48]
Lewis KM, Turner RJ, Vink R. Blocking neurogenic inflammation for the treatment of acute disorders of the central nervous system. Int J Inflamm 2013; 2013: 1-16.
[http://dx.doi.org/10.1155/2013/578480] [PMID: 23819099]
[49]
Nessler S, Stadelmann C, Bittner A, et al. Suppression of autoimmune encephalomyelitis by a neurokinin-1 receptor antagonist-a putative role for substance P in CNS inflammation. J Neuroimmunol 2006; 179(1-2): 1-8.
[http://dx.doi.org/10.1016/j.jneuroim.2006.06.026] [PMID: 16904192]
[50]
Vandenbroeck K, Fiten P, Heggarty S, et al. Chromosome 7q21–22 and multiple sclerosis: Evidence for a genetic susceptibility effect in vicinity to the protachykinin-1 gene. J Neuroimmunol 2002; 125(1-2): 141-8.
[http://dx.doi.org/10.1016/S0165-5728(02)00023-1] [PMID: 11960650]
[51]
Cunningham S, Patterson CC, McDonnell G, Hawkins S, Vandenbroeck K. Haplotype analysis of the preprotachykinin-1 (TAC1) gene in multiple sclerosis. Genes Immun 2005; 6(3): 265-70.
[http://dx.doi.org/10.1038/sj.gene.6364175] [PMID: 15729363]
[52]
Rösler N, Reuner C, Geiger J, Rissler K, Cramer H. Cerebrospinal fluid levels of immunoreactive substance P and somatostatin in patients with multiple sclerosis and inflammatory CNS disease. Peptides 1990; 11(1): 181-3.
[http://dx.doi.org/10.1016/0196-9781(90)90129-S] [PMID: 1692993]
[53]
Clark JW, Senanayake P, Solomon GD, Gallagher C, Substance P. Correlation of CSF and plasma levels. Headache 1994; 34(5): 261-4.
[http://dx.doi.org/10.1111/j.1526-4610.1994.hed3405261.x] [PMID: 7517924]
[54]
Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels of substance p in patients with the fibromyalgia syndrome. Arthritis Rheum 1994; 37(11): 1593-601.
[http://dx.doi.org/10.1002/art.1780371106] [PMID: 7526868]
[55]
Matsuishi T, Nagamitsu S, Yamashita Y, et al. Decreased cerebrospinal fluid levels of substance P in patients with Rett syndrome. Ann Neurol 1997; 42(6): 978-81.
[http://dx.doi.org/10.1002/ana.410420621] [PMID: 9403492]
[56]
Haschka D, Tymoszuk P, Bsteh G, et al. Expansion of neutrophils and classical and nonclassical monocytes as a hallmark in relapsing-remitting multiple sclerosis. Front Immunol 2020; 11: 594.
[http://dx.doi.org/10.3389/fimmu.2020.00594] [PMID: 32411125]
[57]
Waschbisch A, Schröder S, Schraudner D, et al. Pivotal role for CD16+ monocytes in immune surveillance of the central nervous system. J Immunol 2016; 196(4): 1558-67.
[http://dx.doi.org/10.4049/jimmunol.1501960] [PMID: 26746191]
[58]
Procaccini C, De Rosa V, Pucino V, Formisano L, Matarese G. Animal models of multiple sclerosis. Eur J Pharmacol 2015; 759: 182-91.
[http://dx.doi.org/10.1016/j.ejphar.2015.03.042] [PMID: 25823807]
[59]
Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I. The relevance of animal models in multiple sclerosis research. Pathophysiology 2011; 18(1): 21-9.
[http://dx.doi.org/10.1016/j.pathophys.2010.04.004] [PMID: 20537877]
[60]
Sriram S, Steiner I. Experimental allergic encephalomyelitis: A misleading model of multiple sclerosis. Ann Neurol 2005; 58(6): 939-45.
[http://dx.doi.org/10.1002/ana.20743] [PMID: 16315280]
[61]
Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 2000; 192(3): 393-404.
[http://dx.doi.org/10.1084/jem.192.3.393] [PMID: 10934227]
[62]
Nelson AL, Bieber AJ, Rodriguez M. Contrasting murine models of MS. Int MS J 2004; 11(3): 95-9.
[PMID: 15585167]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy