Abstract
Toxoplasma gondii is an intracellular protozoan parasite that causes neuroinflammation in the brain and a constant need for peripheral leukocyte migration. Matrix metalloproteinase 9 (MMP-9) can play a major role in this neuroinflammation and be implicated in some neurological disorders, such as migraines. Therefore, the genetic polymorphism evaluation of MMP-9 in migraine patients with T. gondii infection was performed. One hundred fourteen migraine patients and 114 healthy controls were evaluated for the presence of anti-Toxoplasma IgG antibodies. Seventy-two migraine patients and 40 healthy controls were randomly selected for assessment of the MMP 9-1562C/T genetic polymorphism. In the preliminary examination, 61 (53.5%) migraine patients and 43 (37.3%) healthy controls were positive for IgG antibodies, with a significant association between T. gondii seropositivity and migraine (OR = 1.90; 95% CI = 1.21–3.223; P = 0.012). Genetic distribution for the polymorphism was not in Hardy–Weinberg equilibrium in cases but showed no significant variation in control groups (P = 0.03 and P = 0.180, respectively). A significant preponderance of the CT + TT genotype was found in migraine subjects compared to controls (P = 0.042) (OR, 1.77, CI, 1.013–2.229). The homozygote muted allele TT had a higher rate in migraine patients (6.9%). There were significant differences in CT + TT genotype between T. gondii positive and negative migraine patients (P = 0.024), but T allele frequencies had no significant variation (OR 1.7 CI, 1.084–2.44 and 0.42 CI, 0.044–3.97, respectively). In conclusion, the results may provide the first evidence for the involvement of the MMP-9 gene polymorphism in the mechanism of migraine pathology following Toxoplasma infection.
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No datasets were generated or analysed during the current study.
References
Alvarado-Esquivel C, Del Rosario Y, Rico-Almochantaf LF, Sanchez-Anguiano G-C, Hernandez-Tinoco J, Torres-Gonzalez J, Gonzalez-Silva MF, Ramirez-Valles EG (2018) Toxoplasma gondii infection and headache: a matched case-control study in a public hospital in Durango City, Mexico. J Clin Med Res 10:27–31
Bernecker C, Pailer S, Kieslinger P, Horejsi R, Möller R, Lechner A, Wallner-Blazek M, Weiss S, Fazekas F, Truschnig-Wilders M, Gruber HJ (2011) Increased matrix metalloproteinase activity is associated with migraine and migraine-related metabolic dysfunctions. Eur J Neurol 18:571–576. https://doi.org/10.1155/2012/952906
Bruschi F, Pinto B (2013) The significance of matrix metalloproteinases in parasitic infections involving the central nervous system. Pathogens 2:105–129. https://doi.org/10.3390/pathogens2010105
Buraczynska K, Kurzepa J, Ksiazek A, Buraczynska M, Rejdak K (2015) Matrix metalloproteinase-9 (MMP-9) gene polymorphism in stroke patients. Neuromolecular Med 17:385–390. https://doi.org/10.1007/s12017-015-8367-5
Burch R, Rizzoli P, Loder E (2021) The prevalence and impact of migraine and severe headache in the United States: updated age, sex, and socioeconomic-specific estimates from government health surveys. Headache 61:60–68. https://doi.org/10.1111/head.14024
Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC, Lipton RB (2012) Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache 52:1456–1470. https://doi.org/10.1111/j.1526-4610.2012.02223.x
Charles A (2018) The pathophysiology of migraine: implications for clinical management. The Lancet Neurol 17:174–182. https://doi.org/10.1016/S1474-4422(17)30435-0
Chen X, Chen B, Hou X, Zheng C, Yang X, Ke J, Hu X, Tan F (2019) Association between Toxoplasma gondii infection and psychiatric disorders in Zhejiang, Southeastern China. Acta Trop 192:82–86. https://doi.org/10.1016/j.actatropica.2019.02.001
Clark RT, Philip Nance J, Noor S, Wilson EH (2011) T-cell production of matrix metalloproteinases and inhibition of parasite clearance by TIMP-1 during chronic Toxoplasma infection in the brain. ASN Neuro 3:e00049-e49. https://doi.org/10.1042/AN20100027
Daryani A, Sarvi S, Aarabi M, Mizani A, Ahmadpour E, Shokri A et al (2014) Seroprevalence of Toxoplasma gondii in the Iranian general population: a systematic review and meta-analysis. Acta Trop 137:185–94. https://doi.org/10.1016/j.actatropica.2014.05.015
Dubey JP, Jones JL (2008) Toxoplasma gondii infection in humans and animals in the United States. Int J Parasitol 38:1257–1278. https://doi.org/10.1016/j.ijpara.2008.03.007
El Mouhawess A, Hammoud A, Zoghbi M, Hallit S, Haddad C, El Haddad K, El Khoury S, Tannous J, Obeid S, Halabi MA, Mammari N (2020) Relationship between Toxoplasma gondii seropositivity and schizophrenia in the Lebanese population: potential implication of genetic polymorphism of MMP-9. BMC Psychiatry 20:264. https://doi.org/10.1186/s12888-020-02683-0
Han H, He X, Tang J, Liu W, Liu K, Zhang J, Wang X, Xu Y, Chen X (2011) The C(−1562)T polymorphism of matrix metalloproteinase-9 gene is associated with schizophrenia in China. Psychiatry Res 190:163–164. https://doi.org/10.1016/j.psychres.2011.04.026
Imamura K, Takeshima T, Fusayasu E, Nakashima K (2008) Increased plasma matrix metalloproteinase-9 levels in migraineurs. Headache 48:135–139. https://doi.org/10.1111/j.1526-4610.2007.00958.x
Jouyani N, Ahady MT, Abbasi V (2020) Serum level of anti-Toxoplasma gondii IgG among the individuals with/without migraine. J SS Univ Med Sci Health Serv. 28: 1–5.https://doi.org/10.18502/ssu.v28i1.3134
Khan J, Asoom LIA, Sunni AA, Rafique N, Latif R, Saif SA, Almandil NB, Almohazey D, AbdulAzeez S, Borgio JF (2021) Genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. Biomed Pharmacother 139:111557. https://doi.org/10.1016/j.biopha.2021.111557
Koseoglu E, Yazar S, Koc I (2009) Is Toxoplasma gondii a causal agent in migraine? Am J Med Sci 338:120–122. https://doi.org/10.1097/MAJ.0b013e31819f8cac
Kursun O, Yemisci M, Maagdenberg AMJM, Karatas H (2021) Migraine and neuroinflammation: the inflammasome perspective. J Headache Pain 22:55. https://doi.org/10.1186/s10194-021-01271-1
Lakhan SE, Avramut M (2012) Matrix metalloproteinases in neuropathic pain and migraine: friends, enemies, and therapeutic targets. Pain Res Treat 2012:952906. https://doi.org/10.1155/2012/952906
Lee HH, Chou HL, Chen KM, Lai SC (2004) Association of matrix metalloproteinase-9 in eosinophilic meningitis of BALB/c mice caused by Angiostrongylus cantonensis. Parasitol Res 94:321–328. https://doi.org/10.1007/s00436-004-1196-3
Leira R, Sobrino T, Rodríguez-Yáñez M, Blanco M, Arias S, Castillo J (2007) Mmp-9 immunoreactivity in acute migraine. Headache 47:698–702. https://doi.org/10.1111/j.1526-4610.2006.00641.x
Lu C-Y, Lai SC (2013) Matrix metalloproteinase-2 and -9 lead to fibronectin degradation in astroglia infected with Toxoplasma gondii. Acta Trop 125:320–329. https://doi.org/10.1016/j.actatropica.2012.11.002
Martins-Oliveira A, Speciali JG, Dach F, Marcaccini AM, Gonçalves FM, Gerlach RF, Tanus-Santos JE (2009) Different circulating metalloproteinases profiles in women with migraine with and without aura. Clinica Chim Acta 408:60–64. https://doi.org/10.1016/j.cca.2009.07.008
Martins-Oliveira A, Gonçalves FM, Speciali JG, Fontana V, Izidoro-Toledo TC, Belo VA, Dach F, Tanus-Santos JE (2012) Specific matrix metalloproteinase 9 (MMP-9) haplotype affect the circulating MMP-9 levels in women with migraine. J Neuroimmunol 252:89–94. https://doi.org/10.1016/j.jneuroim.2012.07.016
Mitra R, Sapolsky RM, Vyas A (2013) Toxoplasma gondii infection induces dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion. Dis Model Mech 6:516–520. https://doi.org/10.1242/dmm.009928
Mohammadi P, Khodamorovati M, Vafaee K, Hemmati M, Darvishi N, Ghasemi H (2023) Prevalence of migraine in Iran: a systematic review and meta-analysis. BMC Neurol 23:172. https://doi.org/10.1186/s12883-023-03215-5
Olesen J (2018) Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edn. Cephalalgia 38:1–211. https://doi.org/10.1177/0333102417738202
Prandota J (2007) Recurrent headache as the main symptom of acquired cerebral toxoplasmosis in nonhuman immunodeficiency virus-infected subjects with no lymphadenopathy: the parasite may be responsible for the neurogenic inflammation postulated as a cause of different types of headaches. Am J Ther 14:63–105. https://doi.org/10.1097/01.mjt.0000208272.42379.aa
Prandota J (2009) The importance of toxoplasma gondii infection in diseases presenting with headaches. Headaches and aseptic meningitis may be manifestations of the Jarisch-Herxheimer reaction. Int J Neurosci 119:2144–2182. https://doi.org/10.3109/00207450903149217
Rybakowski JK, Skibinska M, Leszczynska-Rodziewicz A, Kaczmarek L, Hauser J (2009) Matrix metalloproteinase-9 gene and bipolar mood disorder. Neuromol Med 11:128–132. https://doi.org/10.1007/s12017-009-8072-3
Santoni JR, Santoni-Williams CJ (1993) Headache and painful lymphadenopathy in extracranial or systemic infection: etiology of new daily persistent headaches. Intern Med 32:530–532
Silva CS, Neves S, Benchimol EI, Moraes DR (2008) Postnatal acquired toxoplasmosis patients in an infectious diseases reference center. Braz J Infect Dis 12:438–441. https://doi.org/10.1590/s1413-86702008000500016
Stovner LJ, Nichols E, Steiner TJ, Abd-Allah F, Abdelalim A, Al-Raddadi RM, Geleto Ansha M et al (2018) Global, regional, and national burden of migraine and tension-type headache, 1990–2013;2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 17:954–976. https://doi.org/10.1016/S1474-4422(18)30322-3
Welch KM, Goadsby PJ (2002) Chronic daily headache: nosology and pathophysiology. Curr Opin Neurol 15:287–295. https://doi.org/10.1097/00019052-200206000-00011
Wong WK, Upton A, Thomas MG (2013) Neuropsychiatric symptoms are common in immunocompetent adult patients with Toxoplasma gondii acute lymphadenitis. Scand J Infect Dis 45:357–361. https://doi.org/10.3109/00365548.2012.737017
World Health Organization 22-07 (2020) https://www.who.int/news/item/22-07-2020-wha-report-on-addressing-the-burden-of-epilepsy-and-other-neurological-disorders-available-online
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This study was supported by the Babol University of Medical Sciences (Grant No: 140114225).
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T.G.F., P.S, and E.F.S. made substantial contributions to the conception and design of the study. All authors contributed to data acquisition, T.G.F., and S.H. performed experimental works. T.G.F. analyzed and interpreted the data. T.G.F. has written the first draft of the manuscript and revised it critically. All authors read and approved the final manuscript.
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Hashemi, S., Saadat, P., Gorgani-Firouzjaee, T. et al. Potential genetic polymorphism of matrix metalloproteinase (MMP)-9 in Iranian migraine patients with Toxoplasma gondii infection. Parasitol Res 123, 140 (2024). https://doi.org/10.1007/s00436-024-08156-7
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DOI: https://doi.org/10.1007/s00436-024-08156-7