Research Article| Volume 367, P291-297, August 15, 2016

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Evaluation of serum matrix metalloproteinase-3 as a biomarker for diagnosis of epilepsy


      • Epilepsy patients have lower serum MMP-3 levels than healthy controls.
      • Serum MMP-3 concentrations were significantly higher in males than in females.
      • Serum MMP-3 levels were significantly increased as a function of age.
      • Serum MMP-3 may be a potential biomarker for epilepsy if age and gender were considered.



      Reliable molecular biomarkers for epilepsy have yet to be identified. The present study aims to evaluate the utility of serum metalloproteinase-3 as a diagnostic biomarker for epilepsy.


      Serum MMP-3 levels were assessed in 227 individuals with epilepsy and 97 healthy control subjects. Individuals in the control group had no complaints or signs of any neurological disorder for at least 12 months before serum collection. The Luminex FLEXMAP 3D assay was used to determine serum MMP-3 levels.


      Compared with controls, subjects with epilepsy had significantly lower serum MMP-3 concentrations (p < 0.05). Serum MMP-3 concentrations were significantly higher in males than in females (p < 0.001). Furthermore, Serum MMP-3 concentrations were strongly correlated with age in both epileptic and control groups. For these reasons, ROC curve analyses were performed in age-matched and gender matched groups. In the population aged 20–40 years, when cut-off values of 23.87 ng/ml and 12.31 ng/ml were chosen for MMP-3 in males and females respectively, the sensitivity and specificity for patients with epilepsy versus controls were 72.22% and 76.67% for males, and 45% and 94.12% for females. And when cut-off MMP-3 concentrations of 20.70 ng/ml and 10.92 ng/ml were chosen for the ≥40 years age group, the sensitivity and specificity to distinguish between epileptic and control subjects were 85.71% and 47.62% versus 85.62% and 100% for male and female groups, respectively.


      MMP-3 is reduced in epilepsy patients compared to healthy controls. The potential of MMP-3 as an epilepsy biomarker is limited to certain age brackets and depends on the gender.


      MMP-3 (matrix metalloproteinase-3), EEG (electroencephalogram), ELISAs (enzyme-linked immunosorbent assays), AED (anti-epileptic drug), ROC (Receiver Operator Characteristic), MG (Myasthenia gravis)


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        • Yong V.W.
        • Power C.
        • Forsyth P.
        • Edwards D.R.
        Metalloproteinases in biology and pathology of the nervous system.
        Nat. Rev. Neurosci. 2001; 2: 502-511
        • Ikonomidou C.
        Matrix metalloproteinases and epileptogenesis.
        Mol. Cell. Pediatr. 2014; 1
        • Yong V.W.
        Metalloproteinases: mediators of pathology and regeneration in the CNS.
        Nat. Rev. Neurosci. 2005; 6: 931-944
        • Ethell I.M.
        • Ethell D.W.
        Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets.
        J. Neurosci. Res. 2007; 85: 2813-2823
        • Birkedal-Hansen H.
        Proteolytic remodeling of extracellular matrix.
        Curr. Opin. Cell Biol. 1995; 7: 728-735
        • Romi F.
        • Helgeland G.
        • Gilhus N.E.
        Serum levels of matrix metalloproteinases: implications in clinical neurology.
        Eur. Neurol. 2012; 67: 121-128
        • Horstmann S.
        • Budig L.
        • Gardner H.
        • Koziol J.
        • Deuschle M.
        • Schilling C.
        • et al.
        Matrix metalloproteinases in peripheral blood and cerebrospinal fluid in patients with Alzheimer's disease.
        Int. Psychogeriatr. 2010; 22: 966-972
        • Suenaga N.
        • Ichiyama T.
        • Kubota M.
        • Isumi H.
        • Tohyama J.
        • Furukawa S.
        Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures.
        J. Neurol. Sci. 2008; 266: 126-130
        • Li S.
        • Yu S.
        • Zhang C.
        • Shu H.
        • Liu S.
        • An N.
        • et al.
        Increased expression of matrix metalloproteinase 9 in cortical lesions from patients with focal cortical dysplasia type IIb and tuberous sclerosis complex.
        Brain Res. 2012; 1453: 46-55
        • Li Y.J.
        • Wang Z.H.
        • Zhang B.
        • Zhe X.
        • Wang M.J.
        • Shi S.T.
        • et al.
        Disruption of the blood-brain barrier after generalized tonic–clonic seizures correlates with cerebrospinal fluid MMP-9 levels.
        J. Neuroinflammation. 2013; 10: 80
        • Penkowa M.
        • Florit S.
        • Giralt M.
        • Quintana A.
        • Molinero A.
        • Carrasco J.
        • et al.
        Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acid-induced epileptic seizures.
        J. Neurosci. Res. 2005; 79: 522-534
        • Lee J.
        • Lim E.
        • Kim Y.
        • Li E.
        • Park S.
        Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus.
        J. Endocrinol. 2010; 205: 263-270
        • Luckman S.P.
        • Gilhus N.E.
        • Romi F.
        Matrix metalloproteinase-3 in myasthenia gravis compared to other neurological disorders and healthy controls.
        Autoimmune Dis. 2011; 2011: 151258
        • Dupont N.C.
        • Wang K.
        • Wadhwa P.D.
        • Culhane J.F.
        • Nelson E.L.
        Validation and comparison of luminex multiplex cytokine analysis kits with ELISA: determinations of a panel of nine cytokines in clinical sample culture supernatants.
        J. Reprod. Immunol. 2005; 66: 175-191
        • Hong Z.
        • Shi M.
        • Chung K.A.
        • Quinn J.F.
        • Peskind E.R.
        • Galasko D.
        • et al.
        DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease.
        Brain. 2010; 133: 713-726
      1. Epilepsia. 1981; 22: 489-501
        • Hong Z.
        • Li W.
        • Qu B.
        • Zou X.
        • Chen J.
        • Sander J.W.
        • et al.
        Serum brain-derived neurotrophic factor levels in epilepsy.
        Eur. J. Neurol. 2014; 21: 57-64
        • Wang J.
        • Tan L.
        • Tan L.
        • Tian Y.
        • Ma J.
        • Tan C.C.
        • et al.
        Circulating microRNAs are promising novel biomarkers for drug-resistant epilepsy.
        Sci. Rep. 2015; 5: 10201
        • Lukasiuk K.
        • Becker A.J.
        Molecular biomarkers of epileptogenesis.
        Neurotherapeutics. 2014; 11: 319-323
        • Pitkanen A.
        • Lukasiuk K.
        Molecular biomarkers of epileptogenesis.
        Biomark. Med. 2011; 5: 629-633
        • Mizoguchi H.
        • Yamada K.
        Roles of matrix metalloproteinases and their targets in epileptogenesis and seizures.
        Clin. Psychopharmacol. Neurosci. 2013; 11: 45-52
        • Kim H.J.
        • Fillmore H.L.
        • Reeves T.M.
        • Phillips L.L.
        Elevation of hippocampal MMP-3 expression and activity during trauma-induced synaptogenesis.
        Exp. Neurol. 2005; 192: 60-72
        • Falo M.C.
        • Fillmore H.L.
        • Reeves T.M.
        • Phillips L.L.
        Matrix metalloproteinase-3 expression profile differentiates adaptive and maladaptive synaptic plasticity induced by traumatic brain injury.
        J. Neurosci. Res. 2006; 84: 768-781
        • Gorter J.A.
        • Van Vliet E.A.
        • Rauwerda H.
        • Breit T.
        • Stad R.
        • van Schaik L.
        • et al.
        Dynamic changes of proteases and protease inhibitors revealed by microarray analysis in CA3 and entorhinal cortex during epileptogenesis in the rat.
        Epilepsia. 2007; 48: 53-64
        • Ma J.D.
        • Zhou J.J.
        • Zheng D.H.
        • Chen L.F.
        • Mo Y.Q.
        • Wei X.N.
        • et al.
        Serum matrix metalloproteinase-3 as a noninvasive biomarker of histological synovitis for diagnosis of rheumatoid arthritis.
        Mediat. Inflamm. 2014; 2014: 179284
        • Arends S.
        • van der Veer E.
        • Groen H.
        • Houtman P.M.
        • Jansen T.L.
        • Leijsma M.K.
        • et al.
        Serum MMP-3 level as a biomarker for monitoring and predicting response to etanercept treatment in ankylosing spondylitis.
        J. Rheumatol. 2011; 38: 1644-1650
        • Samnegard A.
        • Silveira A.
        • Tornvall P.
        • Hamsten A.
        • Ericsson C.G.
        • Eriksson P.
        Lower serum concentration of matrix metalloproteinase-3 in the acute stage of myocardial infarction.
        J. Intern. Med. 2006; 259: 530-536
        • Helgeland G.
        • Petzold A.
        • Luckman S.P.
        • Gilhus N.E.
        • Plant G.T.
        • Romi F.R.
        Matrix metalloproteinases in myasthenia gravis.
        Eur. Neurol. 2011; 65: 53-58
        • Tadbir A.A.
        • Purshahidi S.
        • Ebrahimi H.
        • Khademi B.
        • Malekzadeh M.
        • Mardani M.
        • et al.
        Serum level of MMP-3 in patients with oral squamous cell carcinoma—lack of association with clinico-pathological features.
        Asian Pac. J. Cancer Prev. 2012; 13: 4545-4548
        • Andisheh-Tadbir A.
        • Khademi B.
        • Kamali F.
        • Fattahi M.J.
        • Malekzadeh M.
        • Taghva M.
        Upregulation of serum vascular endothelial growth factor and matrix metalloproteinase-3 in patients with oral squamous cell carcinoma.
        Tumour Biol. 2014; 35: 5689-5693
        • Romi F.R.
        • Gilhus N.E.
        • Luckman S.P.
        Serum matrix metalloproteinase-3 levels are elevated in myasthenia gravis.
        J. Neuroimmunol. 2008; 195: 96-99
        • Kotajima L.
        • Aotsuka S.
        • Fujimani M.
        • Okawa-Takatsuji M.
        • Kinoshita M.
        • Sumiya M.
        • et al.
        Increased levels of matrix metalloproteinase-3 in sera from patients with active lupus nephritis.
        Clin. Exp. Rheumatol. 1998; 16: 409-415
        • Zucker S.
        • Lysik R.M.
        • Zarrabi M.H.
        • Greenwald R.A.
        • Gruber B.
        • Tickle S.P.
        • et al.
        Elevated plasma stromelysin levels in arthritis.
        J. Rheumatol. 1994; 21: 2329-2333
        • Gao J.W.
        • Zhang K.F.
        • Lu J.S.
        • Su T.
        Serum matrix metalloproteinases-3 levels in patients with ankylosing spondylitis.
        Genet. Mol. Res. 2015; 14: 17068-17078