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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 295-299

Role of matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-1 in recurrent depression


1 Department of Psychiatry, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
2 Department of Medical Biochemistry, National Research Centre, Cairo, Egypt
3 Department of Pharmacology, National Research Centre, Cairo, Egypt
4 Department of Clinical Pathology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

Date of Submission28-Apr-2020
Date of Decision14-May-2020
Date of Acceptance19-May-2020
Date of Web Publication29-Jun-2020

Correspondence Address:
MD Rania A Hamed
Department of Psychiatry, Faculty of Medicine for Girls, Al-Azhar University, 66 Ahmed El Zomor Street, Nasr City, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_51_20

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  Abstract 


Objectives Matrix metalloproteinases (MMPs) play a major role in inflammatory processes, and their effect in depression has been examined. This study evaluates MMP-2, MMP-9, and tissue inhibitors of metalloproteinase-1 (TIMP-1) in patients with major depressive disorder and in a control group of healthy individuals, as well as correlation between their levels and the risk of recurrence of depression.
Patients and methods The study included 50 patients with depression (22 in their first episode and 28 had recurrent episodes), of both sexes, aged between 18 and 65 years, diagnosed with major depressive disorder, from psychiatric outpatient clinic in Al-Zahraa Hospital, Cairo, Egypt, as well as 50 matched healthy individuals as a control group. Serum MMP-2, MMP-9, and TIMP-1 levels were determined.
Results MMP-2 and MMP-9 showed a statistically significant difference in depressed patients compared with the control group. Moreover, recurrent depression group was significantly different from first episode depression group regarding MMP-2 and MMP-9 with higher levels, whereas TIMP-1 was higher in the control group.
Conclusion Changes in the serum levels of MMPs and TIMP in patients with depression are common and can be used to predict recurrence.

Keywords: matrix metalloproteinase-2, matrix metalloproteinase-9, recurrent depression, tissue inhibitors of metalloproteinase-1


How to cite this article:
Hamed RA, Elmalt HA, Salama AA, Abozaid SY, Abd Elaziz SY. Role of matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-1 in recurrent depression. Sci J Al-Azhar Med Fac Girls 2020;4:295-9

How to cite this URL:
Hamed RA, Elmalt HA, Salama AA, Abozaid SY, Abd Elaziz SY. Role of matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-1 in recurrent depression. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Jul 12];4:295-9. Available from: http://www.sjamf.eg.net/text.asp?2020/4/2/295/288286




  Introduction Top


Major depressive disorder (MDD) is one of the most common mental disorder, and according to the WHO, it will have moved up to the second cause of impairment by the year 2030 (after coronary heart disease) [1].

MDD is a debilitating condition that exhibits somatic manifestations in its presentation. Moreover, it was proven that cardiovascular insults, brain strokes, and cancers are associated with high risk of depression [2]. MDD is most probably due to a widespread inflammation occurring in both depression and somatic disorders [3].

Many studies have identified the connection between inflammation and depression, and there is growing evidence that inflammation plays a role in the pathophysiology of depression [4].

It is becoming more evident that inflammation can increase the severity of the presentation of depression, as well as the response to treatment among individuals with MDD [5].

Matrix metalloproteinases (MMPs) play a major role in inflammatory processes, and their effect in depression has been examined [6].

MMPs are zinc-dependent proteases that can influence synaptic plasticity, synaptogenesis, and neurite outgrowth in central nervous system. In many physiological and pathological processes within the brain, MMPs have been shown to play a significant role. They have been shown to affect cognitive processes such as memory and learning, as well as cause other neuropsychiatric disorders such as schizophrenia, epilepsy, and depression [7].

The MMP subfamily of gelatinases, the most prominent of which were MMP-2 and MMP-9, is critically involved in the remodeling of synaptic circuits, including structural changes of dendritic spines, either in healthy or diseased state [8].

MMP-9 and MMP-2 are structurally similar and can handle different extracellular matrix substrates enzymatically. These enzymes are also included in many pathological processes such as neurodegenerative and inflammatory disorders, including depression, as depression tends to be closely linked to systemic inflammation [9].

Transient activation of MMP-9 has been critically involved in cognitive processes that underlie synaptic plasticity, and abnormal activity of MMP-9 may lead to cognitive dysfunction. Interestingly, MMP-9 was found to be increased in macrophage cells of depressed patients, particularly in conjunction with high stress levels [10].

Serum tissue inhibitors of metalloproteinases (TIMPs) are endogenous proteins that inhibit MMPs activity. They also play a protective role in modulating inflammations in the tissue [11].


  Aim Top


The aim of this study was to test gene expression of MMP-2 and MMP-9, which are believed to have a major role in the development of depression, as well as TIMP-1 in a group of patients with MDD and in a control group of healthy people and to correlate between their levels and the risk of recurrence of depression.


  Patients and methods Top


A total of 50 patients of both sexes, aged between 18 and 65 years, diagnosed with MDD according to DSM 5 criteria of MDD were recruited from the Psychiatric Outpatient Clinic in Al-Zahraa Hospital, Cairo, Egypt. Twenty-two of them were in their first episode, whereas 28 patients had recurrent episode. Data were collected between September 2018 and January 2019. Exclusion criteria were past or present history of other psychiatric disorders, neurological disturbances, or any other chronic medical disorder. Moreover, 50 concurrent age-matched and sex-matched controlled were selected from employees working in the hospital with no past history of MDD. All participants provided written informed consent .The study was explained, and confidentiality of the data was assured. The study was done in consistent with the good clinical practice and Declaration of Helsinki and WHO guidelines. 202001120/Research Ethics Committee of Faculty of Medicine for Girls, Cairo, Al-Azhar University (FMG-IRB).

Methods

Determination of serum matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-1 levels with the use of enzyme-linked immunosorbent assay

Determination of serum MMP-2, MMP-9, and TIMP-1 levels was done using enzyme-linked immunosorbent assay.

The RayBio human enzyme-linked immunosorbent assay from RayBiotech (Norcross, Georgia, United States) was used to quantitatively evaluate circulating serum human MMP-2, MMP-9, and TIMP-1. Each serum sample was analyzed three times. We followed the instructions of the supplier for defining and calculating results. Standards and samples were pipetted into wells with immobilized antibodies specific for human MMP-2, MMP-9, and TIMP-1, and then were incubated. Biotinylated antihuman MMP-2, MMP-9, and TIMP-1 antibodies were added. Having washed away any unbound substances, biotinylated antibody and horseradish peroxidase-conjugated streptavidin was pipetted into the wells, which were washed once again. Tetramethylbenzidine substrate solution was added to the wells; a color was formed in proportion to the amount of MMP-2, MMP-9, and TIMP-1 level. The color production (Stop Solution) was discontinued, and its intensity was measured using the Thermo Labsystems Multiskan Ascent 354 (Lab Recyclers) at 450 nm.

Statistical analysis

All the results are presented as mean±SD. Comparison between various groups was done using one-way analysis of variance. Difference was considered significant when P value less than 0.05. GraphPad Prism 5 software (GraphPad, Inc., La Jolla, CA, USA) was used to do these statistics.


  Results Top


Sociodemographic data of cases and control showed that they were matching in age and sex ([Table 1]).
Table 1 Sociodemographic characteristics of the sample

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MMP-2 and MMP-9 showed statistically significant difference in depressed patients compared with healthy individuals of the control group. Moreover, recurrent depression group was significantly different from first episode depression group regarding MMP-2 and MMP-9. However, TIMP-1 was higher in the control group ([Table 2]).
Table 2 Serum level of matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitors of metalloproteinase-1 in depressed patients (first episode and recurrent) and in the control group

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Comparison of serum level of matrix metalloproteinase-2 in depressed patients (first episode and recurrent) and in the control group

MMP-2 serum level was lower in the control group, whereas MMP-2 serum levels were statistically elevated in patients with first episode depression by 1.8 fold and in patient with recurrent depression by 3.7 fold, respectively, as compared with the control group. In addition, MMP-2 serum level was higher in patients with recurrent depression than patients with first episode depression by 62% ([Figure 1]).
Figure 1 Serum levels of MMP-2 in patient with first episode depression and in patient with recurrent depression. MMP-2, matrix metalloproteinase-2.

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Comparison of serum level of matrix metalloproteinase-9 in depressed patients (first episode and recurrent) and in the control group

MMP-9 serum level was lower in the control group, whereas all examined MMP-9 serum levels were statistically increased in patients with first episode depression by 1.5 fold and in patient with recurrent depression by three fold, respectively, as compared with the control group. Moreover, MMP-9 serum level was statistically elevated in patients with recurrent depression than patients with first episode depression by 61% ([Figure 2]).
Figure 2 Serum levels of MMP-9 in patient with first episode depression and in patient with recurrent depression. MMP-9, matrix metalloproteinase-9.

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Comparison of serum level of tissue inhibitors of metalloproteinase-1 in patients with depression (first episode and recurrent) and in the control group

Serum level of TIMP-1 shows significant elevation in the control group, whereas it was reduced in patients with first episode depression by 77% and in patient with recurrent depression by 88%, compared with the control group. In addition, TIMP-1 serum level was lower in patients with recurrent depression than patient with first episode depression by 48%. The results are presented in [Figure 3].
Figure 3 Serum level of TIMP-1 in patient with first episode depression and in patient with recurrent depression. TIMP-1, tissue inhibitors of metalloproteinase-1.

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All the values are presented as mean±SD and N=50.

Statistical analysis was carried out by one-way analysis of variance.


  Discussion Top


Recently, focus has been put on the need to establish a panel of ‘biomarkers’ for depression that can provide a ‘biological signature’ that can help predict response to treatment [12].

MMP-2 and MMP-9 were established as strong biomarkers of MDD when a large study was performed to identify novel biomarkers in psychiatry [13].

TIMPs are endogenous inhibitors of these metalloproteinases and are therefore essential regulators of the turnover of extracellular matrix, remodeling of tissue, and behavior of cells [14].

In our study, the levels of MMP-2, MMP-9, and its inhibitor TIMP-1 were assessed.

The overexpression of MMP-2 and MMP-9 in patient group, being more in recurrent depression compared to first episode depression, is a strong evidence to the presence of ongoing inflammatory process.

These results are consistent with those of Bobińska et al. [15] who examined 142 patients with depression and 100 persons as a control group and found that for all tested MMPs, gene expression was higher in patients with depression than in the control group.

Moreover, the study by Garvin et al. [16] demonstrated a significant relation between symptoms of depression and levels of MMP-9 in a Swedish study.

In addition, in another study, Bobińska et al. [17] examined 203 depressed patients and 99 persons as a control group. The study demonstrated the relationship between MMP-2 and MMP-9 and depression, as well as the risk of depression occurrence, and the results were similar to our study. They found that the evaluated MMP genes have significant importance for the occurrence of depression as well as affect the recurrence of depression.Another study found that an elevated level of MMP-9 was found in patients with depression [18]. Moreover, Yoshida et al. [19] correlated MMP-9 levels with the degree of depression in these patients and their quality of life. Brew and Nagase [14] indicated a significantly greater increase in the pro-MMP-2/MMP-2 and pro-MMP-9/MMP-9 in depressed patients than the control group.


  Conclusion Top


Our findings suggest that changes in serum level of MMPs and TIMP in patients with depression is common and can be used to predict recurrence in depressed patients. Increasing knowledge in this area can lead to the discovery of new therapeutic approaches, especially in recurrent depression.

Acknowledgements

The authors would like to express their gratitude to all patients for their participation in this study.

The manuscript has been read and approved by all the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organization. The global burden of disease: 2004 update. Geneva: World Health Organisation; 2008.  Back to cited text no. 1
    
2.
Banaś A, Wichowicz H, Gałuszko M, Jakuszkowiak K. Comorbidity of somatic and depressive disorders. Psychiatr Prakt Ogólnolek 2005; 5:69–73.  Back to cited text no. 2
    
3.
Maes M, Galecki P, Chang YS, Berk M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:676–692.  Back to cited text no. 3
    
4.
Martinez JM, Garakani A, Yehuda R, Gorman JM. Proinflammatory and ‘resiliency’ proteins in the CSF of patients with major depression. Depress Anxiety 2012; 29:32–38.  Back to cited text no. 4
    
5.
Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37:137–162.  Back to cited text no. 5
    
6.
Bobińska K. Metalloproteinases − their role in inflammatory processes and central nervous system diseases. Med Sci Rev 2015; 2:35–40.  Back to cited text no. 6
    
7.
Beroun A, Mitra S, Michaluk P, Pijet B, Stefaniuk M, Kaczmarek L. MMPs in learning and memory and neuropsychiatric disorders. Cell Mol Life Sci 2019; 76:3207.  Back to cited text no. 7
    
8.
van der Kooij M, Fantin M, Rejmak E, Grosse J, Zanoletti O, Fournier C et al. Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations. Nat Commun 2014; 5:4995.  Back to cited text no. 8
    
9.
Chiyo S, Kei I, Hiromi A, Naoto K, Okada-Tsuchioka M, Minoru T. Possible association between serum matrix metalloproteinase-9 (MMP-9) levels and relapse in depressed patients following electroconvulsive therapy (ECT). Int J Neuropsychopharmacol 2018; 21:236–241.  Back to cited text no. 9
    
10.
Ganguly K, Rejmak E, Mikosz M, Nikolaev E, Knapska E, Kaczmarek L. Matrix metalloproteinase (MMP) 9 transcription in mouse brain induced by fear learning. J Biol Chem 2013; 88:20978–20991.  Back to cited text no. 10
    
11.
Lipka D, Boratynski J, Metaloproteinazy MMP. Metalloproteinases. Structure and function. Postepy Hig Med Dosw 2008; 62:328–336.  Back to cited text no. 11
    
12.
Schmidt HD, Shelton RC, Duman RS. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 2011; 36:2375–2394.  Back to cited text no. 12
    
13.
Domenici E, Wille DR, Tozzi F, Prokopenko I, Miller S, McKeown A et al. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS ONE 2010; 5:e9166.  Back to cited text no. 13
    
14.
Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010; 1803:55–71.  Back to cited text no. 14
    
15.
Bobińska K, Szemraj J, Czarny P, Gałecki P. Expression and activity of metalloproteinases in depression. Med Sci Monit 2016; 22:1334–1341.  Back to cited text no. 15
    
16.
Garvin P, Nilsson L, Carstensen J, Jonasson L, Kristenson M. Plasma levels of matrix metalloproteinase-9 are independently associated with psychosocial factors in a middle-aged normal population. Psychosom Med 2009; 71:292–300.  Back to cited text no. 16
    
17.
Bobińska K, Szemraj J, Czarny P, Gałecki P. Role of MMP-2, MMP-7, MMP-9 and TIMP-2 in the development of recurrent depressive disorder. J Aff Disorders 2016; 205:119–129.  Back to cited text no. 17
    
18.
Domenici E, Wille DR, Tozzi F, Prokopenko I, Miller S, McKeown A et al. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS ONE 2016; 5:e9166.  Back to cited text no. 18
    
19.
Yoshida T, Ishikawa M, Niitsu T, Nakazato M, Watanabe H, Shiraishi T et al. Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS ONE 2012; 7:e42676.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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