Redox dysregulation, immuno-inflammatory alterations and genetic variants of BDNF and MMP-9 in schizophrenia: Pathophysiological and phenotypic implications

Schizophr Res. 2017 Oct;188:98-109. doi: 10.1016/j.schres.2017.01.016. Epub 2017 Jan 15.


Background: Although a clear mechanism underlying the pathophysiology of schizophrenia (SZ) remains elusive, oxidative stress, inflammatory syndrome and immune activation have become an attractive hypothesis for explaining the pathophysiology of SZ. Data from prior studies on the role of matrix metalloproteinase 9 (MMP-9) and brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms (SNPs) in SZ are contradictory. We aimed to investigate whether oxidative stress, inflammatory and immune activation markers as well as MMP-9 levels may be implicated in SZ pathogenesis. The association of MMP-9 and BDNF SNPs with the clinical expression of SZ was examined.

Subjects and methods: Ninety-four subjects were recruited, including 44 SZ patients and 50 healthy controls. Serum levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), nitrite, C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), Beta-2 microglobulin (Β2M), complement component 3 (C3), C4 and MMP-9 were measured. The MMP-9 -1562C>T and BDNF196G>A SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay. Psychopathology was assessed using the positive and negative syndrome scale (PANSS).

Results: SZ patients showed significantly higher TBARS, PCC, nitrite, CRP, IL-6, TNF-α, Β2M, C3 and MMP-9 levels than controls. In distinguishing SZ patients from healthy controls, CRP and MMP-9 yielded similar discriminatory performance, and both perform better than IL-6, Β2M, C3, nitrite, TBARS, PCC, TNF-α and C4. The MMP-9 -1562C>T SNP genotypes distribution didn't differ significantly between controls and SZ patients. As compared to controls, SZ patients harbor a significantly higher frequency of the BDNF196GG genotype and a lower frequency of the BDNF196GA/AA genotype. Patients carrying the MMP-9 -1562CC or BDNF196GG genotype revealed a significantly higher PANSS than those carrying MMP-9 -1562CT/TT or BDNF196GA/AA genotype. Male gender and the MMP-9 -1562CC genotype were identified as independent predictive factors for higher PANSS.

Conclusions: Redox dysregulation and alterations in the immuno-inflammatory pathways are major culprits in the pathogenesis of SZ. MMP-9 and BDNF SNPs are associated with the clinical phenotype of SZ and, thus, may be a useful marker predicting the phenotypic expression and prognosis of SZ patients.

Keywords: Brain-derived neurotrophic factor; Clinical phenotype; Matrix metalloproteinase 9; Schizophrenia; Single nucleotide polymorphisms.

MeSH terms

  • Adult
  • Biomarkers / blood
  • Brain-Derived Neurotrophic Factor / genetics*
  • Cohort Studies
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Heterozygote
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / blood
  • Matrix Metalloproteinase 9 / genetics*
  • Oxidation-Reduction
  • Oxidative Stress / physiology
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Psychiatric Status Rating Scales
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism*
  • Schizophrenic Psychology
  • Sex Factors
  • Young Adult


  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • BDNF protein, human
  • MMP9 protein, human
  • Matrix Metalloproteinase 9