Abstract
Evidence demonstrates that brain-derived neurotrophic factor (BDNF) has a pivotal role in the pathogenesis of major depressive disorder (MDD). Precursor-BDNF (proBDNF) and mature BDNF (mBDNF) have opposing biological effects in neuroplasticity, and the tissue-type plasminogen activator (tPA)/plasmin system is crucial in the cleavage processing of proBDNF to mBDNF. However, very little is known about the role of the tPA–BDNF pathway in MDD. We examined serum protein concentrations in the tPA–BDNF pathway, including tPA, BDNF, tropomyosin receptor kinase B (TrkB), proBDNF and p75NTR, obtained from 35 drug-free depressed patients before and after 8 weeks of escitalopram (mean 12.5 mg per day) or duloxetine (mean 64 mg per day) treatment and 35 healthy controls using sandwich ELISA (enzyme-linked immunosorbent assay) methods. Serum tPA and BDNF and the ratio of BDNF/proBDNF were significantly lower in the MDD patients than in controls, whereas TrkB, proBDNF and its receptor p75NTR were higher. After 8 weeks of treatment, tPA, BDNF and proBDNF and the BDNF/proBDNF ratio were reversed, but p75NTR was higher than baseline, and TrkB was not significantly changed. tPA, BDNF, TrkB, proBDNF and p75NTR all yielded fairly good or excellent diagnostic performance (area under the receiver operating characteristic curve (AUC) >0.8 or 0.9). Combination of these five proteins demonstrated much better diagnostic effectiveness (AUC: 0.977) and adequate sensitivity and specificity of 88.1% and 92.7%, respectively. Our results suggest that the tPA–BDNF lysis pathway may be implicated in the pathogenesis of MDD and the mechanisms underlying antidepressant therapeutic action. The combination of tPA, BDNF, TrkB, proBDNF and p75NTR may provide a diagnostic biomarker panel for MDD.
Highlights
Major depressive disorder (MDD) is one of the most common psychiatric disorders, with a lifetime risk of 20–25% for women and 7–12% for men.[1]
In this study, we found that the dysfunction of the tissue plasminogen activator (tPA)–brain-derived neurotrophic factor (BDNF) lysis pathway in serum was implicated in MDD pathogenesis, and it was partially reversed by antidepressant treatment
We found that serum levels of tPA and BDNF and the ratio of BDNF/precursor BDNF (proBDNF)
Summary
Major depressive disorder (MDD) is one of the most common psychiatric disorders, with a lifetime risk of 20–25% for women and 7–12% for men.[1]. Treatments are not satisfactory and are often delayed in their onset and afflicted with side effects. The neurotrophin hypothesis has received significant attention, and brain-derived neurotrophic factor (BDNF) is one of the most important neurotrophic factors that is widely measured.[3,4,5,6] The hypothesis proposes that decreased neurotrophic signaling is a major factor underlying the pathophysiology of depression, and its restoration underlie the actions of antidepressant treatment. The tissue plasminogen activator (tPA)/plasmin system is the most significant protease involved in the cleavage of proBDNF.[14,15]
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