Ethnic differences in the serum levels of proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), in mood disorders.

Abstract

included 35 studies with a total of 2238 patients with BD, and 1560 healthy controls. Levels of BDNF were lower in crude blood samples from BD patients (P = 0.02), as well as in the serum of manic (P = 0.01) and depressed patients (P = 0.002), compared with healthy control subjects. No differences in peripheral BDNF levels were observed in any of the affective states. Furthermore, a longer illness duration was associated with higher BDNF levels in BD patients [6]. The BDNF enzyme-linked immunosorbent assay (ELISA) kits used in early reports recognized both proBDNF and mature BDNF, due to the limited specificity of the BDNF antibody [7]. Using new, commercial human BDNF ELISA kits capable of differentiating between proBDNF and mature BDNF, we reported high concentrations of both BDNF forms in human serum [7, 8] (Table 1). Serum levels of proBDNF in approximately 38 percent of the healthy Japanese control subjects were less than the minimum detectable concentration (0.5 ng/mL) of the kit (Table 1) [8]. Noting the high concentrations and putative opposing functions of proBDNF and mature BDNF, authors have focused their attention on the separate measurements of these factors in human blood [2, 9, 10]. Sodersten et al. [11] reported that serum levels of mature BDNF in mood-stabilized patients with BD were significantly higher than in healthy controls, whereas serum levels of proBDNF in BD patients were significantly lower than those of controls (Swedish samples) [11]. In this study, serum levels of proBDNF could be measured in all healthy control subjects (Table 1) [11]. In contrast, serum levels of mature BDNF in depressed patients were significantly lower than those of healthy controls [8]. It is therefore possible that measuring blood levels of mature BDNF and proBDNF could provide a method for distinguishing between depression and BD, thus reducing the high rates of misdiagnosis between these diseases Brain-derived neurotrophic factor (BDNF), a major neurotrophic factor in the brain, plays an important role in the pathophysiology of mood disorders, such as depression and bipolar disorder (BD) [1–3]. BDNF (mature BDNF) is a 13-kDa polypeptide, synthesized initially as a precursor protein, preproBDNF, in the endoplasmic reticulum. Following cleavage of its signal peptide, proBDNF (~32 kDa) is converted to mature BDNF by intracellular or extracellular proteases. It was first thought that only secreted, mature BDNF possessed biological activity, and that proBDNF, which localizes intracellularly, served as an inactive precursor. However, accumulating evidence demonstrates that both proBDNF and mature BDNF are active, eliciting opposing effects via the p75 and TrkB receptors, respectively, and that both forms play a key role in several physiological functions [2, 3]. In 2003, we reported that serum levels of BDNF in drugnaive patients with depression were significantly lower than those of healthy controls [4]. Since then, a number of studies have replicated our initial finding. A recent meta-analysis of 179 associations (N = 9484 subjects) showed that serum levels of total BDNF (mature BDNF and proBDNF), in antidepressant-free patients with depression were significantly lower (Cohen’s d = −0.71, P < 0.0000001) than those of healthy controls [5]. Furthermore, Munkholm et al. [6] performed a systematic and quantitative metaanalysis of BDNF (mature BDNF and proBDNF) levels in blood samples from patients with BD. This analysis