ReviewCritical role of brain-derived neurotrophic factor in mood disorders
Introduction
Mood disorders are among the most prevalent, recurrent, and disabling of mental illness. Major depressive disorder (MDD) is a serious disorder that affects approximately 17% of the population at some point in life, resulting in major social and economic consequences [39], [51]. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [3], MDD is a heterogeneous disorder that manifests with symptoms at the psychological, behavioral, and physiological levels. There is still very little known about the neurobiological alterations that underlie the pathophysiology or treatment of MDD. Several lines of evidence suggest that depression in most people is caused by interactions between a genetic predisposition and some environmental factors [15], [76], [82], [83].
Bipolar disorder (BD), also known as manic-depressive illness, is a brain disorder that causes unusual shifts in a person's mood, energy, and ability to function. More than 2 million American adults, or about 1% of the population age 18 and older in any given year, have BD [39], [110]. BD typically develops in late adolescence or early adulthood. However, some people have their first symptoms during childhood, and some develop them later in life. BD is often not recognized as an illness, and people may suffer for years before it is properly diagnosed and treated. Like diabetes or heart disease, BD is a long-term illness that must be carefully managed throughout a person's lifetime [15], [39], [76].
Brain-derived neurotrophic factor (BDNF) is a 27-kDa polypeptide that is recognized as playing an important role in the survival, differentiation, and outgrowth of select peripheral and central neurons during development and in adulthood [41], [99]. It is well known that BDNF participates in use-dependent plasticity mechanisms such as long-term potentiation, learning, and memory [41], [68], [99]. Recently, it has been demonstrated that activation of the TrkB/phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway by BDNF in the hippocampus is important for spatial memory [68], [77].
In this review, we focus on recent findings regarding the role of BDNF in the pathophysiology of mood disorders such as MDD and BD, and we summarize the mechanisms of action of certain therapeutic drugs commonly used to treat these disorders. Furthermore, we also discuss the development of potential therapeutic agents for mood disorders.
Section snippets
Antidepressants
Several lines of evidence suggest that the expression of BDNF may be a downstream target of a variety of antidepressant treatments; BDNF might therefore be an important agent for therapeutic recovery from depression, and it might also provide protection against stress-induced neuronal damage [1], [16], [23], [24], [82], [83]. The molecular elements known to regulate neuronal plasticity in models of learning and memory are also involved in the actions of drugs used for the treatment of MDD and
Postmortem brain and human serum
Several human studies have provided data that are suggestive of the roles played by BDNF in the pathophysiology of MDD and in the action of antidepressants. For example, Chen et al. [13] reported finding increased levels of BDNF immunoreactivity in postmortem hippocampal tissue obtained from subjects treated with antidepressant medications at the time of death, compared with the BDNF levels observed in samples from antidepressant-untreated subjects. Furthermore, levels of CREB immunoreactivity
Approach for novel antidepressant treatment
As discussed above, there is a growing body of data suggesting that BDNF plays a pivotal role in the pathophysiology of mood disorders, and that agents which modulate the BDNF/TrkB/CREB cascade may in the future be useful for developing new mood stabilizers (Fig. 1). One possible approach in this context would be to use an inhibitor of phosphodiesterase type IV (PDE-IV), the enzyme responsible for the breakdown of cAMP. In the early 1980s, it was reported that rolipram, a specific PDE-IV
Concluding remarks
As shown in this paper, there are a number of pharmacological agents that may be of considerable utility in the future treatment of mood disorders. Additional detailed studies of the mechanisms of action of mood stabilizers and antidepressants in terms of intracellular signaling pathways will be necessary to discover novel therapeutic drugs for mood disorders. In addition, mood stabilizers used in the treatment of BD are known to modify apoptotic pathways, including the BCL-2 pathway [69] (Fig.
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