Sonic hedgehog, Wnt, and brain‐derived neurotrophic factor cell signaling pathway crosstalk: potential therapy for depression

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Depression is a crucial public health issue. It is a serious and recurrent disorder linked to decline in quality and function of a normal, healthy life and associated with comorbidity and mortality (Nemeroff, 2007; Ustun, 2004). It represents the fourth leading cause of disability, and it has been estimated to become the leading cause of disability worldwide by 2030 (Murray & Lopez, 1996; Thornicroft et al., 2017) (WHO, EB130/9, 2011). Depression is a common psychiatric disorder that may occur as early as 3 years of age (Ferrari et al., 2013). According to the International Association for Suicide Prevention 2015 (facts and figures), depression carries a higher risk of suicide, and approximately every 40 seconds a suicidal death occurs.
Psychiatric disorders like depression have been explained by ancient philosophers for several millennia. The Greek philosopher Hippocrates first used the term melancholia around 400 B.C. (Nestler et al., 2002). The term was collectively used when referring to many mental disorders. Most of the symptoms of major depressive disorder (MDD) observed today were already recognized in ancient times (Nestler et al., 2002; Paykel, 2008). The ancient literature also validates that depression and anxiety overlap each other and increase with alcohol consumption, something that is well established today. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5, 2013) of the American Psychiatric Association, and the ICD‐10 Classification of Mental and Behavioral Disorders of the World Health Organization, diagnosis of MDD is based on symptomatic criteria (Barchas & Brody, 2015). Although the pathophysiology of depression has not been deciphered yet, in recent decades it has been speculated that deregulation of molecular and cellular signaling pathways might play a significant role in the initiation and progression of depression.
Currently, available antidepressant drugs follow the monoamine hypothesis by modulating the synaptic levels of serotonin (5‐HT) and norepinephrine (NE), but they have some potential drawbacks like delayed therapeutic effect and low response rate (Voleti & Duman, 2012). To disclose these limitations, there must be more intense research on the molecular biology of depression. This would further facilitate the generation of hypotheses that might enable exploration of the possible underlying molecular cell signaling mechanisms in the pathophysiology of depression. Moreover, some brain imaging studies demonstrate that alterations occur in the neural network, which is involved in the regulation of normal behavior and of various mood disorders including depression. Also, recent studies have shown a rapid antidepressant effect after deep brain stimulation (DBS), which strongly suggests that depression is a neural circuit disorder (Chaudhury, Liu, & Han, 2015; Holtzheimer & Mayberg, 2010; Mayberg, 2009). Specific molecular signaling and epigenetic changes might be involved in the neuronal development of depression. It is therefore of great importance to identify the pathways that would reveal possible targets for the diagnosis of depression and for the design of specific therapies against depression.
Despite the available leading theories of depression, which involve brain‐derived neurotrophic factor (BDNF) and the role of Wnt signaling in depression, this review solely highlights a brief overview of the sonic hedgehog (Shh) pathway and its crosstalk with BDNF and Wnt signaling as potential therapeutic targets for depression.
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