Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets

Abstract

Depression is the most prevalent and among the most debilitating of psychiatric disorders. The precise neurobiology of this illness is unknown. Several lines of evidence suggest that peripheral and central inflammation plays a role in depressive symptoms, and that anti-inflammatory drugs can improve depressive symptoms in patients with inflammation-related depression. Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomycin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants. A recent paper showed that lipopolysaccharide (LPS)-induced inflammation gave rise to depression-like phenotype by altering BDNF-TrkB signaling in the prefrontal cortex, hippocampus, and nucleus accumbens, areas thought to be involved in the antidepressant effects of TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist, ANA-12. Here we provide an overview of the tryptophan-kynurenine pathway and BDNF-TrkB signaling in the pathophysiology of inflammation-induced depression, and propose mechanistic actions for potential therapeutic agents. Additionally, the authors discuss the putative role of TrkB agonists and antagonists as novel therapeutic drugs for inflammation-related depression.

Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation

“…It is well known that LPS can induce sickness behavior that peaks 2 to 6 h after a single administration and then gradually wanes [1,6]. The behavior results from the activation of proinflammatory cytokine signaling in the brain, in response to peripheral LPS injection, and the ensuing depression-like behavior peaks 24 h post-LPS injection [1,6].…”

“…Although the precise mechanism underlying the pathophysiology of depression is unknown, multiple lines of evidence suggest that inflammation plays a key role in the pathophysiology of depression [1][2][3][4][5][6]. Meta-analyses showed higher blood levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin-6 (IL-6), in drugfree depressed patients, compared with healthy controls [7,8].…”

“…A study using postmortem brain samples showed elevated gene expression of proinflammatory cytokines in the frontal cortex of participants with a history of depression [9]. When the bacterial endotoxin lipopolysaccharide (LPS) is administered to rodents, depression-like behaviors are observed 24 h after inflammation [1,6,10]. The current antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), are able to prevent depression-like behavior and alterations in serum proinflammatory cytokines, such as TNF-α, induced by LPS administration [10][11][12][13].…”

Soluble epoxide hydrolase: a new therapeutic target for depression

“…Given the role of inflammation in the development of depression [9][10][11], it is possible that sEH contribute to the pathophysiology of this disorder. Recently, Ren et al [12] reported that the sEH inhibitor TPPU (1-(1-propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea) conferred prophylactic and antidepressant effects in the inflammation and social defeat stress models of depression.…”

Brain-derived neurotrophic factor-TrkB signaling in the medial prefrontal cortex plays a role in the anhedonia-like phenotype after spared nerve injury

“…pathophysiology of depression and in the antidepressant functions of antidepressants [10][11][12][13][14][15][16][17][18]. Alterations in BDNF-TrkB signaling in the brain have been implicated in the pathogenesis of depression and antidepressant mechanisms.…”