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Review
, 14 (7), 721-31

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

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Review

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

Ji-Chun Zhang et al. Curr Neuropharmacol.

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.

Figures

Fig. (1)
Fig. (1)
The relationship between sickness behavior and depression-like behavior. (A): The sickness behavior that peaks 2 to 6 hours later and gradually wanes by peripheral administration of lipopolysaccharide (LPS). Pro-inflammatory cytokine signaling is activated in the brain as a response to peripheral LPS injection, with depression-like behavior peaking 24 hours after LPS injection. (B): The sickness behavior was induced by pro-inflammatory cytokines which also can enhance activity of the ubiquitous indoleamine 2,3-dioxygenase (IDO), peaking 24 hours after LPS administration. Activation of IDO results in decreased tryptophan (TRP) levels and increased production of kynurenine (KYN) and other tryptophan-derived metabolites. Anti-inflammatory drugs (e.g. minocycline) can block both LPS-induced sickness behavior and depression-like behavior. By contrast, administration of 1-methyl tryptophan (1-MT), a competitive inhibitor of IDO, blocks LPS induced depression-like behavior without altering LPS-induced sickness behavior. This figure is a modified version from a previous report [45].
Fig. (2)
Fig. (2)
Tryptophan-kynurenine pathway. The essential amino acid L-tryptophan is converted to 5-hydroxytryptophan by tryptophan hydroxylase (TPH), and this is metabolized to serotonin (5-HT) by 5-hydroxytryptophan decarboxylase. The kynurenine pathway is initiated by the conversion of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Kynurenine is mostly hydroxylated (kynurenine hydroxylase) to 3-hydroxykynurenine. Kynureninase acts upon both 3-hydroxykynurenine and kynurenine; on 3-hydroxykynurenine to form 3-hydroxyanthranilic acid; and on kynurenine to form anthranilic acid (this latter conversion accounts for only a minority of kynureninase activity). Three-hydroxyanthranilic acid is converted into quinolinic acid, an NMDA receptor agonist by 3-hydroxyanthranilic acid oxygenase. Kynurenine can also be converted into kynurenic acid by kynurenine aminotransferase. By contrast, kynurenic acid is an antagonist at NMDA and α7 nicotinic acetylcholine receptors (nAChRs), both of which play roles in the pathophysiology of psychiatric disease.
Fig. (3)
Fig. (3)
Structure of proBDNF and mature BDNF. (A): Arrowheads indicate known protease cleavage sites involved in the processing to mature BDNF. The position of the single nucleotide polymorphism (rs6265, Val66Met) in human BDNF is indicated by arrows. (B): Extrasynaptic cleavage of proBDNF to mature BDNF. ProBDNF preferentially binds p75NTR. ProBDNF is cleaved by extracellular proteases at synapses and converted to mature BDNF. Mature BDNF preferentially binds the TrkB receptor. This figure is a modified version taken from a previous report (88).
Fig. (4)
Fig. (4)
Schematic outline for the proposed use of TrkB ligands as novel therapeutic drugs in depression. In preclinical studies, inflammation promotes reduced BDNF in the PFC and hippocampus, as well as increased BDNF in the NAc of the brain, resulting in a depression-like phenotype in rodents. From preclinical data, we propose that TrkB agonists and current antidepressants, such as SSRIs and SNRIs could be effective therapeutic drugs for depressed patients with decreased levels of BDNF in the PFC and hippocampus. In contrast, TrkB antagonists confer potential therapeutic benefits for patients with treatment-resistant depression showing increased BDNF levels in the VTA-NAc pathway.

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