Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation

Abstract

Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the healthy and diseased brain. As a result, there is a large body of evidence that associates BDNF with neuronal maintenance, neuronal survival, plasticity, and neurotransmitter regulation. Patients with psychiatric and neurodegenerative disorders often have reduced BDNF concentrations in their blood and brain. A current hypothesis suggests that these abnormal BDNF levels might be due to the chronic inflammatory state of the brain in certain disorders, as neuroinflammation is known to affect several BDNF-related signaling pathways. Activation of glia cells can induce an increase in the levels of pro- and antiinflammatory cytokines and reactive oxygen species, which can lead to the modulation of neuronal function and neurotoxicity observed in several brain pathologies. Understanding how neuroinflammation is involved in disorders of the brain, especially in the disease onset and progression, can be crucial for the development of new strategies of treatment. Despite the increasing evidence for the involvement of BDNF and neuroinflammation in brain disorders, there is scarce evidence that addresses the interaction between the neurotrophin and neuroinflammation in psychiatric and neurodegenerative diseases. This review focuses on the effect of acute and chronic inflammation on BDNF levels in the most common psychiatric and neurodegenerative disorders and aims to shed some light on the possible biological mechanisms that may influence this effect. In addition, this review will address the effect of behavior and pharmacological interventions on BDNF levels in these disorders.

Keywords: Brain-derived neurotrophic factor; Neuroinflammation; Neurological disorders; Neurotoxicity.

Fig. 1

BDNF induces survival-related signaling mechanisms: BDNF induces survival-related signaling mechanisms: In physiological conditions, binding of BDNF to TrkB receptor in either paracrine or autocrine signaling elicits three distinct downstream pathways. BDNF-dependent phospholipase C-gamma (PLC-γ) can induce short-term signaling by increasing Ca2+ neuronal response and inhibit inflammatory-dependent apoptosis cascade (dashed lines) by inhibition of glycogen synthase kinase 3-beta (GSK-3β). Induction of phosphatidylinositol 3-Phosphate (PI3K) induces transcription of BDNF mRNA by activating mTOR-dependent translation of BDNF. Additionally, BDNF can modulate gene regulation by activating NF-κB and CREB transcription factors by inducing Akt and Erk downstream pathways, respectively. Gene modulation induces neuronal survival, growth, long-term potentiation (LTP), and de novo expression of BDNF. In addition, BDNF-independent transactivation of TrkB can also play an important role in the neurotrophic pathway regulation by factors, such as adenosine, zinc, epidermal growth factor (EGF), glucocorticoids, and pituitary adenylate-cyclase-activating polypeptide (PACAP), further enhancing TrkB signaling in the synapse

Fig. 2

BDNF response after inflammatory brain pathogenicity. In chronically stressful situations, such as brain pathologies, there is an induction of NF-κB-dependent pro-inflammatory activation of microglia after induction of the pattern recognition receptor (PRR) by the challenge (e.g., stress or pathology). Pro-inflammatory cytokines, especially IL-1, can directly bind microglial cells, which result in induction of the expression and release of several mediators, most of which are neurotoxic, including reactive oxygen (ROS) and nitrogen species (RNS), pro-inflammatory cytokines (such as tumor necrosis factor), and chemokines (such as CC-chemokine ligand 2, CCL2; also known as MCP1). Additionally, there is a decrease of BDNF signaling in the synaptic cleft, further reducing BDNF-dependent survival-related signaling (black dashed lines) and inhibition of apoptotic pathways, such as glycogen synthase kinase 3-beta (GSK-3: red dashed line). Such factors will lead to an increase of NF-κB complex binding to genes that express pro-inflammatory cytokines (e.g., interleukin 1-β, IL-6, IL-8, TNF). The effect of transactivation factors on the BDNF-independent maintenance of TrkB is not clear yet