Brain-derived Neurotrophic Factor Signaling Cascade Research Articles

The salt-inducible kinases inhibitor HG-9-91-01 exhibits antidepressant-like actions in mice exposed to chronic unpredictable mild stress

Major depressive disorder is a frequently occurring neuropsychiatric disorder throughout the world. However, the limited and delayed therapeutic efficacy of monoaminergic medications has led to intensive research efforts to develop novel antidepressants. We have previously demonstrated that hippocampal salt-inducible kinase 2 (SIK2) plays a role in the pathogenesis of depression via regulating the downstream CREB-regulated transcription coactivator 1 (CRTC1)-cAMP response element-binding protein (CREB)-brain derived neurotrophic factor (BDNF) pathway. HG-9-91-01 is a potent and selective inhibitor of salt-inducible kinases (SIKs). The present study aims to explore whether HG-9-91-01 has antidepressant-like actions in male C57BL/6J mice. The chronic unpredictable mild stress (CUMS) model of depression, various behavioral tests, western blotting, co-immunoprecipitation, immunofluorescence, stereotactic infusion, and viral-mediated genetic knockdown were used together. It was found that hippocampal infusion of HG-9-91-01 induced significant antidepressant-like effects in the CUMS model, accompanied with preventing the enhancement of CUMS on the hippocampal SIK2 expression and cytoplasmic translocation of CRTC1. HG-9-91-01 treatment also reversed the decreasing effects of CUMS on the BDNF signaling cascade and adult neurogenesis in the hippocampus. Moreover, the antidepressant-like actions of HG-9-91-01 in mice required the hippocampal CRTC1-CREB-BDNF pathway. In conclusion, HG-9-91-01 has potential of being a novel antidepressant candidate.

Tenuifolin ameliorates the sleep deprivation-induced cognitive deficits.

Tenuifolin (TEN), a natural neuroprotective compound obtained from the Polygala tenuifolia Willd plant, has improved cognitive symptoms. However, the impact of TEN on memory impairments caused by sleep deprivation (SD) is unclear. Accordingly, the objective of this study was to investigate the mechanisms behind the preventative benefits of TEN on cognitive impairment caused by SD. TEN (10 and 20 mg/kg) and Huperzine A (0.1mg/kg) were given to mice through oral gavage for 28 days during the SD process. The results indicate that TEN administrations improve short- and long-term memory impairments caused by SD in the Y-maze, object identification, and step-through tests. Moreover, TEN stimulated the generation of anti-inflammatory cytokines (interleukin-10), lowered the production of pro-inflammatory cytokines (interleukin-1β, interleukin-6, and interleukin-18), and activated microglia, improving antioxidant status in the hippocampus. TEN treatments significantly boosted the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 while considerably decreasing the expression of NOD-like receptor thermal protein domain associated protein 3 and caspase-1 p20. Additionally, TEN restored the downregulation of the brain-derived neurotrophic factor signaling cascade and the impaired hippocampal neurogenesis induced by SD. When considered collectively, our data suggest that TEN is a potentially effective neuroprotective agent for cognition dysfunction.

D-Serine produces antidepressant-like effects in mice through suppression of BDNF signaling pathway and regulation of synaptic adaptations in the nucleus accumbens

Objectived-Serine is a crucial endogenous co-agonist of N-methyl-d-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (BDNF) system, which plays an essential role in modulating synaptic plasticity. The current study aimed to systematically evaluate the role and mechanisms of d-serine in depressive behavior in nucleus accumbens (NAc).Methodsd-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured using high-performance liquid chromatography (HPLC). The antidepressant-like effects of d-serine were identified using forced swim test (FST) and tail suspension test (TST) in control mice and then assessed in CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and d-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant-like mechanism of d-serine. Moreover, d-serine effects on synaptic plasticity in NAc were investigated using electrophysiological methods.Resultsd-Serine concentration was decreased in depression susceptible mice in NAc. d-Serine injections into NAc exhibited antidepressant-like effects in FST and TST without affecting the locomotor activity of mice. d-Serine was also effective in CSDS model of depression. Moreover, d-serine down-regulated the BDNF signaling pathway in NAc during CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of d-serine. We also found that d-serine was essential for NMDARs-dependent long-term depression (LTD).Conclusiond-Serine exerts antidepressant-like effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc.

Hippocampal miR-206-3p participates in the pathogenesis of depression via regulating the expression of BDNF

As a widely-known neuropsychiatric disorder, the exact pathogenesis of depression remains elusive. MiRNA-206 (miR-206) is conventionally known as one of the myomiRs and has two forms: miR-206-3p and miR-206-5p. Recently, miR-206 has been demonstrated to regulate the biosynthesis of brain-derived neurotrophic factor (BDNF), a very popular target involved in depression and antidepressant responses. Here we assumed that miR-206 may play a role in depression, and various methods including the chronic social defeat stress (CSDS) model of depression, quantitative real-time reverse transcription PCR, western blotting, immuofluorescence and virus-mediated gene transfer were used together. It was found that CSDS robustly increased the level of miR-206-3p but not miR-206-5p in the hippocampus. Both genetic overexpression of hippocampal miR-206-3p and intranasal administration of AgomiR-206-3p induced not only notable depressive-like behaviors but also significantly decreased hippocampal BDNF signaling cascade and neurogenesis in naïve C57BL/6J mice. In contrast, both genetic knockdown of hippocampal miR-206-3p and intranasal administration of AntagomiR-206-3p produced significant antidepressant-like effects in the CSDS model of depression. Furthermore, it was found that the antidepressant-like effects induced by miR-206-3p inhibition require the hippocampal BDNF-TrkB system. Taken together, hippocampal miR-206-3p participates in the pathogenesis of depression by regulating BDNF biosynthesis and is a feasible antidepressant target.

Sirt1 improves heart failure through modulating the NF-κB p65/microRNA-155/BNDF signaling cascade.

Heart failure (HF) affects over 26 million people worldwide, yet the pathologies of this complex syndrome have not been completely understood. Here, we investigated the involvement of deacetylase Sirtuin 1 (Sirt1) in HF and its downstream signaling pathways. A HF model was induced by the ligation of the left coronary artery in rats, where factors associated with left ventricular echocardiography, heart hemodynamics and ventricular mass indexes were recorded. Collagen volume fraction in heart tissues was determined by Masson’s trichrome staining. Cell models of HF were also established (H2O2, 30 min) in cardiomyocytes harvested from suckling rats. HF rats presented with downregulated expressions of Sirt1, brain-derived neurotrophic factor (BDNF) and exhibited upregulated expressions of NF-κB p65 and miR-155. Repressed Sirt1 expression increased acetylation of NF-κB p65, resulting in the elevation of NF-κB p65 expression. NF-κB p65 silencing improved heart functions, decreased ventricular mass and reduced apoptosis in cardiomyocytes. MiR-155 inhibition upregulated its target gene BDNF, thereby reducing cardiomyocyte apoptosis. Sirt1 overexpression upregulated BDNF, improved heart function, and reduced apoptosis in cardiomyocytes. In conclusion, Sirt1 alleviates HF in rats through the NF-κB p65/miR-155/BDNF signaling cascade.

Suppression of BACE1 and amyloidogenic/RAGE axis by sitagliptin ameliorates PTZ kindling-induced cognitive deficits in rats

The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and β-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3β (GSK-3β). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both β-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3β/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.

Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1–cAMP Response Element Binding–Brain-Derived Neurotrophic Factor Pathway

BackgroundDeveloping novel pharmacological targets beyond monoaminergic systems is now a popular strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator (CRTC) by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC system may contribute to the pathogenesis of depression. MethodsChronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, viral-mediated gene transfer, Western blotting, coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5). ResultsBoth CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic overexpression of hippocampal SIK2 in naïve mice simulated chronic stress, inducing depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference test, and social interaction test, as well as decreasing the brain-derived neurotrophic factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB–brain-derived neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1 pathway, which was necessary for their antidepressant actions. ConclusionsThe hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression, and hippocampal SIK2 could be a novel target for the development of antidepressants.

Antidepressant-like effects of tetrahydroxystilbene glucoside in mice: Involvement of BDNF signaling cascade in the hippocampus.

Current antidepressants in clinic need weeks of administration and always have significant limitations. Tetrahydroxystilbene glucoside (TSG) is one of the major bioactive ingredients of Polygonum multiflorum with neuroprotective effects. This study aimed to evaluate the antidepressant effects of TSG in mice. The antidepressant-like effects of TSG in mice were examined in the forced swim test (FST), tail suspension test (TST), and chronic social defeat stress (CSDS) model of depression. The effects of CSDS and TSG on the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway and neurogenesis were further investigated. Moreover, the pharmacological inhibitors and lentiviral-shRNA were used to explore the antidepressant mechanisms of TSG. TSG produced antidepressant-like effects in the FST and TST and also reversed the CSDS-induced depressive-like symptoms. Moreover, TSG treatment significantly restored the decreased hippocampal BDNF signaling pathway and neurogenesis in CSDS mice. Importantly, blockade of the hippocampal BDNF system fully abolished the antidepressant-like effects of TSG in mice. In conclusion, TSG produces antidepressant-like effects in mice via enhancement of the hippocampal BDNF system.

Antidepressant-like effects of ginsenoside Rg5 in mice: Involving of hippocampus BDNF signaling pathway

Ginsenoside Rg5 is one of the major bioactive ingredients of Panax ginseng with little toxicity and has been shown to have pharmacological effects on the central nervous system. In this study, we investigated the antidepressant effects of Rg5 in mice models of depression. The effects of Rg5 were first assessed in the forced swimming test (FST) and tail suspension test (TST), and then investigated in the chronic social defeat stress (CSDS) model of depression. The changes in hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway after CSDS and Rg5 treatment were also examined. The tryptophan hydroxylase inhibitor and tyrosine kinase B inhibitor were used to explore the antidepressant mechanisms of Rg5. It was found that Rg5 exhibited antidepressant-like activities in the FST and TST without affecting locomotor activity. Rg5 was also effective in the CSDS model of depression, and restored the CSDS-induced decrease in hippocampal BDNF signaling cascade. Moreover, the usage of the tyrosine kinase B inhibitor blocked the antidepressant effects of Rg5, while the tryptophan hydroxylase inhibitor did not. Collectively, ginsenoside Rg5 has antidepressant activities via the activation of hippocampal BDNF system.

Antidepressant-like effects of ginsenoside Rg3 in mice via activation of the hippocampal BDNF signaling cascade.

Current antidepressants are clinically effective only after several weeks of administration. Ginsenoside Rg3 is one component of ginsenosides, with a similar chemical structure to ginsenoside Rg1. Here, we investigated the antidepressant effects of Rg3 in mouse models of depression. The antidepressant actions of Rg3 were first examined in the forced swim test (FST) and tail suspension test (TST), and then assessed in the chronic social defeat stress (CSDS) model of depression. The changes in the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway after CSDS and Rg3 treatment were investigated. A tryptophan hydroxylase inhibitor and a BDNF signaling inhibitor were also used to determine the pharmacological mechanisms of Rg3. It was found that Rg3 produced antidepressant effects in the FST and TST without affecting locomotor activity. Rg3 also prevented the CSDS-induced depressive-like symptoms. Moreover, Rg3 fully restored the CSDS-induced decrease in the hippocampal BDNF signaling pathway, and use of the BDNF signaling inhibitor blocked the antidepressant effects of Rg3. In conclusion, ginsenoside Rg3 has antidepressant effects via promotion of the hippocampal BDNF signaling pathway.

GM1 ganglioside reverses the cognitive deficits induced by MK801 in mice.

Cognitive deficits are core symptoms of schizophrenia, but effective treatments are still lacking. Previous studies have reported that the brain-derived neurotrophic factor (BDNF) signaling is closely involved in learning and memory. Monosialotetrahexosylganglioside (GM1) is a ganglioside with wide-ranging pharmacologic effects that enhances the BDNF signaling cascade. This study aimed to assess the effects of GM1 on schizophrenia-related cognitive impairments. A brief disruption of N-methyl-D-aspartate receptors with MK801 was used to generate the animal model for cognitive deficits in schizophrenia. It was found that MK801-treated mice showed significant deficits in memory ability compared with control mice in different behavior tests, and this was accompanied by decreased hippocampal BDNF signaling pathway. Consecutive administration of GM1 fully restored the MK801-induced cognitive deficits and the impaired BDNF signaling in the hippocampus. Furthermore, a BDNF system inhibitor abolished the effects of GM1 in the MK801 model. Taken together, our results show that GM1 could reverse the MK801-induced cognitive deficits, suggesting a potential usefulness of GM1 in treating the schizophrenia-related cognitive impairments.

Developmental exposure to cuprizone reduces intermediate-stage progenitor cells and cholinergic signals in the hippocampal neurogenesis in rat offspring

The exposure to cuprizone (CPZ) leads to demyelination in the central nervous system in rodents. To examine the developmental effects of CPZ exposure on hippocampal neurogenesis, pregnant rats were treated with 0, 0.1 or 0.4% CPZ in the diet from gestational day 6 to day 21 after delivery. On postnatal day 21, male offspring had a decreased density of new glue2+ oligodendrocyte progenitor cells in the dentate hilus and in the area of the cerebellar medulla in the presence of 0.4% CPZ. With regard to neurogenesis-related parameters, offspring had decreased T box brain 2+ progenitor cells and increased apoptotic cells, as detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling, which was accompanied by the up-regulation of Casp12 and Bcl2l11 in the subgranular zone, and increased reelin+ interneurons in the dentate hilus. In addition, the density of phosphorylated TrkB+ interneurons decreased in the dentate hilus, which was accompanied by transcript down-regulation of Bdnf and Chrna7 in the dentate gyrus. Moreover, granule cells expressing gene products of immediate-early genes, i.e., Arc and Fos, decreased. These results suggest that maternal exposure to 0.4% CPZ decreases proliferative type-2 progenitor cells via endoplasmic reticulum stress-mediated apoptosis and inhibition of cholinergic signals to intermediate-stage progenitor cells following reduced oligodendrocyte production and suppression of the brain-derived neurotrophic factor signaling cascade. Increases in reelin-expressing interneurons may compensate for impaired granule cell migration and/or correct positioning due to decreased immediate-early gene-mediated neuronal plasticity. However, all observed fluctuations disappeared at the adult stage, suggesting that CPZ-induced developmental neurotoxicity was reversible.

WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway.

Current anti-depressants are clinically effective only after several weeks of administration and always produce side effects. WY14643 is a selective agonist of peroxisome proliferator-activated receptor-α with neuroprotective and neurotrophic effects. Here, we investigated the anti-depressant effects of WY14643 in mice models of depression. We assessed the anti-depressant effects of WY14643 in the forced swim test (FST), tail suspension test (TST) and chronic social defeat stress (CSDS) model. Western blotting and immunohistochemistry studies were further performed to detect the effects of WY14643 on the brain-derived neurotrophic factor (BDNF) signaling pathway and hippocampal neurogenesis. The anti-BDNF antibody, BDNF signaling inhibitor, and tryptophan hydroxylase inhibitor were also used to explore the anti-depressant mechanisms of WY14643. WY14643 exhibited robust anti-depressant effects in the FST and TST and also protected against the CSDS stress in mice models. Moreover, WY14643 reversed the stress-induced elevation of corticosterone, deficiency of BDNF signaling pathway, and hippocampal neurogenesis. Blockade of BDNF signaling cascade, not the monoaminergic system, abolished all the anti-depressant effects of WY14643. These data provide the first evidence that WY14643 exerts anti-depressant-like activity through promoting the BDNF signaling pathway.

Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake

We recently identified brain-derived neurotrophic factor (BDNF) in the dorsal striatum to be a major component of a homeostatic pathway controlling ethanol consumption. We hypothesized that ethanol-mediated activation of the BDNF signaling cascade is required for the ethanol-related function of the neurotrophic factor. Here, we demonstrate that exposure of striatal neurons to ethanol results in the activation of the BDNF receptor TrkB, leading to the activation of the mitogen-activated protein kinase (MAP kinase) signaling pathway and the subsequent increase in the expression of preprodynorphin (Pdyn) via BDNF. Finally, we show that activation of the dynorphin receptor, the kappa opioid receptor (KOR), is required for the BDNF-mediated decrease in ethanol intake, illustrating a function of dynorphin in BDNF's homeostatic control of ethanol consumption. Taken together, these results demonstrate that BDNF regulates ethanol intake by initiation of MAP kinase signaling and the ensuing production of downstream gene products, including Pdyn.

Amyloid-β at sublethal level impairs BDNF-induced arc expression in cortical neurons

Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive dysfunction that probably due to a deficit in synaptic plasticity. One member of neurotrophins, brain-derived neurotrophic factor (BDNF), is known to be involved in the hippocampal long-term potentiation (LTP), a cellular model for learning and memory. Moreover, activity-regulated cytoskeleton-associated gene ( Arc), an immediate early gene, is found to be a downstream effector of the BDNF signaling cascade. Inhibition of Arc protein synthesis impairs both the maintenance of LTP and the consolidation of long-term memory. In addition, the formation of senile plaques is a pathological feature in AD and mainly consists of the deposition of amyloid-β (Aβ), a proteolytic product of amyloid precursor protein. Several studies concerning neurobehavioral performance have suggested that Aβ at sublethal levels interfere with the signaling cascades critical for synaptic plasticity and thus lead to the cognitive impairment in early stage of AD. Whether the BDNF-mediated Arc synthesis is impaired by sublethal Aβ in early AD is still unclear. Therefore, in the present study, primary cultures of neonatal rat cortical neurons were used to evaluate the effect of sublethal Aβ on the BDNF-induced Arc protein expression. Consistent with the literature, Arc, an indicator of synaptic plasticity, was induced by BDNF (25 ng/ml) in both dose- and time-dependent manners. After treating cultures with sublethal Aβ (5 μM), a significant suppression was observed on the level of BDNF-induced Arc protein expression. This result indicates that Aβ at sublethal level impairs the BDNF-mediated signaling in cortical neurons and thus underlies the deficits of synaptic plasticity occurred at the early stage of AD before significant neuronal loss.

Naturally Occurring Truncated trkB Receptors Have Dominant Inhibitory Effects on Brain-Derived Neurotrophic Factor Signaling

trkB encodes a receptor tyrosine kinase activated by three neurotrophins--brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4/5. In vivo, three isoforms of the receptor are generated by differential splicing--gp145trkB or the full-length trkB receptor, and trkB.T1 and trkB.T2, two cytoplasmically truncated receptors that lack kinases, but contain unique C termini. Although the truncated receptors appear to be precisely regulated during nervous system development and regeneration, their role in neurotrophin signaling has not been directly tested. In this paper, we studied the signaling properties and interactions of gp145trkB, trkB.T1, and trkB.T2 by expressing the receptors in a Xenopus oocyte microinjection assay. We found that oocytes expressing gp145trkB, but not trkB.T1 or trkB.T2, were capable of eliciting 45Ca efflux responses (a phospholipase C-gamma-mediated mechanism) after stimulation by BDNF. When trkB.T1 and trkB.T2 were coexpressed with gp145trkB, they acted as dominant negative receptors, inhibiting the BDNF signal by forming nonfunctional heterodimers with the full-length receptors. An ATP-binding mutant of gp145trkB had similar dominant inhibitory effects. Our data suggest that naturally occurring truncated trkB receptors function as inhibitory modulators of neurotrophin responsiveness. Furthermore, the homodimerization of gp145trkB appears to be an essential step in activation of the BDNF signaling cascade.