Brain-derived Neurotrophic Factor Pathway Research Articles

Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder.

In this interventional pilot study, we investigated the effects of a modified ketogenic diet (KD) on children with autism spectrum disorder (ASD). We previously observed improved behavioral symptoms in this cohort following the KD; this trial was registered with Clinicaltrials.gov (NCT02477904). This report details the alterations observed in the microbiota, inflammation markers, and microRNAs of seven children following a KD for a duration of 4 months. Our analysis included blood and stool samples, collected before and after the KD. After 4 months follow up, we found that the KD led to decreased plasma levels of proinflammatory cytokines (IL-12p70 and IL-1b) and brain-derived neurotrophic factor (BDNF). Additionally, we observed changes in the gut microbiome, increased expression of butyrate kinase in the gut, and altered levels of BDNF-associated miRNAs in the plasma. These cohort findings suggest that the KD may positively influence ASD sociability, as previously observed, by reducing inflammation, reversing gut microbial dysbiosis, and impacting the BDNF pathway related to brain activity.

Brain-Derived Neurotrophic Factor, Nociception, and Pain.

This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of synaptic transmission. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF's involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.

Neuroprotective effects of the salidroside derivative SHPL-49 via the BDNF/TrkB/Gap43 pathway in rats with cerebral ischemia

Ischemic stroke is a common intravascular disease and one of the leading causes of death and disability. The salidroside derivative SHPL-49, which we previously synthesized, significantly attenuates cerebral ischemic injury in a rat model of permanent middle cerebral artery occlusion. To explore the neuroprotective mechanism of SHPL-49, the effects of SHPL-49 on the expression levels of neurotrophic factors in neurons and microglia and the polarization of microglia were investigated in the present study. SHPL-49 activated the brain-derived neurotrophic factor (BDNF) pathway, decreased the number of degenerated neurons, and accelerated neurogenesis in rats with cerebral ischemia. In addition, SHPL-49 promoted the polarization of microglia toward the M2 phenotype to alleviate neuroinflammation. In BV2 cells, SHPL-49 upregulated CD206 mRNA and protein levels and inhibited CD86 mRNA and protein levels. SHPL-49 also increased neurotrophic factor secretion in BV2 cells, which indirectly promoted the survival of primary neurons after oxygen-glucose deprivation (OGD). Proteomics analysis revealed that SHPL-49 promoted growth-associated protein 43 (Gap43) expression. SHPL-49 enhanced synaptic plasticity and increased Gap43 protein levels via activation of the BDNF pathway in the OGD primary neuron model. These results indicate that SHPL-49 prevents cerebral ischemic injury by activating neurotrophic factor pathways and altering microglial polarization. Thus, SHPL-49 is a potential neuroprotective agent.

Possible Role of Correlation Coefficients and Network Analysis of Multiple Intracellular Proteins in Blood Cells of Patients with Bipolar Disorder in Studying the Mechanism of Lithium Responsiveness: A Proof-Concept Study.

Background: The mechanism of lithium treatment responsiveness in bipolar disorder (BD) remains unclear. The aim of this study was to explore the utility of correlation coefficients and protein-to-protein interaction (PPI) network analyses of intracellular proteins in monocytes and CD4+ lymphocytes of patients with BD in studying the potential mechanism of lithium treatment responsiveness. Methods: Patients with bipolar I or II disorder who were diagnosed with the MINI for DSM-5 and at any phase of the illness with at least mild symptom severity and received lithium (serum level ≥ 0.6 mEq/L) for 16 weeks were divided into two groups, responders (≥50% improvement in Montgomery-Asberg Depression Rating Scale and/or Young Mania Rating Scale scores from baseline) and non-responders. Twenty-eight intracellular proteins/analytes in CD4+ lymphocytes and monocytes were analyzed with a tyramine-based signal-amplified flow cytometry procedure. Correlation coefficients between analytes at baseline were estimated in both responders and non-responders and before and after lithium treatment in responders. PPI network, subnetwork, and pathway analyses were generated based on fold change/difference in studied proteins/analytes between responders and non-responders. Results: Of the 28 analytes from 12 lithium-responders and 11 lithium-non-responders, there were more significant correlations between analytes in responders than in non-responders at baseline. Of the nine lithium responders with pre- and post-lithium blood samples available, the correlations between most analytes were weakened after lithium treatment with cell-type specific patterns in CD4+ lymphocytes and monocytes. PPI network/subnetwork and pathway analyses showed that lithium response was involved in four pathways, including prolactin, leptin, neurotrophin, and brain-derived neurotrophic factor pathways. Glycogen synthase kinase 3 beta and nuclear factor NF-kappa-B p65 subunit genes were found in all four pathways. Conclusions: Using correlation coefficients, PPI network/subnetwork, and pathway analysis with multiple intracellular proteins appears to be a workable concept for studying the mechanism of lithium responsiveness in BD. Larger sample size studies are necessary to determine its utility.

Repetitive transcranial magnetic stimulation via the hippocampal brain-derived neurotrophic factor-tyrosine kinase receptor B pathway to affect sexual behavior and neuroplasticity in rapid ejaculation rats.

Premature ejaculation (PE) is the most prevalent sexual dysfunction among men. Eejaculation involves a complex nervous mechanism in which the ejaculatory centers play a key role in modulating sperm emission. Although treatment possibilities span from psychotherapy to pharmacological approaches, results show inconsistent efficacy. In this context, the emergence of repetitive transcranial magnetic stimulation (rTMS) as a non-invasive neuromodulatory approach represents a compelling avenue for potential therapeutic exploration. To investigate whether high-frequency transcranial magnetic stimulation can modulate the ejaculatory behavior of rats with rapid ejaculation by altering neurotransmitter levels and neuroplasticity in the hippocampus. Rats have been screened for rapid ejaculation by observing behavioral indices of mating, and subsequently divided into two groups. The intervention group was administered with a 10Hz rTMS stimulation, whereas the control group received a sham procedure. Upon the delivery of rTMS, we investigated ejaculation latency (EL), the hippocampal 5-hydroxytryptamine (5-HT) concentration, brain-derived neurotrophic factor (BDNF), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95) expressions, as well as BDNF-receptor tyrosine kinase receptor B (TrkB) pathway upregulation. After 14 days, EL was increased in the intervention group compared with the control group. 5-HT concentration in the hippocampal region was increased, and high-frequency rTMS activated the BDNF and TrkB pathways, including phosphorylation of cAMP response element-binding protein (CREB), and upregulated the transcription and protein expression of SYN, and PSD95. RTMS upregulates BDNF, SYN, and PSD95 expression through activation of the BDNF-TrkB pathway and increases brain 5-hydroxytryptamine thereby regulating neuroplasticity and improving ejaculation.

1,5-anhydro-D-fructose induces anti-aging effects on aging-associated brain diseases by increasing 5'-adenosine monophosphate-activated protein kinase activity via the peroxisome proliferator-activated receptor-γ co-activator-1α/brain-derived neurotrophic factor pathway.

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor that serves as a cellular housekeeper; it also controls energy homeostasis and stress resistance. Thus, correct regulation of this factor can enhance health and survival. AMPK signaling may have a critical role in aging-associated brain diseases. Some in vitro studies have shown that 1,5-anhydro-D-fructose (1,5-AF) induces AMPK activation. In the present study, we experimentally evaluated the effects of 1,5-AF on aging-associated brain diseases in vivo using an animal model of acute ischemic stroke (AIS), stroke-prone spontaneously hypertensive rats (SHRSPs), and the spontaneous senescence-accelerated mouse-prone 8 (SAMP8) model. In the AIS model, intraperitoneal injection of 1,5-AF reduced cerebral infarct volume, neurological deficits, and mortality. In SHRSPs, oral administration of 1,5-AF reduced blood pressure and prolonged survival. In the SAMP8 model, oral administration of 1,5-AF alleviated aging-related decline in motor cognitive function. Although aging reduced the expression levels of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) and brain-derived neurotrophic factor (BDNF), we found that 1,5-AF activated AMPK, which led to upregulation of the PGC-1α/BDNF pathway. Our results suggest that 1,5-AF can induce endogenous neurovascular protection, potentially preventing aging-associated brain diseases. Clinical studies are needed to determine whether 1,5-AF can prevent aging-associated brain diseases.

D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels

The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+-CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.

Effect of acupuncture on BDNF signaling pathways in several nervous system diseases.

In recent years, the understanding of the mechanisms of acupuncture in the treatment of neurological disorders has deepened, and considerable progress has been made in basic and clinical research on acupuncture, but the relationship between acupuncture treatment mechanisms and brain-derived neurotrophic factor (BDNF) has not yet been elucidated. A wealth of evidence has shown that acupuncture exhibits a dual regulatory function of activating or inhibiting different BDNF pathways. This review focuses on recent research advances on the effect of acupuncture on BDNF and downstream signaling pathways in several neurological disorders. Firstly, the signaling pathways of BDNF and its function in regulating plasticity are outlined. Furthermore, this review discusses explicitly the regulation of BDNF by acupuncture in several nervous system diseases, including neuropathic pain, Parkinson's disease, cerebral ischemia, depression, spinal cord injury, and other diseases. The underlying mechanisms of BDNF regulation by acupuncture are also discussed. This review aims to improve the theoretical system of the mechanism of acupuncture action through further elucidation of the mechanism of acupuncture modulation of BDNF in the treatment of neurological diseases and to provide evidence to support the wide application of acupuncture in clinical practice.

Human iPSC-derived endothelial cells promote CNS remyelination via BDNF and mTORC1 pathway.

Damage of myelin is a component of many diseases in the central nervous system (CNS). The activation and maturation of the quiescent oligodendrocyte progenitor cells (OPCs) are the crucial cellular processes for CNS remyelination, which is influenced by neuroinflammation in the lesion microenvironment. Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) have shown promise in restoring function in various preclinical animal models. Here we ask whether and whether transplantation of hiPSC-ECs could benefit remyelination in a mouse model of CNS demyelination. Our results show that in vitro, hiPSC-ECs increase OPC proliferation, migration and differentiation via secreted soluble factors including brain-derived neurotrophic factor (BDNF). hiPSC-ECs also promote the survival of oligodendrocyte lineage cells in vitro and in vivo. Transplantation of hiPSC-ECs into a toxin-induced demyelination lesion in mouse corpus callosum (CC) leads to increased density of oligodendrocyte lineage cells and level of myelin in demyelinated area, correlated with a decreased neuroinflammation and an increased proportion of pro-regenerative M2 phenotype in microglia/macrophages. The hiPSC-EC-exposed oligodendrocyte lineage cells showed significant increase in the level of phosphorylated S6 ribosomal protein (pS6) both in vitro and in vivo, indicating an involvement of mTORC1 pathway. These results suggest that hiPSC-ECs may benefit myelin protection and regeneration which providing a potential source of cell therapy for a wide range of diseases and injuries associated with myelin damage.

Isochlorogenic acid B alleviates lead-induced anxiety, depression and neuroinflammation in mice by the BDNF pathway

Lead (Pb) can cause neurobehavioral abnormalities. Isochlorogenic acid B (ICAB), a dietary flavonoid found in tea, sweet potato, artichoke, propolis and several plants, exhibited potential neuroprotective properties. In this study, we aimed to investigate the mechanisms of Pb-induced anxiety, depression and neuroinflammation, and the neuroprotective effect of ICAB in mouse brains. We found that ICAB supplementation significantly improved behavioral abnormalities, neuroinflammation and oxidative stress induced by Pb. ICAB attenuated Pb-induced anxiety and depression behavior in mice, as indicated by decreasing the duration of immobility in tail suspension test and increasing the crossing number, rearing number and time in center in open field test. Accordingly, ICAB inhibited oxidative stress by decreasing malondialdehyde (MDA) level and increasing the antioxidant enzyme activity. ICAB also inhibited Pb-induced inflammation in brain, as indicated by decreasing the tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels. ICAB increased the expression levels of brain derived neurotrophic factor (BDNF) and the phosphorylation of cAMP-responsive element binding protein (CREB), phosphoinositide 3-kinases-protein kinase B (PI3K/AKT). Furthermore, ICAB decreased the levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), glycogen synthase kinase-3 beta (GSK-3β) and p38. Collectively, this study demonstrated that ICAB improved Pb-induced anxiety, depression, neuroinflammation and oxidative stress by regulating the BDNF signaling pathway.

A Pharmacological Evaluation of the Analgesic Effect and Hippocampal Protein Modulation of the Ketamine Metabolite (2R,6R)-Hydroxynorketamine in Murine Pain Models.

The ketamine metabolite (2R,6R)-hydroxynorketamine ([2R,6R]-HNK) has analgesic efficacy in murine models of acute, neuropathic, and chronic pain. The purpose of this study was to evaluate the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) dependence of (2R,6R)-HNK analgesia and protein changes in the hippocampus in murine pain models administered (2R,6R)-HNK or saline. All mice were CD-1 IGS outbred mice. Male and female mice underwent plantar incision (PI) (n = 60), spared nerve injury (SNI) (n = 64), or tibial fracture (TF) (n = 40) surgery on the left hind limb. Mechanical allodynia was assessed using calibrated von Frey filaments. Mice were randomized to receive saline, naloxone, or the brain-penetrating AMPA blocker (1,2,3,4-Tetrahydro-6-nitro-2,3-dioxobenzo [f]quinoxaline-7-sulfonamide [NBQX]) before (2R,6R)-HNK 10 mg/kg, and this was repeated for 3 consecutive days. The area under the paw withdrawal threshold by time curve for days 0 to 3 (AUC 0-3d ) was calculated using trapezoidal integration. The AUC 0-3d was converted to percent antiallodynic effect using the baseline and pretreatment values as 0% and 100%. In separate experiments, a single dose of (2R,6R)-HNK 10 mg/kg or saline was administered to naive mice (n = 20) and 2 doses to PI (n = 40), SNI injury (n = 40), or TF (n = 40) mice. Naive mice were tested for ambulation, rearing, and motor strength. Immunoblot studies of the right hippocampal tissue were performed to evaluate the ratios of glutamate ionotropic receptor (AMPA) type subunit 1 (GluA1), glutamate ionotropic receptor (AMPA) type subunit 2 (GluA2), phosphorylated voltage-gated potassium channel 2.1 (p-Kv2.1), phosphorylated-calcium/calmodulin-dependent protein kinase II (p-CaMKII), brain-derived neurotrophic factor (BDNF), phosphorylated protein kinase B (p-AKT), phosphorylated extracellular signal-regulated kinase (p-ERK), CXC chemokine receptor 4 (CXCR4), phosphorylated eukaryotic translation initiation factor 2 subunit 1 (p-EIF2SI), and phosphorylated eukaryotic translation initiation factor 4E (p-EIF4E) to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). No model-specific gender difference in antiallodynic responses before (2R,6R)-HNK administration was observed. The antiallodynic AUC 0-3d of (2R,6R)-HNK was decreased by NBQX but not with pretreatment with naloxone or saline. The adjusted mean (95% confidence interval [CI]) antiallodynic effect of (2R,6R)-HNK in the PI, SNI, and TF models was 40.7% (34.1%-47.3%), 55.1% (48.7%-61.5%), and 54.7% (46.5%-63.0%), greater in the SNI, difference 14.3% (95% CI, 3.1-25.6; P = .007) and TF, difference 13.9% (95% CI, 1.9-26.0; P = .019) compared to the PI model. No effect of (2R,6R)-HNK on ambulation, rearing, or motor coordination was observed. Administration of (2R,6R)-HNK was associated with increased GluA1, GluA2, p-Kv2.1, and p-CaMKII and decreased BDNF ratios in the hippocampus, with model-specific variations in proteins involved in other pain pathways. (2R,6R)-HNK analgesia is AMPA-dependent, and (2R,6R)-HNK affected glutamate, potassium, calcium, and BDNF pathways in the hippocampus. At 10 mg/kg, (2R,6R)-HNK demonstrated a greater antiallodynic effect in models of chronic compared with acute pain. Protein analysis in the hippocampus suggests that AMPA-dependent alterations in BDNF-TrkB and Kv2.1 pathways may be involved in the antiallodynic effect of (2R,6R)-HNK.

Apigenin Attenuates Hippocampal Microglial Activation and Restores Cognitive Function in Methotrexate-Treated Rats: Targeting the miR-15a/ROCK-1/ERK1/2 Pathway

Microglial activation underpins the methotrexate (MTX)-induced neurotoxicity; however, the precise mechanism remains unclear. This study appraised the potential impact of apigenin (Api), a neuroprotective flavonoid, in MTX-induced neurotoxicity in rats in terms of microglial activation through targeting the miR-15a/Rho-associated protein kinase-1 (ROCK-1)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Male Sprague Dawley rats were randomly divided into 4 groups: Normal control (saline i.p. daily and i.v. on days 8 and 15); Api control (20 mg/kg, p.o.) daily for 30 days; MTX-alone (75 mg/kg, i.v.) on days 8 and 15, then four i.p. injections of leucovorin (LCV): 6 mg/kg after 18 h, then three doses (3 mg/kg) every 8 h post-MTX; and Api co-treated (20 mg/kg/day, p.o.) throughout the model for 30 days, with administration of MTX and LCV as in group 3. MTX administration elevated hippocampal ionized calcium-binding adaptor protein-1 (Iba-1) immunostaining, indicating microglial activation. This was accompanied by neuroinflammation, oxidative stress, and enhanced apoptosis manifested by elevated hippocampal interleukin-1β, malondialdehyde, and caspase-3, and decreased reduced glutathione levels. Concurrently, abated miR-15a expression, overexpression of its target ROCK-1, diminished downstream ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation, and decreased hippocampal brain-derived neurotrophic factor (BDNF) levels were observed. Api mitigated the MTX-induced neurotoxicity by reversing the biochemical, histopathological, and behavioral derangements tested by novel object recognition and Morris water maze tests. Conclusively, Api lessens MTX-induced neuroinflammation, oxidative stress, and apoptosis and boosts cognitive function through inhibiting microglial activation via modulating the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway.Graphical Graphical abstract showing the effects of methotrexate and apigenin co-treatment in MTX-induced neurotoxicity model.On the left, methotrexate (MTX) administration to rats resulted in hippocampal miR-15a downregulation, which triggered an enhanced expression of its target ROCK-1, consequently inhibiting the downstream ERK1/2/CREB/BDNF pathway, instigating a state of microglial activation, neuroinflammation, oxidative stress, and apoptosis. On the other hand, apigenin (Api) co-treatment restored miR-15a, inhibited ROCK-1 expression, and activated the ERK1/2/CREB/BDNF pathway, leading to diminished hippocampal microglial activation, neuroinflammation, and apoptosis, and restoration of the redox balance, along with improvement in memory and cognitive function of the MTX-treated rats.

Relation between Selected Sleep Parameters, Depression, Anti-Tumor Necrosis Factor Therapy, and the Brain-Derived Neurotrophic Factor Pathway in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) patients often have sleep and mood disorders. Brain-derived neurotrophic factor (BDNF) and proBDNF were shown to modulate interactions between the central nervous system and the gastrointestinal tract, possibly contributing to psychological issues. Anti-tumor necrosis factor (TNF) therapy in IBD can alter BDNF expression and further affect the brain-gut axis. Eighty IBD patients and 44 healthy controls (HCs) were enrolled and divided into subsets based on disease activity and condition (ulcerative colitis (UC)/Crohn's disease (CD)). Questionnaires evaluating sleep parameters and depression as well as venous blood were collected. The IBD group had a lower expression of BDNF mRNA, but higher proBDNF and BDNF protein concentration than HCs. The UC group had a higher BDNF protein concentration than the CD. BDNF protein was positively correlated to sleep efficiency in the IBD group. Depression severity was associated positively with BDNF mRNA and negatively with BDNF protein in the remission group. Anti-TNF therapy enhanced BDNF mRNA expression. The BDNF pathway might be disturbed in IBD, linking it to sleep disorders and depression. Systemic inflammation could be the main cause of this disruption. BDNF mRNA is a more reliable parameter than protein due to numerous post-translational modifications.

Can Brain-derived Neurotrophic Factor (BDNF) Mimetics be a Way Out for Neurodegenerative Diseases?

Neurodegenerative diseases are chronic and progressive disease groups characterized by the decline of neural transmission because of the loss of structure and function of neurons. Although there is currently no effective treatment for neurodegenerative diseases, new treatment strategies need to be developed urgently. Among neurotrophins, BDNF has been extensively investigated, and it has emerged as an important regulator of synaptic plasticity, neuronal survival, and differentiation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases. Moreover, promising results have been obtained for BDNF in many experimental studies on animal models. In addition, BDNF serves as a crucial molecular target for developing drugs to treat neurological diseases. However, several pharmacokinetic difficulties have limited its use in clinical practice, such as its inability to cross the blood-brain barrier, short half-life, and potential adverse effects. To avoid these difficulties, several approaches have been explored, but they have led to disappointing results. One way to overcome the limitations of BDNF may be with mimetic molecules that can effectively stimulate the receptors it has an affinity with and thus activates BDNF pathways. In this perspective article, an evaluation of the efficacy of different BDNF mimetics against neurodegenerative diseases was made.

Suppressive effects of bilobalide on depression-like behaviors induced by chronic unpredictable mild stress in mice.

Background: Depression is a psychiatric disorder with depressed mood and even suicide attempts as the main clinical symptoms, and its pathogenesis has not yet been fully elucidated. Brain derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of depression. Purpose: The main aim of the present study was to evaluate the effectiveness and reveal the potential mechanisms of bilobalide (BB) intervention in alleviating depression-like behaviors by using chronic unpredictable mild stress (CUMS) mice via mediating the BDNF pathway. Methods: Behavioral assessments were carried out by using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). CUMS mice were randomly divided into 5 groups: CUMS + solvent, CUMS + BB low, CUMS + BB medium, CUMS + BB high and CUMS + fluoxetine. Total serum levels of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were measured by ELISA. Expression of TNF-α, IL-6, AKT, GSK3β, β-catenin, Trk-B and BDNF in the mouse hippocampus was assessed by western blotting. Results: BB treatment reduced the levels of pro-inflammatory cytokines (IL-6 and TNF-α) and increased the protein expression of BDNF in the hippocampus region of the CUMS mice. Moreover, BB treatment enhanced the AKT/GSK3β/β-catenin signaling pathway which is downstream of the BDNF receptor Trk-B in the hippocampus of these mice. Conclusions: Overall, the experimental results indicated that BB reverses CUMS-induced depression-like behavior. BB exerts antidepressant-like effects by inhibiting neuroinflammation and enhancing the function of neurotrophic factors.

Euonymus alatus Twig Extract Protects against Scopolamine-Induced Changes in Brain and Brain-Derived Cells via Cholinergic and BDNF Pathways.

In the current study, the therapeutic and preventive effects of Euonymus alatus (EA) twig extract were investigated in a mouse model of cognitive deficit and B35 cells. Twig extract 1 was extracted with 70% ethanol and later twig extract 2 was extracted through liquid-liquid extraction with 70% ethanol and hexane. EA twig 2 (300 mg/kg) along with the standard drug donepezil (5 mg/kg) were orally administered to the mice for 34 days. Scopolamine was given intraperitoneally for 7 days. Administration of EA twig extract 2 significantly improved the passive avoidance test (PAT) in mice. EA twigs extract also restored the scopolamine-reduced brain-derived neurotrophic factor (BDNF)/extracellular regulated kinase (ERK)/cyclic AMP responsive element binding protein (CREB) signaling in B35 cells and the mouse hippocampus. In addition, EA twig extract significantly inhibited the acetylcholine esterase (AChE) activity in B35 cells in a dose-dependent manner. Chromatography and ESI MS analysis of EA twig extract revealed the presence of flavonoids; epicatechin, taxifolin, aromadendrin, and naringenin with catechin being the most abundant. These flavonoids exerted protective effects alone and had the possibility of synergistic effects in combination. Our work unmasks the ameliorating effect of EA twig extract 2 on scopolamine-associated cognitive impairments through the restoration of cholinergic systems and the BDNF/ERK/CREB pathway.

The GluA1-Related BDNF Pathway Is Involved in PTSD-Induced Cognitive Flexibility Deficit in Attentional Set-Shifting Tasks of Rats.

Background: Post-Traumatic Stress Disorder (PTSD) is a severe psychological disorder characterized by intrusive thoughts, heightened arousal, avoidance, and flashbacks. Cognitive flexibility dysfunction has been linked with the emergence of PTSD, including response inhibition deficits and impaired attentional switching, which results in difficulties for PTSD patients when disengaging attention from trauma-related stimuli. However, the molecular mechanisms of cognitive flexibility deficits remain unclear. Methods: The animals were exposed to a single prolonged stress and electric foot shock (SPS&S) procedure to induce PTSD-like features. Once the model was established, the changes in cognitive flexibility were assessed using an attentional set-shifting task (ASST) in order to investigate the effects of traumatic stress on cognitive flexibility. Additionally, the molecular alterations of certain proteins (AMPA Receptor 1 (GluA1), brain-derived neurotrophic factor (BDNF), and Postsynaptic density protein 95 (PSD95) in the medial prefrontal cortex (mPFC) were measured using Western blot and immunofluorescence. Results: The SPS&S model exhibited PTSD-like behaviors and induced reversal learning and set-shifting ability deficit in the ASST. These behavioral changes are accompanied by decreased GluA1, BDNF, and PSD95 protein expression in the mPFC. Further analysis showed a correlative relationship between the behavioral and molecular alterations. Conclusions: The SPS&S model induced cognitive flexibility deficits, and the potential underlying mechanism could be mediated by GluA1-related BDNF signaling in the mPFC.

Sciatic nerve block downregulates the BDNF pathway to alleviate the neonatal incision-induced exaggeration of incisional pain via decreasing microglial activation

Sciatic nerve block is under investigation as a possible therapeutic strategy for neonatal injury-induced exaggeration of pain responses to reinjury. Spinal microglial priming, brain-derived neurotrophic factor (BDNF) and Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) participate in exaggerated incisional pain induced by neonatal incision. However, effects of sciatic nerve block on exacerbated incisional pain and underlying mechanisms remain unclear. Here, we demonstrated that sciatic nerve block alleviates pain hypersensitivity and microglial activation in rats subjected to neonatal incision and adult incision (nIN-IN). Chemogenetic activation or inhibition of spinal microglia attenuates or mimics effects of sciatic nerve block on pain hypersensitivity, respectively. Moreover, α-amino-3-hydroxy- 5-methy- 4-isoxazole propionate (AMPA) receptor subunit GluA1 contributes to the exaggeration of incisional pain. The inhibition of BDNF or SHP2 blocks upregulations of downstream molecules in nIN-IN rats. Knockdown of SHP2 attenuates the increase of GluA1 induced by injection of BDNF in adult rats with only neonatal incision. The inhibition of microglia or ablation of microglial BDNF attenuates upregulations of SHP2 and GluA1. Additionally, sciatic nerve block downregulates the expression of these three molecules. Upregulation of BDNF, SHP2 or AMPA receptor attenuates sciatic nerve block-induced reductions of downstream molecules and pain hypersensitivity. Microglial activation abrogates reductions of these three molecules induced by sciatic nerve block. These results suggest that decreased activation of spinal microglia contributes to beneficial effects of sciatic nerve block on the neonatal incision-induced exaggeration of incisional pain via downregulating BDNF/SHP2/GluA1-containing AMPA receptor signaling. Thus, sciatic nerve block may be a promising therapy.

Evaluation of neuroprotective agents acting via the BDNF–TrkB pathway using AI‐enabled predictions of ligand–receptor interactions

Glaucoma is the leading cause of irreversible blindness globally and is associated with retinal ganglion cell (RGC) death. Brain-derived neurotrophic factor (BDNF) is a potent neurotrophin that promotes neuronal survival via its receptor, tropomyosin receptor kinase B (TrkB) encoded by NTRK2. Our current understanding of the mechanism of action and therapeutic potential of the BDNF pathway is limited by the lack of knowledge of its interaction with TrkB at atomic resolution. We developed an artificial intelligence (AI) model to predict the three-dimensional protein structures of BDNF and TrkB, as well as their interaction. The AI model was further applied to compare small-molecule drugs that mimic BDNF–TrkB interaction, leading to the identification of 7,8-dihydroxyflavone (DHF) as an agonist of TrkB. We verified the neuroprotective effects of DHF in an in vivo acute glaucoma model in which RGC apoptosis caused by acute elevation of intraocular pressure was prevented by the intraocular application of DHF and to a lesser extent by BDNF. Our results provide AI-enabled prediction of ligand–receptor interactions between BDNF and TrkB at the atomic level and demonstrate the great potential for AI-enabled drug discovery.

Effect of electroacupuncture invention on activities of PGC-1α/Irisin (FNDC5)/BDNF signaling in cerebral cortex, hippocampus and muscles in focal cerebral ischemic/reperfusion injury rats

To observe the effect of electroacupuncture(EA) on the expression of peroxisome proliferator-activated receptor gamma coactivators-1-alpha (PGC-1α), Irisin and brain-derived neurotrophic factor (BDNF) in the ischemic peripheral cortex, hippocampus and local skeletal muscle in rats with focal cerebral ischemic/reperfusion injury (CI/RI), so as to explore its underlying mechanism of improving of CI/RI. Male SD rats were randomly divided into 3 groups: sham-operation, model and EA (11 rats in each group). The focal CI/RI model was established by middle cerebral artery occlusion (MCAO). EA (2 Hz /15 Hz, 2 to 4 mA) was applied to "Quchi" (LI11) and "Zusanli" (ST36) of the affected side for 20 min, once a day for 7 days. Zea-Longa's score and Balance Beam score were used to evaluate the neurological and motor functions. The infarcted volume of the brain was detected by using 2,3,5-triphenyltetrazolium chloride staining. The expression levels of PGC-1α, fibronectin type III domain-containing protein 5(FNDC5) and BDNF proteins in the ischemic peripheral cortex, hippocampus and local skeletal muscle were detected by Western blot. Compared with the sham-operation group, the Zea-Longa's score, Balance Beam score, percentage of cerebral infarct volume were notably increased (P<0.01), while the expression levels of PGC-1α, FNDC5 and BDNF proteins in the cerebral cortex and hippocampus (not in the local muscle) were significantly down-regulated in the model group (P<0.01, P<0.05). In comparison with the model group, the increase of Zea-Longa's score, Balance Beam score, percentage of cerebral infarct volume, and the decrease of expression levels of PGC-1α, FNDC5 and BDNF proteins in the ischemic peripheral cortex and that of BDNF in the hippocampus were reversed in the EA group (P<0.01, P<0.05). No significant changes were found in the expression levels of hippocampal PGC-1α and FNDC5 proteins in the hippocampus and those of PGC-1α, FNDC5 and BDNF proteins in the local muscle after EA intervention (P>0.05). EA can improve neurological and motor functions and reduce cerebral infarction volume in CI/RI rats, which may be related to its functions in activating PGC-1α/Irisin(FNDC5)/BDNF pathway in the cerebral cortex.