Brain-derived Neurotrophic Factor Protein Levels Research Articles

Effect of ethanol extract of nigella sativa L seeds and propofol on BDNF protein level as neuroplasticity and neuroprotection of traumatic brain injury in rats

Background Traumatic brain injury (TBI) is a change in brain function or evidence of brain pathology caused by external mechanical forces. Brain Derived Neurotrophic Factor (BDNF) is a neurotropin that functions as a neuron protective. Nigella sativa L is reported to have an antioxidant effect, administration of Nigella Sativa L to rats treated with ischemia-reperfusion brain injury. Propofol is an anesthetic agent frequently used intravenously in the management of TBI. The effect of propofol on brain tissue after TBI may be neuroprotective. We aimed to compare the potential of Nigella sativa L and propofol as neuroplasticity and neuroprotection in rats with TBI. Methods This was a laboratory experimental animal model with the post-test only control group design, namely measuring the effect of treatment by comparing the five groups of rats consisting of 30 rats. BDNF levels in rat brain tissue were collected at day 7 of treatment and measured by ELISA. Results The average BDNF protein levels per group, namely G1 (221,243 pg/mL), G2 (172,139 pg/mL), G3 (255,483 pg/mL), G4 (227,089 pg/mL), and G5 (272,603 pg/mL) respectively. Based on the ANOVA statistic, p-value = 0.032 (there was a significant difference between groups), with the Levene Test (0.077) or having variance between the same groups, sequentially the difference in average BDNF protein levels of the five groups is G5>G3>G4>G1>G2, meaning that the combination of Nigella sativa and propofol has more potential to increase BDNF protein levels than Nigella sativa, and Nigella sativa has more potential than propofol. Conclusion We concluded that both nigella sativa and propofol have the potential to increase BDNF protein levels. Nigella Sativa L had a better effect than propofol in repairing damaged neuron cells (neuroplasticity) and increasing BDNF protein levels (neuroprotection) for 7 days of administration in rat traumatic brain injury.

453 Ketamine Promotes Sustained Brain-Derived Neurotrophic Factor Levels in the Corticoaccumbens Circuit

OBJECTIVES/GOALS: Neuropsychiatric disorders classified as synaptopathies are marked by a glutamate-associated hypofrontality which impacts decision making and impulsivity. We hypothesized that behavioral efficacy of the psychoplastogen ketamine is mediated in part through lasting promotion of markers of synaptic strength in corticoaccumbens circuit. METHODS/STUDY POPULATION: Male, Sprague-Dawley rats received an intraperitoneal (i.p.) injection of saline, single ketamine (10 mg/kg; 1x/day), or repeated ketamine (10 mg/kg; 1x/day for three days). Twenty-four hrs following the dosing regimen, animals were euthanized, and brains dissected to harvest corticoaccumbens structures including the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). mRNA was extracted and converted to cDNA. Levels of brain derived neurotrophic factor (BDNF) exon II mRNA were quantified using reverse transcriptase polymerase chain reaction (RT-PCR); cyclophilin A (PPIA) was used as a loading control. Gene expression differences in ketamine-treated rats were identified versus saline-treated rats. BDNF protein levels were quantified using capillary-electrophoresis immunoblotting. RESULTS/ANTICIPATED RESULTS: Repeated, but not single, ketamine administration decreased mPFC, but increased NAc, BDNF exon II mRNA levels versus saline (p<0.05). Single and repeated ketamine administration increased NAC BDNF protein (p<0.05), while both dosing paradigms induced a trend towards an increase in mPFC BDNF levels. DISCUSSION/SIGNIFICANCE: We discovered a dosing regimen-dependent and sustained effects of ketamine administration on BDNF levels in the rodent brain. Taken together, ketamine-mediated BDNF levels may sustain synaptic strengthening mechanisms supporting future investigation into the utility of ketamine for diseases characterized by synaptopathies.

Paeoniflorin Alleviates Anxiety and Visceral Hypersensitivity via HPA Axis and BDNF/TrkB/PLCγ1 Pathway in Maternal Separation-induced IBS-like Rats.

Irritable Bowel Syndrome (IBS) is a prevalent gastrointestinal disorder that significantly diminishes the quality of life for affected individuals. The pathophysiology of IBS remains poorly understood, and available therapeutic options for IBS are limited. The crucial roles of brain-gut interaction, which is mediated by the Hypothalamic-Pituitary-Adrenocortical (HPA) axis and the autonomic nervous system in IBS, have attracted increasing attention. The objective of this study was to examine the impact of paeoniflorin (PF) on anxiety and visceral hypersensitivity in maternal separation-induced IBS-like rats. The IBS-like rat model was established through the implementation of Maternal Separation (MS) and subsequently subjected to various doses of PF administered via oral gavage for 14 days. Anxiety-like behavior was evaluated using the Open Field Test (OFT) and Elevated Plus Maze (EPM) test. The assessment of visceral sensitivity involved the utilization of the Abdominal Withdrawal Reflex (AWR) score and electromyographic (EMG) responses of the external oblique muscle in response to colorectal distention. The levels of adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotrophin-releasing hormone (CRH) were examined by ELISA. Quantitative real-time PCR (qRT-PCR) and immunofluorescence were employed to detect the expressions of CRH receptors 1 (CRHR1) and 2 (CRHR2). Glucocorticoid receptors (GR), mineralocorticoid receptor (MR), brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and phospholipase C γ1 (PLCγ1) were examined by Western blot. The results showed that MS induced anxiety-like behavior and visceral hypersensitivity, while PF treatment attenuated these changes. Furthermore, the HPA axis hyperactivity in MS rats was attenuated by PF treatment, indicated by reduced serum ACTH, CORT, and CRH levels and recovered hippocampal CRHR1 and GR expressions. In addition, PF inhibited BDNF/TrkB signaling by downregulating the protein levels of BDNF, TrkB, and phospho-PLCγ1 in the colon. These findings suggest that PF alleviated anxiety and visceral hypersensitivity in MS-induced IBS-like rats, which may be the modulation of HPA axis activity and BDNF/TrkB/PLCγ1 signaling pathway.

The BDNF protein is associated with glucose homeostasis and food intake in carriers of common BDNF gene variants.

The brain-derived neurotrophic factor (BDNF) concentrations may differ between BDNF gene genotype carriers. These changes occur in individuals with metabolic and mental disorders. The aim of this study was to assess the associations of glucose homeostasis parameters and the frequency of food consumption with BDNF protein concentrations based on the BDNF single-nucleotide polymorphisms (SNPs). Among the 439 participants, some common rs10835211 BDNF gene variants were analyzed. We evaluated BDNF concentration, fasting glucose and insulin concentrations and during oral glucose tolerance tests. Anthropometric measurements, body composition, and body fat distribution were assessed, and 3-day food intake diary and food frequency questionnaire were completed. We noticed significant differences in concentration of BDNF between AA and AG genotype rs10835211 carriers (p=0.018). The group of AA genotype holders were older, and positive correlation was found between age and BDNF in the whole study population (p=0.012) and in the GG genotype carriers (p=0.023). Moreover, BDNF protein correlated with fasting insulin (p=0.015), HOMA-IR (p=0.031), HOMA-B (p=0.010) , and the VAT/SAT ratio (p=0.026) in the GG genotype individuals. Presence of the GG genotype was negatively correlated with nut and seed (p=0.047), lean pork consumption (p=0.015) and the BDNF protein. Moreover, we observed correlations between the frequency of chicken (p=0.028), pasta (p=0.033) and sweet food intake (p=0.040) and BDNF concentration in the general population. Among carriers of the AA genotype, we observed a positive correlation between the consumption of rice (p=0.048) and sweet food (p=0.028) and the BDNF protein level. Peripheral BDNF may be associated with visceral fat content and insulin concentrations in the GG genotype carriers and may depend on variable food intake, which warrants further investigation.

Chemical LTP induces confinement of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines.

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development and synaptic plasticity. The discovery that BDNF mRNA can be transported in neuronal dendrites in an activity-dependent manner has suggested that its local translation may support synapse maturation and plasticity. However, a clear demonstration that BDNF mRNA is locally transported and translated at activated synapses in response to long-term potentiation (LTP) is still lacking. Here, we study the dynamics of BDNF mRNA dendritic trafficking following the induction of chemical LTP (cLTP). Dendritic transport of BDNF transcripts was analyzed using the MS2 system for mRNA visualization, and chimeric BDNF-GFP constructs were used to monitor protein synthesis in living neurons. We found that within 15 min from cLTP induction, most BDNF mRNA granules become stationary and transiently accumulate in the dendritic shaft at the base of the dendritic spines, while at 30 min they accumulate inside the spine, similar to the control CamkIIα mRNA which also increased inside the spines at 60 min post-cLTP. At 60 min but not at 15 min from cLTP induction, we observed an increase in BDNF protein levels within the spines. Taken together, these findings suggest that BDNF mRNA trafficking is arrested in the early phase of cLTP, providing a local source of mRNA for BDNF translation at the base of the spine followed by translocation of both the BDNF mRNA and protein within the spine head in the late phase of LTP.

Total Saponins of Panax Notoginseng Modulate the Astrocyte Inflammatory Signaling Pathway and Attenuate Inflammatory Injury Induced by Oxygen- Glucose Deprivation/Reperfusion Injury in Rat Brain Microvascular Endothelial Cells.

Reperfusion after cerebral ischemia causes brain injury. Total saponins of Panax notoginseng (PNS) have potential roles in protecting against cerebral ischemia-reperfusion injury. However, whether PNS regulates astrocytes on oxygen-glucose deprivation/reperfusion (OGD/R) injury in rat brain microvascular endothelial cells (BMECs) and its mechanism still need further clarification. Rat C6 glial cells were treated with PNS at different doses. Cell models were established by exposing C6 glial cells and BMECs to OGD/R. Cell viability was assessed, and levels of nitrite concentration, inflammatory factors (iNOS, IL-1β, IL-6, IL-8, TNF-α), and oxidative stress-related factors (MDA, SOD, GSH-Px, T-AOC) were subsequently measured through CCK8, Grice analysis, Western blot, and ELISA, respectively. The co-cultured C6 and endothelial cells were treated with PNS for 24 hours before model establishment. Then transendothelial electrical resistance (TEER), lactate dehydrogenase (LDH) activity, brain-derived neurotrophic factor (BDNF) content, and mRNA and protein levels and positive rates of tight junction proteins [Claudin-5, Occludin, ZO-1] were measured by a cell resistance meter, corresponding kits, ELISA, RT-qPCR, Western blot, and immunohistochemistry, respectively. PNS had no cytotoxicity. PNS reduced iNOS, IL-1β, IL-6, IL-8, and TNF-α levels in astrocytes, promoted T-AOC level and SOD and GSH-Px activities, and inhibited MDA levels, thus inhibiting oxidative stress in astrocytes. In addition, PNS alleviated OGD/R injury, reduced Na-Flu permeability, and enhanced TEER, LDH activity, BDNF content, and levels of tight junction proteins Claudin-5, Occludin, ZO-1 in the culture system of astrocytes and rat BMECs after OGD/R. PNS repressed astrocyte inflammation and attenuated OGD/R injury in rat BMECs.

Impaired synaptic plasticity and decreased excitability of hippocampal glutamatergic neurons mediated by BDNF downregulation contribute to cognitive dysfunction in mice induced by repeated neonatal exposure to ketamine.

Repeated exposure to ketamine during the neonatal period in mice leads to cognitive impairments in adulthood. These impairments are likely caused by synaptic plasticity and excitability damage. We investigated the precise role of brain-derived neurotrophic factor (BDNF) in the cognitive impairments induced by repeated ketamine exposure during the neonatal period. We evaluated the cognitive function of mice using the Morris water maze test and novel object recognition test. Western blotting and immunofluorescence were used to detect the protein levels of BDNF. Western blotting, Golgi-Cox staining, transmission electron microscopy, and long-term potentiation (LTP) recordings were used to assess synaptic plasticity in the hippocampus. The excitability of neurons was evaluated using c-Fos. In the intervention experiment, pAdeno-CaMKIIα-BDNF-mNeuronGreen was injected into the hippocampal CA1 region of mice to increase the level of BDNF. The excitability of neurons was enhanced using a chemogenetic approach. Our findings suggest that cognitive impairments in mice repeatedly exposed to ketamine during the neonatal period are associated with downregulated BDNF protein level, synaptic plasticity damage, and decreased excitability of glutamatergic neurons in the hippocampal CA1 region. Furthermore, the specific upregulation of BDNF in glutamatergic neurons of the hippocampal CA1 region and the enhancement of excitability can improve impaired synaptic plasticity and cognitive function in mice. BDNF downregulation mediates synaptic plasticity and excitability damage, leading to cognitive impairments in adulthood following repeated ketamine exposure during the neonatal period.

Brain-derived neurotrophic factor (BDNF) as a potential marker of endometriosis: a systematic review and meta-analysis

BackgroundThe existing literature on the association between BDNF protein levels and endometriosis presents inconsistent findings. This systematic review and meta-analysis aim to synthesize the available evidence and evaluate the possible relationship between BDNF protein levels and endometriosis.MethodsElectronic databases (PubMed, Embase, Scopus, PsycINFO, and Web of Science) were used to conduct a comprehensive literature search from inception to June 2023. The search strategy included relevant keywords and medical subject headings (MeSH) terms related to BDNF, endometriosis, and protein levels. A random-effects model was used for the meta-analysis, and to explore heterogeneity subgroup analyses were performed. funnel plots and statistical tests were used for assessing the publication bias.ResultsA total of 12 studies were included. The pooled standardized mean difference (SMD) of BDNF levels between women with endometriosis and controls was 0.87 (95% confidence interval [CI] 0.34 to 1.39, p = 0.001; I2 = 93%). The results showed that blood levels of BDNF are significantly higher in endometriosis patients (SMD: 1.13 95% CI 0.54 to 1.73, p = 0.0002; I2 = 93%). No significant publication bias was observed based on the results of Egger’s regression test ((p = 0.15).ConclusionThis study revealed a significant difference between patients diagnosed with endometriosis and healthy control in the level of BDNF. The results indicate that women with endometriosis have higher levels of BDNF. Further studies are needed to be undertaken to investigate the role of BDNF in endometriosis pathophysiology and the diagnostic value of BDNF in endometriosis.

Brain-derived neurotrophic factor (BDNF): an effect biomarker of neurodevelopment in human biomonitoring programs.

The present narrative review summarizes recent findings focusing on the role of brain-derived neurotrophic factor (BDNF) as a biomarker of effect for neurodevelopmental alterations during adolescence, based on health effects of exposure to environmental chemical pollutants. To this end, information was gathered from the PubMed database and the results obtained in the European project Human Biomonitoring for Europe (HBM4EU), in which BDNF was measured at two levels of biological organization: total BDNF protein (serum) and BDNF gene DNA methylation (whole blood) levels. The obtained information is organized as follows. First, human biomonitoring, biomarkers of effect and the current state of the art on neurodevelopmental alterations in the population are presented. Second, BDNF secretion and mechanisms of action are briefly explained. Third, previous studies using BDNF as an effect biomarker were consulted in PubMed database and summarized. Finally, the impact of bisphenol A (BPA), metals, and non-persistent pesticide metabolites on BDNF secretion patterns and its mediation role with behavioral outcomes are addressed and discussed. These findings were obtained from three pilot studies conducted in HBM4EU project. Published findings suggested that exposure to some chemical pollutants such as fine particle matter (PM), PFAS, heavy metals, bisphenols, and non-persistent pesticides may alter circulating BDNF levels in healthy population. Therefore, BDNF could be used as a valuable effect biomarker to investigate developmental neurotoxicity of some chemical pollutants.

Brain-derived neurotrophic factor (BDNF) levels in panic disorder: A systematic review and meta-analysis.

The existing literature on the association between brain-derived neurotrophic factor (BDNF) protein levels and panic disorder presents inconsistent findings. This systematic review and meta-analysis aim to synthesize the available evidence and determine the overall effect of BDNF protein levels in individuals diagnosed with panic disorder. A comprehensive literature search was conducted using electronic databases (PubMed, Embase, Scopus, PsycINFO, and Web of Science) from inception to April 21, 2023. The search strategy included relevant keywords and medical subject headings terms related to BDNF, panic disorder, and protein levels. A random-effects model was used for the meta-analysis, and subgroup analyses were performed to explore heterogeneity. Publication bias was assessed using funnel plots and statistical tests. A total of 12 studies met the inclusion criteria. The meta-analysis demonstrated a significant decrease in BDNF protein levels in individuals with panic disorder (SMD=-.53, 95% CI: -1.02 to -.04, p<.001; I2 : 92%). The results of subgroup and meta-regression analyses were not statistically significant. No significant publication bias was observed based on the results of Egger's regression test (p-value=.3550). This systematic review and meta-analysis provide evidence of lower BDNF protein levels in individuals diagnosed with panic disorder compared to healthy controls. The findings suggest a potential role for BDNF dysregulation in the pathophysiology of panic disorder. Further research is warranted to elucidate the underlying mechanisms and potential therapeutic implications.

Dentate Gyrus Granule Cells Show Stability of BDNF Protein Expression in Mossy Fiber Axons with Age, and Resistance to Alzheimer's Disease Neuropathology in a Mouse Model.

Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications.

Intranasal insulin intake and exercise improve memory function in amyloid-β induced Alzheimer's-like disease in rats: Involvement of hippocampal BDNF-TrkB receptor

The most prevalent type of dementia, Alzheimer's disease (AD), is a compelling illustration of the link between cognitive deficits and neurophysiological anomalies. We investigated the possible protective effect of intranasal insulin intake with exercise on amyloid-β (Aβ)-induced neuronal damage. The level of hippocampal brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were analyzed to understand the involvement of BDNF-TrkB pathway in this modulation. In this study, we induced AD-like pathology by amyloid-β (Aβ) administration. Then, we examined the impact of a 4-week pretreatment of moderate treadmill exercise and intranasal intake of insulin on working and spatial memory in male Wistar rats. We also analyzed the mechanisms of improved memory and anxiety through changes in the protein level of BDNF and TrkB. Results showed that animals received Aβ had impaired working memory, increased anxiety which were accompanied by lower protein levels of BDNF and TrkB in the hippocampus. The exercise training and intranasal insulin improved working memory deficits, decreased anxiety, and increased BDNF, and TrkB levels in the hippocampus of animals received Aβ. Our finding of improved memory performance after intranasal intake of insulin and exercise may be of significance for the treatment of memory impairments and anxiety-like behavior in AD.

Evaluation of the Continuous Positive Airway Pressure Effect on Neurotrophins’ Gene Expression and Protein Levels

Neurotrophins (NT) might be associated with the pathophysiology of obstructive sleep apnea (OSA) due to concurrent intermittent hypoxia and sleep fragmentation. Such a relationship could have implications for the health and overall well-being of patients; however, the literature on this subject is sparse. This study investigated the alterations in the serum protein concentration and the mRNA expression of the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NTF3), and neurotrophin-4 (NTF4) proteins following a single night of continuous positive airway pressure (CPAP) therapy. This study group consisted of 30 patients with OSA. Venous blood was collected twice after a diagnostic polysomnography (PSG) and PSG with CPAP treatment. Gene expression was assessed with a quantitative real-time polymerase chain reaction. An enzyme-linked immunosorbent assay was used to determine the protein concentrations. After CPAP treatment, BDNF, proBDNF, GDNF, and NTF4 protein levels decreased (p = 0.002, p = 0.003, p = 0.047, and p = 0.009, respectively), while NTF3 increased (p = 0.001). Sleep latency was correlated with ΔPSG + CPAP/PSG gene expression for BDNF (R = 0.387, p = 0.038), NTF3 (R = 0.440, p = 0.019), and NTF4 (R = 0.424, p = 0.025). OSA severity parameters were not associated with protein levels or gene expressions. CPAP therapy could have an impact on the posttranscriptional stages of NT synthesis. The expression of different NTs appears to be connected with sleep architecture but not with OSA severity.

Brain-derived neurotrophic factor levels in perinatal depression: A systematic review and meta-analysis.

This systematic review and meta-analysis aim to synthesize the available evidence and determine the overall brain-derived neurotrophic factor (BDNF) levels in individuals diagnosed with perinatal depression (PND). We performed a thorough search of electronic databases, including PubMed, Embase, PsycINFO, and Web of Science, from their start until April 30, 2023. Our search strategy involved using specific keywords and medical subject headings (MeSH) terms related to BDNF, perinatal, post-partum, and antepartum depression. In the meta-analysis, we employed a random-effects model, and subgroup analyses were conducted to investigate any variations in the results. A total of 15 studies met the inclusion criteria, of which 10 were used in the quantitative analysis. The meta-analysis demonstrated a significant decrease in BDNF levels in both individuals with antepartum depression (SMD: -0.31; 95% CI: -0.48 to -0.13; p-value = 0.0008; I2  = 71%), and post-partum depression (SMD: -0.61; 95% CI: -0.99 to -0.22; p-value = 0.0002 I2  = 77%). Furthermore, a significantly higher rate of PND among individuals in the lowest BDNF quartile (OR: 2.64; 95% CI: 1.01 to 6.89; p-value = 0.05; I2  = 90%) was seen. The results of subgroup analyses showed a statistically significant effect of the depression assessment tool on overall heterogeneity between studies. This systematic review and meta-analysis provide evidence of lower BDNF protein levels in individuals diagnosed with PND. The results indicate that BDNF dysregulation may play a part in the development of PND. More research is needed to understand the mechanisms behind this and explore potential therapeutic applications.

MPFC TNFR2 modulated the impairment of cognitive flexibility induced by adolescent social stress and the relevant neuroplastic molecules

The impairment of cognitive flexibility (CF) exists to varying degrees in several psychiatric disorders and is increasingly recognized as the important etiological and pathological factors in these disorders. Our previous research has demonstrated that adolescent social stress (ASS) can lead to cognitive dysfunction in adult mice, accompanied by immune changes in the medial prefrontal cortex (mPFC), mainly manifested by reduced levels of cytokine TNFα. The present study aimed to further investigate the mechanisms of TNFα receptor and the downstream neuroplasticity-related molecules involved in cognitive dysfunction induced by ASS. Cognitive flexibility was assessed using Attentional Set Shifting Task (AST). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) methods were use to determine mRNA and protein level of TNFα receptor (TNFR) and downstream signaling molecules, including nuclear transcript factor NF-κB and CREB, pCREB and Brain-derived neurotrophic factor (BDNF). We found that ASS significantly decreased the mRNA and protein expression of TNFα receptor 2 (TNFR2), but not TNFR1 of the mPFC in adult mice. Direct up-regulation TNFR2 expression by microinjection of adeno-associated virus (AAV) encoding TNFR2 into the mPFC reversed the impairment of CF and the decrease of BDNF protein levels in stressed adult mice compared to that in controls. These findings demonstrated that mPFC TNFR2 plays critical roles in cognitive inflexibility induced by ASS, which effects may be mediated by neuroplastic molecules, and could be a promising target for treating cognitive dysfunction in psychiatric disorders.

β-glucan, a specific immuno-stimulant, produces rapid antidepressant effects by stimulating ERK1/2-dependent synthesis of BDNF in the hippocampus

A decline in microglia in the dentate gyrus of the hippocampus has recently been described as an important mechanism for the progression of depression. Reversal of this decline by innate immune system stimulants may represent a novel strategy to ameliorate the depressive phenotype in chronically stressed animals. β-glucan is a polysaccharide from Saccharomyces cerevisiae. It can efficiently stimulate microglia without inducing the production of pro-inflammatory cytokines. Therefore, β-glucan could be an ideal drug to ameliorate depressive phenotypes. In the present study, we found that a single injection of β-glucan reversed depression-like behaviors in mice induced by chronic unpredictable stress (CUS) in a dose-dependent manner, which was accompanied by a reversal of the CUS-induced decrease in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus. The crucial role of BDNF signaling in the antidepressant effect of β-glucan was demonstrated by experiments showing that infusion of an anti-BDNF antibody into dentate gyrus, construction of BDNF-Val68Met allele knock-in mice, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of β-glucan. The increased BDNF signaling induced by β-glucan was mediated by extracellular signal-regulated kinase1/2 (ERK1/2)-mediated BDNF synthesis, and inhibition of ERK1/2 by SL327 was able to abolish the antidepressant effect of β-glucan. Moreover, inhibition or depletion of microglia by minocycline or PLX3397 abolished the reversal effect of β-glucan on CUS-induced depression-like behaviors and CUS-induced impairment of ERK1/2-BDNF signaling. These results suggest that β-glucan exhibits antidepressant effects by stimulating microglia-mediated activation of ERK1/2 and synthesis of BDNF in the hippocampus.

Rehabilitation Exercises Supported by Monitor-Augmented Reality for Patients with High-Grade Glioma Undergoing Radiotherapy: Results of a Randomized Clinical Trial.

Exercise has been shown to improve quality of life (QoL) and even treatment outcomes in cancer patients. However, the evidence to support the benefits of exercise in patients with high-grade glioma (HGG) is limited. Therefore, we performed a randomized clinical trial (RCT) to examine the effect of augmented-reality-based rehabilitation exercises on physical and functional fitness, cognitive function, fatigue, mood, QoL, selected blood parameters, brain derived neurotrophic factor (BDNF), and S100 protein in patients with HGG. Adult patients with HGG scheduled to undergo radiotherapy after tumor resection were randomized to participate in an exercise program (experimental group, n = 25) or to receive usual care (controls, n = 22). Physical and mental fitness was measured at baseline, after the completion of radiotherapy, and at 3 months. The following tests were administered: Handgrip Strength Test; 6-Minute Walk Test; Time Up and Go test; Functional Independent Measure scale; Addenbrooke's Cognitive Examination III (ACE III); Hospital Anxiety and Depression Scale; Functional Cancer Therapy Assessment-Brain; and Functional Assessment of Chronic Illness Therapy-Fatigue. We also measured blood parameters, BDNF, and S100 protein levels. No significant changes were observed in the exercise group. However, the controls experienced a significant decrease in HGS and in the ACE III attention domain. No significant changes were observed in QoL, fatigue, BDNF, or S100 levels in either group. Augmented-reality-based exercise during radiation therapy may prevent loss of muscle strength and attention in patients with HGG.

Cannabidiol Modulates Emotional Function and Brain-Derived Neurotrophic Factor Expression in Middle-Aged Female Rats Exposed to Social Isolation.

Aging is associated with changes in cognitive and emotional function. Cannabidiol (CBD) has been reported to attenuate stress and anxiety in human and animal studies. In this study, we aimed to assess the therapeutic potential of CBD among middle-aged female rats exposed to social isolation (SI) and the potential involvement of brain-derived neurotrophic factor (BDNF) in these effects. Thirteen-month-old female rats were group-housed (GH) or exposed to social isolation (SI) and treated with vehicle or CBD (10 mg/kg). CBD restored the SI-induced immobility in the forced swim test and the SI-induced decrease in the expression of BDNF protein levels in the nucleus accumbens (NAc). CBD also increased the time that rats spent in the center in an open field, improved spatial training, and increased BDNF expression in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). BDNF expression was found to be correlated with an antidepressant (in the NAc) and an anxiolytic (in the mPFC, BLA, NAc) phenotype, and with learning improvement in the PFC. Together, our results suggest that CBD may serve as a beneficial agent for wellbeing in old age and may help with age-related cognitive decline.

Accelerated Fear Extinction by Regular Light-Intensity Exercise: A Possible Role of Hippocampal BDNF-TrkB Signaling.

Growing concern exists worldwide about stress-related mental disorders, such as posttraumatic stress disorder (PTSD), often linked to hippocampal dysfunctions. Recognizing this connection, regular light-intensity exercise (LIE)-such as yoga, walking, or slow jogging-may offer a solution. Easily accessible even to vulnerable individuals, LIE has been found to enhance hippocampus-based cognitive functions through the stimulation of neurotrophic factors like brain-derived neurotrophic factor (BDNF). A prior study that demonstrated BDNF's role in extinguishing original fear memory further leads us to propose that a consistent LIE training might drive fear extinction learning, offering potential therapeutic benefits through BDNF signaling. Eleven-week-old Wistar rats underwent 4 wk of training under conditions of sedentary, LIE, or moderate-intensity exercise (MOE) after contextual or auditory fear conditioning. Subsequently, fear extinction tests were performed. We then administered intraperitoneal (i.p.) ANA-12, a selective antagonist of tropomyosin receptor kinase B (TrkB), or a vehicle to explore the role of BDNF signaling in exercise-induced fear extinction among the LIE rats. Following the regular exercise training, further fear extinction tests were conducted, and hippocampal protein analysis was performed using Western blotting. Both LIE and MOE over 4 wk accelerated hippocampus-associated contextual fear extinction compared with sedentary. In addition, 4 wk of LIE with i.p. administered vehicle increased hippocampal BDNF and TrkB protein levels. In contrast, i.p. ANA-12 administration fully blocked the LIE-enhanced protein levels and its effect on contextual fear extinction. Our findings reveal that LIE regimen promotes fear extinction learning, at least partially tied to hippocampal BDNF-TrkB signaling. This suggests that even regular light exercise could alleviate the excessive fear response in anxiety disorders and PTSD, providing hope for those affected.

Microglial stimulation triggered by intranasal lipopolysaccharide administration produces antidepressant-like effect through ERK1/2-mediated BDNF synthesis in the hippocampus

We recently reported that reversing the chronic stress-induced decline of microglia in the dentate gyrus (DG) of the hippocampus by intraperitoneal injection of a low dose of lipopolysaccharide (LPS) ameliorated depression-like behavior in chronically stressed mice. In this study, we found that a single intranasal administration of LPS dose-dependently improved depression-like behavior in mice treated with chronic unpredictable stress (CUS), as evidenced by the reduction of immobility time in the tail suspension test (TST) and forced swimming test (FST) and by the increase of sucrose uptake in the sucrose preference test (SPT). The antidepressant effects of intranasal administration of LPS could be abolished by inhibition of brain-derived neurotrophic factor (BDNF) signaling by infusion of an anti-BDNF antibody, by knock-in of the mutant BDNF Val68Met allele, or by the BDNF receptor antagonist K252a. In addition, intranasal administration of LPS was found to exert antidepressant effects in a BDNF-dependent manner via promotion of BDNF synthesis mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling in DG. Inhibition of microglia by minocycline or depletion of microglia by PLX3397 was able to abolish the reversal effect of intranasal LPS administration on CUS-induced depression-like behaviors as well as the CUS-induced decrease in phospho-ERK1/2 and BDNF protein levels in DG. These results demonstrate that stimulation of hippocampal microglia by intranasal LPS administration can induce antidepressant effects via ERK1/2-dependent synthesis of BDNF protein, providing hope for the development of new strategies for the treatment of depression.