Unraveling psilocybin's therapeutic potential: behavioral and neuroplasticity insights in Wistar-Kyoto and Wistar male rat models of treatment-resistant depression.

RATIONALE: Our study aimed to unravel the unknown mechanisms behind the exceptional efficacy of Psilocybin (PSI) in treating treatment-resistant depression (TRD). Focusing on Wistar-Kyoto (WKY) rats with a TRD phenotype and Wistar (WIS) rats as a normative comparison, we investigated behavioral and neuroplasticity-related responses to PSI, striving to shed light on the distinctive features of its antidepressant effects. OBJECTIVES: We set out to assess the behavioral impact of acute and prolonged PSI administration on WKY and WIS rats, employing Novel Object Recognition (NORT), Social Interaction (SI), and Forced Swimming Test (FST). Our secondary objectives involved exploring strain-specific alterations in neuroplasticity-related parameters, including brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc). METHODS: Conducting post-acute and extended assessments after a single PSI administration, we applied behavioral tests and biochemical analyses to measure serum BDNF levels and neuroplasticity-related parameters in the prefrontal cortex. Statistical analyses were deployed to discern significant differences between the rat strains and assess the impact of PSI on behavioral and biochemical outcomes. RESULTS: Our findings uncovered significant behavioral disparities between WKY and WIS rats, indicating passive behavior and social withdrawal in the former. PSI demonstrated pronounced pro-social and antidepressant effects in both strains, each with its distinctive temporal trajectory. Notably, we identified strain-specific variations in BDNF-related signaling and observed the modulation of Arc expression in WKY rats. CONCLUSIONS: Our study delineated mood-related behavioral nuances between WKY and WIS rat strains, underscoring the antidepressant and pro-social properties of PSI in both groups. The distinct temporal patterns of observed changes and the identified strain-specific neuroplasticity alterations provide valuable insights into the TRD phenotype and the mechanisms underpinning the efficacy of PSI.

Navß2 Intracellular Fragments Contribute to Aß1-42-Induced Cognitive Impairment and Synaptic Deficit Through Transcriptional Suppression of BDNF.

A pathological hallmark of Alzheimer's disease (AD) is the region-specific accumulation of the amyloid-beta protein (Aß), which triggers aberrant neuronal excitability, synaptic impairment, and progressive cognitive decline. Previous works have demonstrated that Aß pathology induced aberrant elevation in the levels and excessive enzymatic hydrolysis of voltage-gated sodium channel type 2 beta subunit (Navß2) in the brain of AD models, accompanied by alteration in excitability of hippocampal neurons, synaptic deficits, and subsequently, cognitive dysfunction. However, the mechanism is unclear. In this research, by employing cell models treated with toxic Aß1-42 and AD mice, the possible effects and potential mechanisms induced by Navß2. The results reveal that Aß1-42 induces remarkable increases in Navß2 intracellular domain (Navß2-ICD) and decreases in both BDNF exons and protein levels, as well as phosphorylated tropomyosin-related kinase B (pTrkB) expression in cells and mice, coupled with cognitive impairments, synaptic deficits, and aberrant neuronal excitability. Administration with exogenous Navß2-ICD further enhances these effects induced by Aß1-42, while interfering the generation of Navß2-ICD and/or complementing BDNF neutralize the Navß2-ICD-conducted effects. Luciferase reporter assay verifies that Navß2-ICD regulates BDNF transcription and expression by targeting its promoter. Collectively, our findings partially elucidate that abnormal enzymatic hydrolysis of Navß2 induced by Aß1-42-associated AD pathology leads to intracellular Navß2-ICD overload, which may responsible to abnormal neuronal excitability, synaptic deficit, and cognition dysfunction, through its transcriptional suppression on BDNF. Therefore, this work supplies novel evidences that Navß2 plays crucial roles in the occurrence and progression of cognitive impairment of AD by transcriptional regulatory activity of its cleaved ICD.

Regional-specific changes in rat brain BDNF in a model of methamphetamine abuse.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays key roles in neuronal protection and synaptic plasticity. Changes in BDNF are associated with various pathological conditions, including methamphetamine (meth) addiction, although the effects of meth on BDNF expression are not always consistent. We have previously demonstrated region-specific effects of a chronic meth regime on BDNF methylation and expression in the rat brain. This study aims to determine the effect of chronic meth administration on the expression of BDNF protein using immunohistochemistry in the rat frontal cortex and hippocampus. Novel object recognition (NOR) as a measure of cognitive function was also determined. Male Sprague Dawley rats were administered a chronic escalating dose (0.1-4 mg/kg over 14 days) (ED) of meth or vehicle; a subgroup of animals receiving meth were also given an acute "binge" (4x6mg) dose on the final day before NOR testing. The results showed that hippocampal CA1 BDNF protein was significantly increased by 72 % above control values in the ED-binge rats, while other hippocampal regions and frontal cortex were not significantly affected. Meth-administered animals also demonstrated deficits in NOR after 24 h delay. No significant effect of the additional binge dose on BDNF protein or NOR findings was apparent. This finding is consistent with our previous results of reduced DNA methylation and increased expression of the BDNF gene in this region. The hippocampal BDNF increase may reflect an initial increase in a protective factor produced in response to elevated glutamate release resulting in neurodegenerative excitotoxicity.

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice.

Activity-induced muscle pain increases interleukin-1ß (IL-1ß) release from muscle macrophages and the development of hyperalgesia is prevented by blockade of IL-1ß in muscle. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1ß and mediates both inflammatory and neuropathic pain. Thus, we hypothesize that in activity-induced pain, fatigue metabolites combined with IL-1ß activate sensory neurons to increase BDNF release, peripherally in muscle and centrally in the spinal dorsal horn, to produce hyperalgesia. We tested the effect of intrathecal or intramuscular injection of BDNF-Tropomyosin receptor kinase B (TrkB) inhibitors, ANA-12 or TrkB-Fc, on development of activity-induced pain. Both inhibitors prevented the hyperalgesia when given before or 24hr after induction of the model in male but not female mice. BDNF messenger ribonucleic acid (mRNA) and protein were significantly increased in dorsal root ganglion (DRG) 24hr after induction of the model in both male and female mice. Blockade of IL-1ß in muscle had no effect on the increased BNDF mRNA observed in the activity-induced pain model, while IL-1ß applied to cultured DRG significantly induced BDNF expression, suggesting IL-1ß is sufficient but not necessary to induce BNDF. Thus, fatigue metabolites, combined with IL-1ß, upregulate BDNF in primary DRG neurons in both male and female mice, but contribute to activity-induced pain only in males.

[Tongdu Tiaoshen acupuncture for subjective tinnitus:a randomized controlled trial].

OBJECTIVE: To observe the clinical effect of Tongdu Tiaoshen acupuncture (acupuncture for promoting the circulation of the governor vessel and regulating the spirit) for subjective tinnitus, and explore its potential mechanism. METHODS: A total of 92 patients with subjective tinnitus were randomly divided into an acupuncture group (46 cases, 5 cases dropped out) and a medication group (46 cases, 2 cases dropped out). The acupuncture group received Tongdu Tiaoshen acupuncture at Shuigou (GV 26), Yintang (GV 24+), Shenting (GV 24), Baihui (GV 20), Fengfu (GV 16), Dazhui (GV 14) and Zhongzhu (TE 3), Tinghui (GB 2), Yifeng (TE 17) on the affected side, 30 min each time, once every other day, 3 times a week. The medication group was orally administered ginkgo biloba leaves tablets (40 mg each time) and mecobalamin tablets (0.5 mg each time), 3 times a day. Both groups were treated for 4 weeks. The scores of tinnitus severity, tinnitus loudness visual analogue scale (VAS) and depression anxiety stress scale-21(DASS-21) before and after treatment were observed in the two groups, serum level of brain-derived neurotrophic factor (BDNF) before and after treatment in the two groups was detected, and the clinical effect was evaluated in the two groups. RESULTS: After treatment，the scores of tinnitus severity, tinnitus loudness VAS and DASS-21 were decreased compared with those before treatment in the two groups (P<0.01), and the scores in the acupuncture group were lower than those in the medication group (P<0.05). After treatment, the serum level of BDNF was decreased compared with that before treatment in the two groups (P<0.01), and the serum level of BDNF in the acupuncture group was lower than that in the medication group (P<0.05). The total effective rate of the acupuncture group was 82.9% (34/41), which was higher than 70.5% (31/44) in the medication group (P<0.05). CONCLUSION: Tongdu Tiaoshen acupuncture could improve the severity of tinnitus, tinnitus loudness and negative emotion in patients with subjective tinnitus. Its mechanism may be related to the regulation of serum level of BDNF and thus affect auditory central plasticity.

Multisensory Fusion Training and 7, 8-Dihydroxyflavone Improve Amyloid-ß-Induced Cognitive Impairment, Anxiety, and Depression-Like Behavior in Mice Through Multiple Mechanisms.

Background: There is growing interest in the role of physical activity in patients with of Alzheimer's disease (AD), particularly regarding its impact of cognitive function, gut microbiota, metabolites, and neurotrophic factors. Objective: To investigate the impact of multisensory fusion training (MSFT) combined with 7, 8-dihydroxyflavone (DHF) on the behavioral characteristics, protein expression, microbiome, and serum metabolome using the AD model in mice induced with amyloid-ß (Aß). Methods: We assessed cognitive ability, anxiety-like and depression-like behaviors in Aß mice using behavioral measures. Western blotting was employed to detect the expression of relevant proteins. The 16S rRNA gene sequencing and metabolomics were used to analyze changes in the intestinal microbial composition and serum metabolic profile, respectively, of Aß mice. Results: The behavioral outcomes indicated that a 4-week intervention combining DHF and MSFT yielded remarkable improvements in cognitive function and reduced anxiety and depression-like behaviors in Aß mice. In the hippocampus of Aß mice, the combined intervention increased the levels of BDNF, VGF, PSD-95, Nrf2, p-GSK3ß and p-CREB proteins. Analyses of sequence and metabolomic data revealed that Bacteroides and Ruminococcaceae were remarkably more abundant following the combined intervention, influencing the expression of specific metabolites directly linked to the maintenance of neuronal and neurobehavioral functions. These metabolites play a crucial role in vital processes, such as amino acid metabolism, lipid metabolism, and neurotransmitter metabolism in mice. Conclusion: Our study highlighted that MSFT combined with DHF improves cognitive impairment, anxiety, and depression-like behavior in Aß mice through multiple mechanisms, and further validated the correlation between the gut microbiome and serum metabolome. These findings open up a promising avenue for future investigations into potential treatment strategies for AD.

Effects of computerized cognitive training on biomarker responses in older adults with mild cognitive impairment: A scoping review.

Background and Aims: Mild cognitive impairment (MCI) is a widespread condition in older individuals, posing significant risk of dementia. However, limited research has been conducted to explore effective interventions and clarify their impact at the neural level. Therefore, this study aimed to investigate the effects of computerized cognitive training (CCT) and explore the associated neural mechanisms in preventing dementia in older individuals with MCI, with a view to inform future intervention efforts. Methods: We reviewed the effects of CCT on biomarker outcomes in older adults with MCI. The search was conducted for studies published between 2010 and May 10, 2023, using three search engines: PubMed, Scopus, and Cumulative Index to Nursing and Allied Health Literature. The inclusion criteria were as follows: studies that involved participants diagnosed with MCI, included CCT, included quantitative assessment of biomarker results, and conducted randomized controlled trials. Results: Sixteen studies that used biomarkers, including magnetic resonance imaging, electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and blood or salivary biomarkers, were extracted. The results showed that CCT caused changes in structure and function within the main brain network, including the default mode network, and decreased both theta rhythm activity on EEG and prefrontal activity on fNIRS, with improvement in cognitive function. Furthermore, CCT combined with physical exercise showed more significant structural and functional changes in extensive brain regions compared with CCT alone. Virtual reality-based cognitive training improved not only executive function but also instrumental activities of daily living. Conclusion: CCT causes functional and structural changes in extensive brain regions and improves cognitive function in older adults with MCI. Our findings highlight the potential of individualized intervention methods and biomarker assessment according to the specific causes of MCI. Future research should aim to optimize these personalized therapeutic strategies to maximize the benefits of CCT in older adults with MCI.

Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice.

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.

BDNF Signaling in Vascular Dementia and Its Effects on Cerebrovascular Dysfunction, Synaptic Plasticity, and Cholinergic System Abnormality.

Vascular dementia (VaD) is the second most common type of dementia and is characterized by memory impairment, blood-brain barrier disruption, neuronal cell loss, glia activation, impaired synaptic plasticity, and cholinergic system abnormalities. To effectively prevent and treat VaD a good understanding of the mechanisms underlying its neuropathology is needed. Brain-derived neurotrophic factor (BDNF) is an important neurotrophic factor with multiple functions in the systemic circulation and the central nervous system and is known to regulate neuronal cell survival, synaptic formation, glia activation, and cognitive decline. Recent studies indicate that when compared with normal subjects, patients with VaD have low serum BDNF levels and that BDNF deficiency in the serum and cerebrospinal fluid is an important indicator of VaD. Here, we review current knowledge on the role of BDNF signaling in the pathology of VaD, such as cerebrovascular dysfunction, synaptic dysfunction, and cholinergic system impairment.

Up-regulation of systemic and local BDNF in non-allergic Nasal Polyps in China.

Objective: Although the role of brain-derived neurotrophic factor (BDNF) in allergic rhinitis and/or nasal polyps (NPs) development has been studied, the contribution of BDNF in non-allergic NPs has not been evaluated yet. This study was to investigate the possible role of BDNF in non-allergic NPs pathogenesis. Methods: The study was carried out at The Second Hospital of Shandong University from December 2020 to November 2021. The non-allergic NPs patients (n=26) and the control group (n=22) were included. Lund-Mackay CT scores, nasal endoscopy scores, and pulmonary function testing were evaluated before surgery. Tissue and serum levels of BDNF, eosinophil cationic protein (ECP), and cytokeratins 5 (CK5) were assessed between different groups. Result: The BDNF level in serum and tissue, CK5 count, and eosinophil infiltration in tissue were higher in non-allergic NPs. The eosinophils infiltration, ECP mRNA expression level, as well as BDNF mRNA level were increased in the BDNFhigh subgroup compared with BDNFlow subgroup. Significantly negative correlations between BDNF count and the situation of airway obstruction were found in non-allergic NPs. Conclusion: BDNF may have both local and systemic effects in non-allergic NPs pathogenesis. BDNF may be a possible therapeutic target or an indicator for eosinophilic NPs management.

DNA Methylation, Inflammation, and Neurobehavior in Preterm Infants.

Objectives: Inflammation contributes to disparate neurodevelopmental outcomes between preterm and term-born infants. In this context, DNA methylation may contribute to inflammation by affecting gene expression. Brain-derived neurotrophic factor (BDNF) and nuclear factor-kappa-B-inhibitor alpha (NFKBIA) are important genes for targeted DNA methylation analysis. The aims of this study were to (1) identify associations between inflammatory factors and BDNF and NFKBIA methylation, and (2) identify associations between BDNF and NFKBIA methylation and early neurobehavior in preterm infants. Methods: In a longitudinal cohort study of preterm infants born 28-31 weeks gestational age, blood samples were collected weekly for the quantification of inflammatory factors. We extracted DNA from saliva samples and quantified methylation of six BDNF cytosine-phosphate-guanine (CpG) sites and five NFKBIA CpG sites. Neurobehavior was assessed using the Neurobehavioral Assessment of the Preterm Infant. Results: Sixty-five infants were included in the analysis. In females, inflammatory factors were positively associated with BDNF methylation of most CpG sites. Interleukin-1 receptor antagonist was negatively associated with NFKBIA methylation at two CpG sites. In males, interleukin-6 was negatively associated with BDNF and NFKBIA methylation at most CpG sites. In females, BDNF methylation at two sites was inversely associated with motor performance. In males, NFKBIA methylation at one site was inversely associated with motor performance. Conclusion: This study provides evidence for the relationship between inflammation and neurobehavior in preterm infants, working mechanistically through DNA methylation. The finding of a difference between males and females suggests that female infants are potentially more vulnerable to inflammation and warrants future study.

The association between levels of brain-derived neurotrophic factor and comorbid depression in patients with cardiovascular disease: The Framingham Heart Study.

AIM: The current study aims to investigate the association of serum brain-derived neurotrophic factor (BDNF) levels with symptoms of depression in adults with and without prevalent cardiovascular disease (CVD), an often burdensome comorbidity. METHODS: This cross-sectional study included participants from FHS (Framingham Heart Study) who had available serum BDNF levels. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression Scale (CES-D) with a score ≥16 indicating mild to moderate and ≥21 severe depression. Participants taking antidepressant medications were excluded from the study. RESULTS: Altogether 3716 FHS participants were included in the final analysis (mean age, 64.3 ± 11.5 years; 55% women). After adjusting for potential confounders, greater BDNF levels were associated with reduced severe depression risk (odds ratio [OR], 0.78 [95% CI, 0.64-0.96]; P = 0.016). Among participants with CVD, greater BDNF levels were related to lower risk of depressive symptoms (CES-D ≥ 16 OR, 0.63 [95% CI, 0.45-0.89], P = 0.008; CES-D ≥ 21 OR, 0.49 [95% CI, 0.31-0.76], P = 0.002). The inverse relationship between BDNF and depressive symptom risk was present in women with CVD (CES-D ≥ 16 OR, 0.63 [95% CI, 0.40-0.99], P = 0.047; CES-D ≥ 21 OR, 0.38 [95% CI, 0.21-0.70], P = 0.002) but not in men. CONCLUSION: Lower serum BDNF levels are associated with a higher risk of depressive symptoms in CVD, particularly among women. These findings implicate BDNF in the complex biological mechanisms that underlie prior associations observed between CVD and depression. To reduce the burden of depression in the large proportion of midlife and older adults with CVD, a better understanding of how BDNF may modify these pathways is merited.

Role of Brain Derived Neurotrophic Factor and Related Therapeutic Strategies in Central Post-Stroke Pain.

Brain-derived neurotrophic factor (BDNF) is vital for synaptic plasticity, cell persistence, and neuronal development in peripheral and central nervous systems (CNS). Numerous intracellular signalling pathways involving BDNF are well recognized to affect neurogenesis, synaptic function, cell viability, and cognitive function, which in turn affects pathological and physiological aspects of neurons. Stroke has a significant psycho-socioeconomic impact globally. Central post-stroke pain (CPSP), also known as a type of chronic neuropathic pain, is caused by injury to the CNS following a stroke, specifically damage to the somatosensory system. BDNF regulates a broad range of functions directly or via its biologically active isoforms, regulating multiple signalling pathways through interactions with different types of receptors. BDNF has been shown to play a major role in facilitating neuroplasticity during post-stroke recovery and a pro-nociceptive role in pain development in the nervous system. BDNF-tyrosine kinase receptors B (TrkB) pathway promotes neurite outgrowth, neurogenesis, and the prevention of apoptosis, which helps in stroke recovery. Meanwhile, BDNF overexpression plays a role in CPSP via the activation of purinergic receptors P2X4R and P2X7R. The neuronal hyperexcitability that causes CPSP is linked with BDNF-TrkB interactions, changes in ion channels and inflammatory reactions. This review provides an overview of BDNF synthesis, interactions with certain receptors, and potential functions in regulating signalling pathways associated with stroke and CPSP. The pathophysiological mechanisms underlying CPSP, the role of BDNF in CPSP, and the challenges and current treatment strategies targeting BDNF are also discussed.

Neuromuscular electrical stimulation to combat cognitive aging in people with spinal cord injury: protocol for a single case experimental design study.

INTRODUCTION: Individuals with spinal cord injury (SCI) can experience accelerated cognitive aging. Myokines (factors released from muscle cells during contractions), such as brain-derived neurotrophic factor (BDNF), are thought to have beneficial effects on cognition. Neuromuscular electrical stimulation (NMES) was shown to elicit a large release of myokines. However, the effects of NMES on cognitive function have not been studied. OBJECTIVE: To present the study protocol for a clinical trial evaluating the effects of NMES aimed at improving cognition and BDNF. METHODS: A replicated randomized three-phases single-case experimental design (SCED) with sequential multiple baseline time series and a single-armed prospective trial will be conducted with 15 adults with chronic SCI (> 12 months after injury) above L1 neurological level undergoing 30-min quadriceps NMES, 3 days per week for 12 weeks. MAIN STUDY ENDPOINTS: Primary endpoint is cognitive performance (assessed by a smartphone test) conducted three times per week during the baseline phase with random duration of 3 to 8 weeks, the intervention phase of 12 weeks, and the follow-up phase of 3 weeks after a no measurement rest period of 12 weeks. Secondary endpoints are changes in BDNF levels and cognitive performance measured before the baseline period, before and after intervention and after a 12 weeks follow-up. CONCLUSION: This will be the first study investigating the effects of 12 weeks NMES on both cognition and BDNF levels in individuals with SCI. The SCED results provide information on individual treatment effect courses which may direct future research. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05822297, 12/01/2023).

Effects of exercise on brain-derived neurotrophic factor in Alzheimer's disease models: A systematic review and meta-analysis.

A growing body of research examining effects of exercise on brain-derived neurotrophic factor (BDNF) in Alzheimer's disease (AD) models, while due to differences in gender, age, disease severity, brain regions examined, and type of exercise intervention, findings of available studies were conflicting. In this study, we aimed to evaluate current evidence regarding effects of exercise on BDNF in AD models. Searches were performed in PubMed, Web of Science, Cochrane, and EBSCO electronic databases, through July 20, 2023. We included studies that satisfied the following criteria: eligible studies should (1) report evidence on experimental work with AD models; (2) include an exercise group and a control group (sedentary); (3) use BDNF as the outcome indicator; and (4) be randomized controlled trials (RCTs). From 1196 search records initially identified, 36 studies met the inclusion criteria. There was a significant effect of exercise on increasing BDNF levels in AD models [standardized mean differences (SMD) = 0.98, P < 0.00001]. Subgroup analysis showed that treadmill exercise (SMD = 0.92, P< 0.0001), swimming (SMD = 1.79, P< 0.0001), and voluntary wheel running (SMD = 0.51, P= 0.04) were all effective in increasing BDNF levels in AD models. In addition, exercise significantly increased BDNF levels in the hippocampus (SMD = 0.92, P< 0.00001) and cortex (SMD = 1.56, P= 0.02) of AD models. Exercise, especially treadmill exercise, swimming, and voluntary wheel running, significantly increased BDNF levels in hippocampus and cortex of AD models, with swimming being the most effective intervention type.

Involvement of dysregulated hippocampal histone H3K9 methylation at the promoter of the BDNF gene in impaired memory extinction.

RATIONALE: Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Impaired extinction of fear memory (EFM) is one of the core symptoms of PTSD and is associated with stress-induced epigenetic change in gene expression. OBJECTIVES: In this study, we examined whether the involvement of histone H3 lysine 9 dimethylation (H3K9me2) in EFM is mediated through brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and whether BIX01294, a selective G9a and GLP histone methyltransferase inhibitor, could be treatment for impaired EFM in an animal model of PTSD. METHODS: The single prolonged stress (SPS) paradigm was used to model PTSD. We measured BDNF mRNA levels by RT-PCR, and H3K9me2 levels in the BDNF gene promoters by chromatin immunoprecipitation-qPCR. After undergoing contextual fear conditioning and hippocampal injection of BIX01294, male rats were subjected to extinction training and extinction testing and their freezing times and BDNF mRNA levels were measured. RESULTS: Compared to sham rats, SPS rats showed decreased BDNF mRNA levels 2 h after extinction training, no significant changes in levels of global H3K9me2 prior to extinction training, and increased levels of H3K9me2 in BDNF gene promoter IV, but not in BDNF gene promoter I. Administration of BIX01294 ameliorated the decrease in BDNF mRNA levels 2 h after extinction training and subsequently alleviated impaired EFM in extinction tests in SPS rats. CONCLUSION: We conclude that reduced hippocampal levels of BDNF mRNA due to increase in H3K9me2 levels may play a role in PTSD-associated EFM impairment, and BIX01294 could be a PTSD treatment option.

Serum brain derived neurotrophic factor levels and post-stroke depression in ischemic stroke patients.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is crucial for neuronal survival and may be implicated in the pathophysiological process of depression. This study aimed to prospectively investigate the association between serum BDNF and post-stroke depression (PSD) at 3 months in a multicenter cohort study. METHODS: A total of 611 ischemic stroke patients with serum BDNF measurements from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this analysis. We used the 24-item Hamilton Depression Rating Scale to assess depression status at 3 months after ischemic stroke, and PSD was defined as a score of ≥8. RESULTS: Baseline serum BDNF was inversely associated with the risk of depression after ischemic stroke. The multivariable-adjusted odds ratio of PSD for the highest tertile of BDNF was 0.53 (95 % confidence interval, 0.34-0.82; P for trend = 0.004) compared with the lowest tertile. Multivariable-adjusted spline regression model also showed a linear does-response association between serum BDNF levels and PSD at 3 months (P for linearity = 0.006). In addition, adding serum BDNF to conventional risk factors significantly improved the risk reclassification of PSD (net reclassification improvement: 16.98 %, P = 0.039; integrated discrimination index: 0.93 %, P = 0.026). LIMITATIONS: All patients in this study were Chinese, so our findings should be applied to other populations cautiously. CONCLUSIONS: Higher serum BDNF levels at baseline were significantly associated with a decreased risk of PSD at 3 months, suggesting that BDNF might be a valuable predictive biomarker and potential therapeutic target for PSD among ischemic stroke patients.

The Neuroprotective Effects of Oroxylum indicum Extract in SHSY-5Y Neuronal Cells by Upregulating BDNF Gene Expression under LPS Induced Inflammation.

The brain-derived neurotrophic factor (BDNF) plays a crucial role during neuronal development as well as during differentiation and synaptogenesis. They are important proteins present in the brain that support neuronal health and protect the neurons from detrimental signals. The results from the present study suggest BDNF expression can be increase up to ~8-fold by treating the neuroblastoma cells SHSY-5Y with an herbal extract of Oroxylum indicum (50 µg/mL) and ~5.5-fold under lipopolysaccharides (LPS)-induced inflammation conditions. The Oroxylum indicum extract (Sabroxy) was standardized to 10% oroxylin A, 6% chrysin, and 15% baicalein. In addition, Sabroxy has shown to possess antioxidant activity that could decrease the damage caused by the exacerbation of radicals during neurodegeneration. A mode of action of over expression of BDNF with and without inflammation is proposed for the Oroxylum indicum extract, where the three major hydroxyflavones exert their effects through additive or synergistic effects via five possible targets including GABA, Adenoside A2A and estrogen receptor bindings, anti-inflammatory effects, and reduced mitochondrial ROS production.

Exploring the Association between Depression, Suicidality, and Serum Brain-Derived Neurotrophic Factor, FAM19A5, Total Antioxidant Status, Total Oxidant Status, Oxidative Stress Index, and Cytokine Levels: A Case-Control Study of Drug-Naive Adolescents with First-Episode Major Depressive Disorder.

INTRODUCTION: Considering the importance of neuroinflammation and neurodegeneration in the pathophysiology of major depressive disorder (MDD), peripheral blood biomarkers are promising for the prediction of diagnosis and treatment outcomes. We aimed to elucidate the neuroinflammatory pathophysiology of depression by evaluating serum levels of FAM19A5 as a new biomarker of inflammatory activation, proinflammatory cytokines, brain-derived neurotrophic factor (BDNF), and oxidative stress parameters. METHODS: Adolescents diagnosed with first-episode drug-naive MDD (n = 35) were compared neurobiologically healthy control group (n = 33). Serum FAM19A5 levels, cytokine levels, BDNF and oxidative stress parameters were evaluated using the enzyme-linked immunoassay method. All participants were assessed with the Level-2 Depression Severity Scale, Sleep Disturbance Scale, Somatic Symptom Scale. RESULTS: BDNF levels were significantly higher in the patient group compared to the control group. While BDNF showed a positive correlation with all scale scores; BDNF was significantly higher in the suicide risk groups than the control group. IL-1ß levels displayed a negative correlation with the severity of sleep disturbances. CONCLUSIONS: In adolescents with MDD, inflammatory and oxidative stress markers were not raised in peripheral blood, unlike in adults. However, BDNF levels, which typically decrease in neurodegenerative conditions, were higher in those with MDD.

[Brain-derived neurotrophic factor in the acute and early recovery period of ischemic stroke: the role of nocturnal hypoxemia]. / Mozgovoi neirotroficheskii faktor pri ishemicheskom insul'te v ostrom i rannem vosstanovitel'nom periodakh: rol' nochnoi gipoksemii.

OBJECTIVE: To study the relationship between brain-derived neurotrophic factor (BDNF) and the severity of nocturnal hypoxemia in patients in the acute and early recovery period of ischemic stroke (IS). MATERIAL AND METHODS: We enrolled 44 patients (27 men, 17 women), aged 18-85 years, in the acute phase of IS. At 3-month follow-up, 35 people were examined (21 men and 14 women). In the acute period, in addition to routine diagnostic procedures, respiratory monitoring was carried out, and the serum level of BDNF was measured by enzyme-linked immunosorbent assay. BDNF level was also evaluated at 3-month follow-up visit. Neurological status and its dynamics in the acute period of stroke were assessed as part of the clinical routine according to the National Institutes of Health Stroke Scale (NIHSS) at admission and discharge. RESULTS: We found a direct correlation between the duration of hypoxemia with SpO2 less than 90% (r=0.327, p=0.035) and less than 85% (r=0.461, p=0.003) and BDNF level in the acute phase of IS. BDNF level in the acute period of IS was negatively correlated with the minimum saturation value (r=-0.328, p=0.034). There was a direct relationship between BDNF level in the early recovery period and the duration of hypoxemia with SpO2 less than 85% (r=-0.389, p=0.028). A regression model showed that BDNF level was associated with the minimum SpO2 level. No significant associations were found with indicators of sleep-disordered breathing severity, such as the apnea-hypopnea index and the oxygen desaturation index. CONCLUSION: The severity of nocturnal hypoxemia is associated with the increase in BDNF levels both in the acute and recovery periods of IS, regardless of the presence of concomitant breathing disorders during sleep.