Brain-derived Neurotrophic Factor Research Articles

Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation

Neuronal differentiation and maturation are crucial for developing research models and therapeutic applications. Brain-derived neurotrophic factor (BDNF) is a widely used biochemical stimulus for promoting neuronal maturation. However, the broad effects of biochemical stimuli on multiple cellular functions limit their applicability in both in vitro models and clinical settings. Electrical stimulation (ES) offers a promising physical method to control cell fate and function, but it is hampered by lack of standard and optimised protocols. In this study, we demonstrate that ES outperforms BDNF in promoting neuronal maturation in human neuroblastoma SH-SY5Y. Additionally, we address the question regarding which ES parameters regulate biological responses. The neuronal differentiation and maturation of SH-SY5Y cells were tested under several pulsed ES regimes. We identified accumulated charge and effective electric field time as novel criteria for determining optimal ES regimes. ES parameters were obtained using electrochemical characterisation and equivalent circuit modelling. Our findings show that neuronal maturation in SH-SY5Y cells correlates with the amount of accumulated charge during ES. Higher charge accumulation (~ 50 mC/h) significantly promotes extensive neurite outgrowth and ramification, and enhances the expression of synaptophysin, yielding effects exceeding those of BDNF. In contrast, fewer charge injection to the culture (~ 0.1 mC/h) minimally induces maturation but significantly increases cell proliferation. Moreover, ES altered the concentration and protein cargo of secreted extracellular vesicles (EV). ES with large enough accumulated charge significantly enriched EV proteome associated with neural development and function. These results demonstrate that each ES regime induces distinct cellular responses. Increased accumulated charge facilitates the development of complex neuronal morphologies and axonal ramification, outperforming exogenous neurotrophic factors. Controlled ES methods are immediately applicable in creating mature neuronal cultures in vitro with minimal chemical intervention.

A Nurr1 Agonist Derived from the Natural Ligand DHI Induces Neuroprotective Gene Expression.

The dopamine metabolite 5,6-dihydroxyindole (DHI) has been discovered as a natural Nurr1 ligand with potential biological relevance and is an attractive lead for Nurr1 modulator development but exhibits chemical reactivity and weak potency. We have systematically explored the SAR of 5-chloroindole-6-carboxamide as a DHI mimetic scaffold and identified the first high-affinity (Kd 0.08-0.12 μM) ligands of the DHI binding site of Nurr1. An optimized Nurr1 agonist of this scaffold endowed with favorable physicochemical properties, high selectivity, and low toxicity emerges as a chemical tool to explore the biological impact of Nurr1 activation via the DHI binding site. Treatment of neuronal cells with this compound mediated enhanced expression of Nurr1-regulated neuroprotective genes like brain-derived neurotrophic factor (BDNF), supporting the great potential of Nurr1 activation in neurodegeneration.

Ultra-Sensitive Nanoplatform for Detection of Brain-Derived Neurotrophic Factor Using Silica-Coated Gold Nanoparticles with Enzyme-Formed Quantum Dots

A fluorescence-based detection platform was developed for brain-derived neurotrophic factor (BDNF), a key biomarker of Alzheimer’s disease (AD). This platform utilizes localized surface plasmon resonance effects resulting from the interactions between silica-coated gold nanoparticles (Au@SiO2) and enzymatically synthesized quantum dots (QDs). The gold nanoparticles were silica coated via the hydrolysis of tetraethyl orthosilicate, which allowed for precise control over the distance between the nanoparticles and QDs and refined the dynamics of fluorescence quenching and enhancement. Antibody conjugation was performed via sequential amination and carboxylation, followed by EDC/NHS coupling. BDNF was detected across a range of concentrations, from 1 ng/mL to 1 ng/mL, using an alkaline phosphatase (ALP)-conjugated polyclonal antibody targeting a secondary epitope of BDNF. The enzymatic hydrolysis of p-nitrophenyl phosphate by immobilized ALP led to the formation of cadmium sulfide QDs, with the fluorescence intensity correlating directly with the BDNF concentration. This platform offers a refined and precise method for detecting BDNF and is a reliable tool for the early diagnosis of AD.

The therapeutic potential of exercise in post-traumatic stress disorder and its underlying mechanisms: A living systematic review of human and non-human studies

Background Exercise for post-traumatic stress disorder (PTSD) is a potentially effective adjunct to psychotherapy. However, the biopsychosocial mechanisms of exercise are not well understood. This co-produced living systematic review synthesizes evidence from human and non-human studies. Methods We Included controlled human and non-human studies involving searches of multiple electronic databases (until 31.10.23). Records were screened, extracted, assessed for risk of bias, and reconciled by two independent reviewers. The primary outcome for human studies was PTSD symptom severity, while outcomes of interest for non-human studies included freezing behaviour, fear memory, fear generalization, startle response, and locomotion. Data were synthesised with random-effects meta-analysis. Results Eleven human studies met the eligibility criteria. Overall, exercise was not associated with symptom severity improvement compared to control (standardized mean difference [SMD] -0.08, 95% confidence interval [CI] -0.24 to 0.07; 8 studies, one at low risk of bias). High-intensity exercise reduced PTSD symptoms scores more than moderate-intensity exercise. There was insufficient data to examine the effects of exercise on functional impairment, PTSD symptom clusters, and PTSD remission. Only three studies, all at high risk of bias, examined mechanisms of exercise with inconclusive results. Exercise was associated with improvement in all behavioural outcomes, including locomotor activity (SMD 1.30, 95% CI 0.74 to 1.87, 14 studies), and changes in several neurobiological markers, including increase in brain-derived neurotrophic factor (SMD 1.79, 95% CI 0.56 to 3.01). Conclusions While non-human studies provide compelling evidence for the beneficial effects of exercise, human trials do not. Evidence from non-human studies suggest that exercise might increase the levels of brain-derived neurotrophic factor, enhance cognitive appraisal, and improve perceived exertion. Overall, the paucity of data on the effectiveness of exercise in PTSD and mechanisms of action underscore the need for rigorous trials. Registration The protocol was registered with PROSPERO (ID:453615; 22.08.2023).

Multimodal Adaptations to Expiratory Musculature-Targeted Resistance Training: A Preliminary Study in Healthy Young Adults.

Exercise-induced adaptations, including neuroplasticity, are well studied for physical exercise that targets skeletal muscles. However, little is known about the neuroplastic potential of targeted speech and swallowing exercises. The current study aimed to gather preliminary data on molecular and functional changes associated with the neuroplastic effects of 4-week expiratory musculature-targeted resistance training in healthy young adults. Five healthy young adult men aged between 19 and 35 years, M (SD) = 28.8 (2.68) years, underwent 4 weeks of expiratory muscle strength training (EMST). We measured changes in maximum expiratory pressure (MEP), serum brain-derived neurotrophic factor (BDNF), and insulin-like growth factor 1 (IGF-1) levels at baseline and posttraining conditions. Furthermore, functional and structural magnetic resonance images were obtained to investigate the neuroplastic effects of EMST. We analyzed the effects of training using a linear mixed model for each outcome, with fixed effects for baseline and posttraining. MEP and serum BDNF levels significantly increased posttraining. However, this effect was not observed for IGF-1. A significant increase in functional activation in eight regions was also observed posttraining. However, we did not observe significant changes in the white matter microstructure. Preliminary data from our study suggest targeted resistance training of expiratory muscles results in molecular and neuroplastic adaptations similar to exercise that targets skeletal muscles. Additionally, these results suggest that EMST could be a potential intervention to modulate (or prime) neurotrophic signaling pathways linked to functional strength gains and neuroplasticity.

Combined Detection of Serum Brain-Derived Neurotrophic Factor and Interleukin-6 for Evaluating Therapeutic Efficacy in Major Depressive Disorder.

The assessment of major depressive disorder (MDD) treatment efficacy typically relies on clinician-rated scales of depressive symptoms with a notable absence of predictive biomarkers. In this study, a concentration ratio of serum brain-derived neurotrophic factor (BDNF) to interleukin-6 (IL-6) was identified as a promising predictive biomarker. To overcome the significant disparity in blood levels between BDNF (ng·mL-1 range) and IL-6 (pg·mL-1 range), a dual-pathway signal amplification method involving small carbon dots (Fe-CDs and Pb-CDs) was employed. Fe-CDs exhibited a nanozyme-like behavior, effectively enhancing the signal through solution reactions, rendering it ideal for IL-6 detection at low concentrations. Meanwhile, Pb-CDs, laden with numerous signal molecules, amplified signals via the surface pathway and were suitable for BDNF detection. This dual signal output approach met the distinct sensitivity needs for quantifying IL-6 and BDNF, achieving detection limits of 0.1 pg·mL-1 and 0.02 ng·mL-1, respectively. Analysis of clinical samples showed that the concentration ratio of BDNF to IL-6 not only effectively differentiates MDD patients from healthy controls but also strongly correlates with individual treatment responses, affirming its value as a biomarker for MDD diagnosis and treatment efficacy evaluation.

Role of brain-derived neurotrophic factor in dysfunction of short-term to long-term memory transformation after surgery and anaesthesia in older mice.

Memory decline is one of the main manifestations in perioperative neurocognitive disorder. Short-term memory (STM) to long-term memory (LTM) transformation is one aspect of memory consolidation. Early-phase long-term potentiation (E-LTP) to late-phase long-term potentiation (L-LTP) is the molecular correlate of STM to LTM transformation. We examined whether the STM to LTM transformation was impaired after anaesthesia and surgery in older mice. Optogenetics and chemogenetics were used to confirm the role of Vglut1+ glutamatergic neurones in the STM to LTM transformation in older mice. Synaptosomes were isolated to analyse expression of brain-derived neurotrophic factor (BDNF). Golgi-Cox staining and hippocampal field potential recordings were also used to measure synaptic plasticity. We found that the STM to LTM and E-LTP to L-LTP transformations were impaired after anaesthesia and surgery in older mice, and Vglut1+ excitatory neurone activity in the hippocampal CA1 region was reduced. BDNF expression decreased in the postsynaptic fraction, especially in Vglut1+ neurones, whereas cell-type specific overexpression of BDNF in Vglut1+ neurones reversed postoperative STM to LTM transformation dysfunction in older mice. Reduced BDNF expression was involved in anaesthesia and surgery-induced impairment of the STM to LTM transition involving glutamatergic neurones in the hippocampal CA1 region of older mice. This provides a potential target that might be helpful for understanding and developing treatments for postoperative neurocognitive dysfunction.

PKR Inhibition Prevents Neuroinflammation and Rescues Depressive-Like Behaviors via BDNF/TrkB Signaling.

PKR, a kinase implicated in inflammation, accumulates in the brain, but its role in neuroinflammation-related depression is poorly understood. This study aimed to investigate whether pharmacological PKR inhibition using C16 (PKR inhibitor) could reverse LPS-induced neuroinflammation and depressive-like behaviors. Mice (C57BL/6J, 20-22 g, 6-8 weeks old) were administered LPS intraperitoneally for three days to induce depressive-like behavior and neuroinflammation. Simultaneously, mice were treated with C16(a pharmacological PKR inhibitor) intraperitoneally for the same duration, followed by behavioral assessments. After euthanasia, brain-hippocampus tissues were collected for biochemical analysis. To validate these in vivo findings, BV2 and HT22 cells were cultured and subjected to pharmacological and biochemical analysis. LPS treatment significantly increased hippocampal neuroinflammation (GFAP/IBA-1 p < 0.001), cytokine production (IL-1β, IL-6, TNF-α, p < 0.05), PKR phosphorylation (p < 0.05), and inflammatory signaling (NLRP3/ASC, p < 0.001). Concomitantly, LPS exposure induced depressive-like symptoms (p < 0.001), impaired synaptic function (Synasin-1/SNAP25, p < 0.05), spine numbers (p < 0.001), and downregulated brain-derived neurotrophic factor (BDNF) /TrkB signaling (p < 0.001). Importantly, these effects were attenuated by C16, a PKR inhibitor. C16 also reduced LPS-induced ER stress markers in the hippocampus (p < 0.05). Interestingly, K252a, a BDNF/TrkB inhibitor, reversed the protective effects of C16, increasing both neuroinflammation (p < 0.001) and depressive symptoms (p < 0.001) in LPS-treated mice. Notably, in vitro studies using BV2 and HT22 cells corroborated these findings. In conclusion, these findings suggest that PKR is critical in mediating LPS-induced neuroinflammation and depressive-like behaviors, potentially through interactions with BDNF/TrkB signaling.

Tangeretin offers neuroprotection against colchicine-induced memory impairment in Wistar rats by modulating the antioxidant milieu, inflammatory mediators and oxidative stress in the brain tissue

BackgroundTangeretin, a flavone compound (O-polymethoxylated) naturally present in tangerine and other citrus peels has demonstrated effectiveness as an anti-inflammatory and neuroprotective agent in several disease model. This study evaluated the impact of tangeretin in mitigating cognitive dysfunction and oxidative stress induced by colchicine in rats, comparing its efficacy with donepezil hydrochloride.MethodsCognitive dysfunction was induced by administering colchicine (15 µg/rat) intracerebroventricularly (ICV) via a stereotaxic apparatus in male Wistar rats. Colchicine resulted in poor memory retention in acquiring and retaining a spatial navigation task, passive avoidance apparatus, and Morris water maze paradigms. Chronic treatment with tangeretin (at doses of 50, 100, and 200 mg/kg, p.o. once daily) and donepezil hydrochloride (at a dose of 10 mg/kg, p.o. daily) for 28 days, starting seven days before colchicine injection, significantly ameliorated colchicine-induced cognitive impairment.ResultsThe biochemical analysis showed that chronic administration of tangeretin effectively reversed the colchicine-induced increase in the level/activity of lipid peroxidation, hydrogen peroxide (H2O2), myeloperoxidase (MPO), nitrite, reactive oxygen species (ROS), tumour necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), serotonin, dopamine, glutamate, amyloid beta (Aβ) peptide, and caspase-3. Tangeretin also reversed the colchicine-induced reduction in the level/activity of brain-derived neurotrophic factor (BDNF), amma-aminobutyric acid (GABA), acetylcholinesterase (AChE), glutathione S-Transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and total thiol (T-SH) in rat brains. However, donepezil hydrochloride did not prevent oxidative stress.ConclusionsThese findings suggest that chronic administration of tangeretin at 50, 100, and 200 mg/kg, p.o. once daily, was protective in mitigating colchicine-induced cognitive impairment and associated oxidative stress. At the same time, donepezil hydrochloride did not demonstrate similar effects.

Gut Microbiota Influences Developmental Anesthetic Neurotoxicity in Neonatal Rats

BACKGROUND: Anesthetic exposure during childhood is significantly associated with impairment of neurodevelopmental outcomes; however, the causal relationship and detailed mechanism of developmental anesthetic neurotoxicity remain unclear. Gut microbiota produces various metabolites and influences the brain function and development of the host. This relationship is referred to as the gut-brain axis. Gut microbiota may influence developmental anesthetic neurotoxicity caused by sevoflurane exposure. This study investigated the effect of changes in the composition of gut microbiota after fecal microbiota transplantation on spatial learning disability caused by developmental anesthetic neurotoxicity in neonatal rats. METHODS: Neonatal rats were allocated into the Control (n = 10) and Sevo (n = 10) groups in Experiment 1 and the Sevo (n = 20) and Sevo+FMT (n = 20) groups in Experiment 2, according to the randomly allocated mothers’ group. The rats in Sevo and Sevo+FMT groups were exposed to 2.1% sevoflurane for 2 hours on postnatal days 7 to 13. Neonatal rats in the Sevo+FMT group received fecal microbiota transplantation immediately after sevoflurane exposure on postnatal days 7 to 13. The samples for fecal microbiota transplantation were obtained from nonanesthetized healthy adult rats. Behavioral tests, including Open field, Y-maze, Morris water maze, and reversal Morris water maze tests, were performed to evaluate spatial learning ability on postnatal days 26 to 39. RESULTS: Experiment 1 revealed that sevoflurane exposure significantly altered the gut microbiota composition. The relative abundance of Roseburia (effect value: 1.01) and Bacteroides genus (effect value: 1.03) increased significantly after sevoflurane exposure, whereas that of Lactobacillus (effect value: −1.20) decreased significantly. Experiment 2 revealed that fecal microbiota transplantation improved latency to target (mean ± SEM; Sevo group: 9.7 ± 8.2 seconds vs, Sevo+FMT group: 2.7 ± 2.4 seconds, d=1.16, 95% confidence interval: −12.7 to −1.3 seconds, P = .019) and target zone crossing times (Sevo group: 2.4 ± 1.6 vs, Sevo+FMT group: 5.4 ± 1.4, d=1.99, 95% confidence interval: 2.0–5.0, P &lt; .001) in the reversal Morris water maze test. Microbiota analysis revealed that the α-diversity of gut microbiota increased after fecal microbiota transplantation. Similarly, the relative abundance of the Firmicutes phylum (effect value: 1.44), Ruminococcus genus (effect value: 1.69), and butyrate-producing bacteria increased after fecal microbiota transplantation. Furthermore, fecal microbiota transplantation increased the fecal concentration of butyrate and induced histone acetylation and the mRNA expression of brain-derived neurotrophic factor in the hippocampus, thereby suppressing neuroinflammation and neuronal apoptosis. CONCLUSIONS: The alternation of gut microbiota after fecal microbiota transplantation influenced spatial learning ability in neonatal rats with developmental anesthetic neurotoxicity. Modulation of the gut microbiota may be an effective prophylaxis for developmental anesthetic neurotoxicity in children.

The Neuroprotective Effects of Primary Functional Components Mulberry Leaf Extract in Diabetes-Induced Oxidative Stress and Inflammation.

Diabetes-associated neurodegeneration may result from increased oxidative stress in the brain under hyperglycemic conditions, which leads to neuronal cell death. The current study employs the neuroblastoma cell line SH-SY5Y and db/db mouse model of diabetes maintained on a high-fat diet to investigate the neuroprotective effects of the primary functional components of mulberry (Morus alba Linn) leaf extract (MLE), chlorogenic acid (CGA), and neochlorogenic acid (NCGA). CGA and NCGA demonstrated the ability to enhance the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase, and attenuate inflammation via regulating nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-κB (NFκB), and inflammatory cytokines, thereby protecting SH-SY5Y cells from oxidative damage induced by palmitic acid and high glucose. CGA and NCGA were found to decrease the expression of proinflammatory proteins α-synuclein and amyloid-β (Aβ). In addition, CGA and NCGA treatments increased the expression of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF). Furthermore, MLE supplementation in the animal model resulted in decreased levels of α-synuclein and Aβ concomitant with an elevated expression of TH. These experimental findings suggest that the neuroprotective effects of CGA and NCGA may be mediated via three pathways: reducing oxidative stress, decreasing neuronal inflammation, and enhancing BDNF expression.

BDNF expression mediates verbal learning and memory in women in a cohort enriched with risk for Alzheimer's disease.

This study examined whether sex differences in verbal learning and memory (VLM) are mediated by plasma brain-derived neurotrophic factor (BDNF) expression. In a sample of n=201 participants (63.81±6.04 years, 66.2% female, 65.7% family history of Alzheimer's disease [AD], 38% apolipoprotein E [APOE] ε4+) from the Wisconsin Registry for Alzheimer's Prevention, VLM was measured using trials 3 through 5 and delayed recall from the Rey Auditory Verbal Learning Test. Plasma BDNF was measured using a Human BDNF Quantikine Immunoassay. Mediation analysis used bootstrapping, and stratified mediation models tested the conditional dependence of APOE ε4 carriage. BDNF partially mediated the sex-VLM relationship (β=-0.07; 95% confidence interval [CI]: -0.18, -0.01). Female APOE ε4 carriers had higher VLM scores (β=-0.53; p=0.03), while female non-carriers had both higher BDNF levels (β=-0.68; p<0.01) and VLM scores (β=-1.06; p<0.01); BDNF was again a significant mediator (β=-0.18; 95% CI: -0.37, -0.05). This study found that circulating BDNF mediates higher verbal memory scores in females-particularly in APOE ε4 non-carriers. Sex differences in verbal learning and memory (VLM) were mediated by plasma brain-derived neurotrophic factor (BDNF) levels.Women exhibited higher VLM scores and plasma BDNF levels compared to men.The protective effect of BDNF in women was attenuated by apolipoprotein E ε4 carriage.Findings suggest sex-specific mechanisms against verbal memory decline in aging.

Edaravone Mitigates Hippocampal Neuronal Death and Cognitive Dysfunction by Upregulating BDNF Expression in Neonatal Hypoxic-Ischemic Rats.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological injury during infancy, often resulting in long-term cognitive deficits. This study aimed to investigate the neuroprotective effects of Edaravone (EDA), a free radical scavenger, and elucidate the potential role of brain-derived neurotrophic factor (BDNF) in mediating these effects in neonatal HIE rats. Using the Rice-Vannucci model, HIE was induced in neonatal rats, followed by immediate administration of EDA after the hypoxic-ischemic insult. To examine the role of BDNF, a separate group of rats received intrahippocampal injections of a lentiviral vector for BDNF knockdown prior to the induction of HIE and subsequent EDA treatment. Neuronal survival and apoptosis in the hippocampal region were assessed by immunofluorescence and TUNEL staining, respectively. BDNF expression levels in the hippocampus were analysed using enzyme-linked immunosorbent assay (ELISA). Cognitive function was evaluated using the Morris water maze (MWM) and Y maze tests. Results demonstrated that EDA significantly reduced hippocampal neuronal apoptosis and death, increased neuronal survival, and enhanced BDNF expression compared to the control group. However, the therapeutic effects of EDA were mitigated in the BDNF knockdown group, indicating a crucial role of BDNF in mediating the neuroprotective effects of EDA. Behavioural testing confirmed that EDA treatment significantly improved spatial learning and memory abilities in HIE rats, but these improvements were not observed in rats with BDNF knockdown. In conclusion, our study suggests that EDA treatment mitigates hippocampal neuronal death and improves cognitive dysfunction in HIE rats primarily by upregulating BDNF expression. These findings provide experimental support for the potential application of EDA in the treatment of HIE and highlight the essential role of BDNF in neuroprotection and cognitive recovery post-HIE.

B cells upregulate NMDARs, respond to extracellular glutamate, and express mature BDNF to protect the brain from ischemic injury.

Following stroke, B cells enter brain regions outside of the ischemic injury to mediate functional recovery. Although B cells produce neurotrophins that support remote plasticity, including brain-derived neurotrophic factor (BDNF), it remains unclear which signal(s) activate B cells in the absence of infarct-localized pro-inflammatory cues. Activation of N-methyl-d-aspartate (NMDA)-type receptor (NMDAR) subunits on neurons can upregulate mature BDNF (mBDNF) production from a pro-BDNF precursor, but whether this occurs in B cells is unknown. We identified GluN2A and GluN2B NMDAR subunits on B cells that respond to glutamate and mediate nearly half of the glutamate-induced Ca2+ responses in activated B cell subsets. Ischemic stroke recruits GluN2A+ B cells into the ipsilesional hemisphere and both stroke and neurophysiologic levels of glutamate regulate gene and surface expression. Regardless of injury, pro-BDNF+ B localize to spleen/circulation whereas mBDNF+ B cells localize to the brain, including in aged male and female mice. We confirmed B cell-derived BDNF was required for in vitro and in vivo B cell-mediated neuroprotection. Lastly, GluN2A, GluN2B, glutamate-induced Ca2+ responses, and BDNF expression were all clinically confirmed in B cells from healthy donors, with BDNF+ B cells present in post-stroke human parenchyma. These data suggest that B cells express functional NMDARs that respond to glutamate, enhance NMDAR signaling with activation, and upregulate mature BDNF expression within the brain. This study identifies potential glutamate-induced neurotrophic roles for B cells in the brain; an immune response to neurotransmitters unique from established pro-inflammatory stimuli and relevant to any CNS-localized injury or disease.

Intranasal Insulin Diminishes Postoperative Delirium and Elevated Osteocalcin and Brain Derived Neurotrophic Factor in Older Patients Undergoing Joint Replacement: A Randomized, Double-Blind, Placebo-Controlled Trial.

Brain energy metabolism disorders, including glucose utilization disorders and abnormal insulin sensitivity, are linked to the pathogenesis of postoperative delirium. Intranasal insulin has shown significant benefits in improving glucose metabolism, insulin sensitivity and cognitive function. However, its impact on postoperative delirium and insulin sensitivity biomarkers remains unknown. This randomized, double-blind, placebo-controlled trial was to evaluate whether intranasal insulin reduces the incidence and severity of postoperative delirium (POD) in older patients undergoing joint replacement, and its effect on insulin sensitivity-related biomarkers. 212 older patients (≥65 years) were randomly assigned to receive either 40 IU of intranasal insulin (n=106) or a placebo (n=106) for 8 days. The primary objective was to determine the incidence and severity of POD within 5 days after surgery, estimated using the Confusion Assessment Method (CAM) and the Delirium Rating Scale (DRS)-98. The secondary objective was insulin sensitivity, which was assessed using the homeostasis model Assessment of Insulin Resistance (HOMA-IR) and biomarkers, including total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC), and brain-derived neurotrophic factor (BDNF). Compared to placebo, intranasal insulin significantly reduced the incidence of delirium within 5 days after surgery (8 [8.33%] vs 23 [23.23%], P = 0.004, odds ratio [OR] = 3.33 [95% CI 1.41-7.88]) and the severity of delirium (P<0.001). Intranasal insulin elevated the levels of tOC, ucOC, and BDNF in the CSF on D0 (all P<0.001) and tOC levels in the plasma on D0, D1 and D3 (all P<0.001). It elevated ucOC levels in the plasma of the insulin group on D0 but not on D1 and D3 (all P<0.001). Intranasal insulin administration reduced the HOMA-IR on D3 (P=0.002). Intranasal insulin notably reduced the incidence and severity of POD in older patients undergoing joint replacement, which may be related to the elevation in osteocalcin and BDNF levels. Chinese Clinical Trial Registry (ChiCTR2300068073).

Unidirectional and sustainable release of NGF and BDNF from a chitosan gel-mediated multilayer ordered composite membrane in promoting both spinal cord and sciatic nerve injury repair.

To develop a scaffold suitable for simultaneous repair of both spinal cord injury (SCI) and sciatic nerve injury (SNI), we designed a multilayer composite membrane capable of unidirectional and sustained release of two factors: nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). The membrane's morphology, mechanical properties, cytocompatibility, drug release kinetics, swelling, and degradation behavior were thoroughly characterized. Additionally, its ability to promote the differentiation of PC-12 cells was assessed. The findings indicated that the composite membrane featured a tri-layered structure and exhibited robust mechanical strength, enabling it to protect and regulate the release of NGF and BDNF. This regulation ensured the appropriate timing and concentration of the factors necessary for cell differentiation and growth. Moreover, the membrane demonstrated excellent cell compatibility and significantly fostered the differentiation of PC-12 cells into axons. In rat models of SCI and SNI, the composite membrane markedly enhanced axon and neuron regeneration, myelination, neural stem cell proliferation, and nerve fiber clustering, while reducing astrocyte formation. It also improved the integrity of spinal cord tissue and motor function recovery, suggesting that this scaffold holds promise for the repair of both SCI and SNI.

Impact of Parental Ethanol Exposure on Offspring Memory: Sex Differences in Spatial and Passive Avoidance Tasks.

The impact of parental alcohol exposure on subsequent generations recently gained significant attention. Ethanol, widely consumed by humans, is known for its anxiolytic effects upon initial use. However, repeated ethanol consumption leads to cognitive dysfunction, dependence, and other physical abnormalities. In line with recent publications from our group, this study investigated the role of parental ethanol exposure-10 days prior to gestation-on learning and memory, which are critical cognitive abilities, in male and female offspring. Adult male and female Wistar rats (n=12) were exposed to ethanol (in drinking water) for 30 days, followed by a 10-day ethanol-free period. Each rat was then paired to mate with either an ethanol-naïve (control, n=12) or ethanol-exposed rat, resulting in four distinct groups: (1) control male and female, (2) ethanol-exposed male and control female (P.EE), (3) ethanol-exposed female and control male (M.EE), and (4) ethanol-exposed male and female (P+M.EE). Adult male and female offspring were tested for spatial learning and memory (Morris Water Maze) and passive avoidance memory. Additionally, brain-derived neurotrophic factor (BDNF) levels in the cerebrospinal fluid were evaluated. Results showed that spatial memory was negatively affected by parental ethanol consumption in both male and female offspring, while spatial learning was impaired only in female offspring of ethanol-exposed dams. In the passive avoidance paradigm, memory retrieval was impaired in ethanol-exposed male offspring, whereas in females, only the P+M.EE group showed a deficit in memory retention. While BDNF levels decreased in male offspring, an enhancement in BDNF was observed in female offspring of the P.EE group. In conclusion, our findings suggest that parental ethanol exposure before conception has differential impacts on learning and memory, depending on the offspring's sex and the type of memory tested. Spatial memory was affected in both sexes (except for females in the P.EE group), while memory retrieval in the passive avoidance task remained unaffected in female offspring of the P.EE and M.EE groups. Conversely, male offspring of ethanol-exposed sires and dams exhibited deficits in passive avoidance memory. This may suggest that in memory tasks involving inhibitory cues, such as passive avoidance, female offspring of ethanol-exposed dams or sires are more resilient to memory deficits compared to male offspring. This resilience could possibly be attributed to their higher anxiety levels relative to males.

Therapeutic effects of CGS21680, a selective A2A receptor agonist, via BDNF-related pathways in R106W mutation Rett syndrome model.

Rett syndrome (RTT) is a neurological disorder caused by a mutation in the X-linked methyl-CpG binding protein 2 (MECP2), leading to cognitive and motor skill regression. Therapeutic strategies aimed at increasing brain-derived neurotrophic factor (BDNF) levels have been reported; however, BDNF treatment has limitations, including the inability to penetrate the blood-brain barrier, a short half-life, and potential for adverse effects when administered via intrathecal injection, necessitating novel therapeutic approaches. In this study, we focused on the adenosine A2A receptor (A2AR), which modulates BDNF and its downstream pathways, and investigated the therapeutic potential of CGS21680, an A2AR agonist, through in vitro and in vivo studies using R106W RTT model. CGS21680 restored neurite outgrowth, the number of SYN1+/MAP2+ puncta pairs, genes related to the BDNF-TrkB signaling pathway (Bdnf, TrkB, and Mtor) and neural development (Tuj1 and Syn1), and electrophysiological functions in in vitro RTT primary neurons. Additionally, CGS21680 alleviated neurobehavioral impairments and modulated gene expression in an RTT in vivo model. Our findings suggest that activation of A2AR via CGS21680 enhances BDNF-TrkB signaling, which in turn activates downstream pathways, ultimately increasing neurite outgrowth and synaptic plasticity, and restoring neurobehavioral clinical symptoms. This is the first study to report the therapeutic effect of CGS21680 in R106W point mutation RTT models, both in vitro and in vivo. These research results suggest that CGS21680 could be a promising therapeutic candidate for the treatment of RTT.

The Mechanism and Treatment of Cognitive Dysfunction in Diabetes: A Review.

Diabetes mellitus (DM) is one of the fastest growing diseases in terms of global incidence and seriously affects cognitive function. The incidence rate of cognitive dysfunction is up to 13% in diabetes patients aged 65-74 years and reaches 24% in those aged >75 years. The mechanisms and treatments of cognitive dysfunction associated with diabetes mellitus are complicated and varied. Previous studies suggest that hyperglycemia mainly contributes to cognitive dysfunction through mechanisms involving inflammation, autophagy, the microbial-gut-brain axis, brain-derived neurotrophic factors, and insulin resistance. Antidiabetic drugs such as metformin, liraglutide, and empagliflozin and other drugs such as fingolimod and melatonin can alleviate diabetes-induced cognitive dysfunction. Self-management, intermittent fasting, and repetitive transverse magnetic stimulation can also ameliorate cognitive impairment. In this review, we discuss the mechanisms linking diabetes mellitus with cognitive dysfunction and propose a potential treatment for cognitive decline associated with diabetes mellitus.

Relationship between brain-derived neurotrophic factor and tropomyosin kinase receptor type B gene polymorphisms with cerebrospinal fluid visinin-like protein 1 levels in Alzheimer’s disease

Relationship between brain-derived neurotrophic factor and tropomyosin kinase receptor type B gene polymorphisms with cerebrospinal fluid visinin-like protein 1 levels in Alzheimer’s disease