BDNF Levels Research Articles

A highly sensitive enzyme‑linked immunosorbent assay allows accurate measurements of brain‑derived neurotrophic factor levels in human saliva

Background Hitherto, BDNF levels in humans have been primarily measured in serum and/or plasma where these levels are readily measurable, but primarily reflect the content of BDNF in blood platelets. By contrast, previous attempts to measure BDNF levels in readily accessible human body fluids such as saliva have been complicated by a lack of sensitivity and/or specificity of BDNF ELISAs (see Discussion). Recently, the suitability of a highly sensitive BDNF ELISA assay was validated using mouse plasma and serum where conventional BDNF ELISA fail to detect BDNF. In this report, we demonstrate that BDNF levels in human saliva are extremely low, in the low pg/mL range, yet detectable in all saliva samples tested. Methods Saliva samples were collected from healthy volunteers by a passive drool method. All samples were aliquoted and immediately frozen to keep at -80°C until use. At the time of use, the samples were thawed, centrifuged to remove any remaining particles and BDNF measurement conducted by using a previously validated BDNF ELISA assay (see below). Recombinant mature BDNF was used as a reference. Results The intra-assay variability was in the range of CV = 1.8 to 4.9%. Saliva samples could be kept frozen at -80°C for 2 months until use for measurements, but more than 4 freeze and thaw cycles caused BDNF losses presumably due to structural change of the antigen. The measurements were not affected by the method of collection provided the samples were diluted at least 2-fold. Conclusions The results indicate that human saliva samples collected in a non-invasive fashion can be used as a source of material to try and correlate BDNF levels with human conditions of interest. These results also confirm those of an independent study published recently using the same BDNF ELISA kit to measure BDNF levels in human saliva samples.

Modulatory impact of Bifidobacterium longum subsp. longum BL21 on the gut-brain-ovary axis in polycystic ovary syndrome: insights into metabolic regulation, inflammation mitigation, and neuroprotection.

This study evaluates the efficacy of Bifidobacterium longum subsp. longum BL21 in mitigating symptoms of polycystic ovarian syndrome (PCOS) in DHT-induced PCOS model mice. It focuses on BL21's role in modulating metabolic dysregulation, inflammation, and neuroprotection via the gut-brain-ovary axis. Employing an 8-week treatment regimen, this research assessed the effects of BL21 on prenatal androgen-induced PCOS in ICR mice. Evaluations included body weight, glucose tolerance tests, serum analyses of BDNF, inflammatory markers, sex hormone levels, and 16S rRNA gene sequencing for gut microbiota diversity and composition. Twenty-four ICR mice with induced PCOS served as subjects to examine the probiotic's impact. Mice were administered a daily oral dose of 1 × 109 CFU of BL21 continuously for a total of 8 weeks. BL21 significantly enhanced sex hormone levels (P < 0.05), particularly those of follicle-stimulating hormone (FSH) and estradiol (E2), indicating improved ovarian function and offering a novel PCOS treatment approach. The intervention notably curbed weight gain and improved glucose tolerance in PCOS mice (P < 0.05). BL21 reduced inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and lipopolysaccharides (LPS), while increasing IL-10, BDNF, FSH, and E2 levels (P < 0.05 for all). It also enriched gut microbiota diversity, enhancing populations of Bifidobacterium and Lactobacillus. Correlation analyses underscored the positive shifts in microbiota linked to beneficial hormonal and inflammatory profiles. BL21 shows promise in alleviating PCOS symptoms through metabolic regulation, inflammation reduction, and neuroprotection, validating its potential in integrated therapeutic strategies.IMPORTANCEPolycystic ovarian syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age, characterized by metabolic irregularities, hormonal imbalances, and chronic inflammation. Existing treatments are often inadequate, addressing symptoms without targeting the underlying etiological factors. The investigation of Bifidobacterium longum subsp. longum BL21 as a probiotic intervention offers a novel approach by potentially regulating the gut-brain-ovary axis. This could lead to innovative therapeutic strategies that not only manage but also potentially reverse the multifaceted symptoms of PCOS, enhancing quality of life and reproductive health.

Caffeine intake during gestation and lactation causes long-term behavioral impairments in heterogenic mice offspring in a sex-dependent manner.

Growing evidence has indicated a potential association between maternal consumption of caffeine and impaired cognition and behavior in rodent offspring. However, potential sex differences, as well as caffeine-related effects in subsequent generations are still poorly investigated. We aimed to investigate the impact of pre-and/or neonatal exposition to caffeine on the neurodevelopment of male and female mice offspring. Adult female Swiss mice were randomly divided into four experimental groups, which received, via gavage, water or caffeine (120mg/day). Control/control (CC) received water during pregnancy and lactation; treated/control (TC): received caffeine during pregnancy and water during lactation; control/treated (CT): received water during pregnancy and caffeine during lactation; treated/treated (TT): received caffeine during pregnancy and lactation. Dams were euthanized at gestational day 17.5 and fetal brains were collected. Adult mice of F1 and F2 generations were submitted to behavioral analysis and their pre-frontal cortex and hippocampi were dissected to measure the levels of BDNF and CX3CL1. Caffeine induced reduction of CX3CL1 levels in female fetuses compared with controls. Maternal intake of caffeine was associated with anxiety- and compulsive-like behavior in both F1 and F2 female mice offspring. Interestingly, only F2 female mice exhibited caffeine-induced impairment of work memory. Hippocampal levels of CX3CL1 and BDNF were decreased in female F1TT and F2TT groups; while among males exposed to caffeine, only F1 offspring had reduced hippocampal CX3CL1 levels. Our results suggest that both pre- and neonatal exposition to caffeine lead to long-term behavioral and neurochemical impairments in a sex-dependent manner, adversely affecting the subsequent female generation.

Crocin facilitates the effect of fear extinction on freezing behavior and BDNF level in a rat model of fear-conditioning

Crocin facilitates the effect of fear extinction on freezing behavior and BDNF level in a rat model of fear-conditioning

Social isolation during pregnancy disrupts maternal behavior and hippocampal neurochemistry in rats: A role for BDNF, corticosterone, and GABAARα1.

This study aimed to investigate the effects of social isolation stress during pregnancy on maternal behavior and associated neurochemical changes in the hippocampus of rats. Twenty female Sprague-Dawley rats were randomly assigned to either a group housing (two rats per cage: control group) or a social isolation stress group (one rat per cage: SI group) during pregnancy. At the end of the study, we assessed the levels of BDNF, corticosterone, and GABAARα1 in the hippocampus of the maternal brain, along with evaluating the endurance, integration, and emotional aspects of maternal behavior. Results indicated that social isolation stress significantly decreased maternal endurance, integration, and emotionality (self-calming) of maternal behavior. Concurrently, blood and the hippocampal corticosterone concentration significantly increased, while BDNF concentration significantly decreased in the SI stress group compared to controls. Moreover, GABAARα1 mRNA expression was significantly decreased in the hippocampus of socially isolated rats. These findings demonstrate that social isolation stress during pregnancy profoundly impacts maternal behaviors in rats, including endurance, integration, and self-soothing. The altered concentration of corticosterone and BDNF, and GABAARα1 mRNA expression in the hippocampus of social isolation group suggests disruptions in stress response regulation and synaptic plasticity during pregnancy to form normal maternal behavior.

HEalth-Related Quality of Life-Intervention in Survivors of Breast and Other Cancers Experiencing Cancer-Related Fatigue and Associated Cognitive Symptoms Using TraditionAL Chinese Medicine: The 'HERBAL' Trial.

As pharmacological strategies remain limited for relieving fatigue and associated cognitive symptoms, integrative modalities such as traditional Chinese medicine (TCM) could be explored as therapeutic strategies in cancer survivors. Here, we evaluate and report the efficacy and safety of a TCM concoction, modified Xiang Bei Yang Rong Tang (XBYRT), on quality of life (QOL), cancer-related fatigue (CRF), and cognitive symptoms, compared to placebo. In a single-centered, randomized, double-blinded, placebo-controlled pilot trial conducted from 2019 to 2022, fatigued cancer survivors ≥21 years old were recruited to receive the XBYRT intervention or placebo (5% diluted) once daily for the duration of 8 weeks. Patient-reported outcomes for QOL, CRF, cognition, blood samples for biomarker testing, and adverse events were collected at baseline (T0), 4 weeks (T1), 8 weeks (T2), and 10 weeks (T3) after baseline. Linear regression was performed to evaluate differences between groups at T2 and T3. A total of 1502 patients were screened, with 672 patients considered eligible. Of the eligible, 15 XBYRT and 13 placebo subjects with similar mean ages (58.5 vs 58.4) were recruited. Both groups were predominantly Chinese (93% vs 62%), breast cancer patients (87% vs 62%), and diagnosed with stage 2 cancer (60% vs 46%). Although no significant difference was found in QOL between groups, the XBYRT group exhibited improved emotional fatigue at T3 (P = .045) and higher BDNF levels at T2 (P = .047) and T3 (P = .029). After baseline adjustment, XBYRT was associated with better perceived cognitive impairment at T2 (P = .011) and T3 (P = .017), as well as overall perceived cognitive function at T3 (P = .028). XBYRT is well tolerated, with grade 3 adverse events reported in three XBYRT (20%) and two placebo (15%) subjects. In this pilot study, XBYRT as an integrative therapy is safe and generates encouraging improvements in cognitive and fatigue symptoms. Difficulties with recruitment limited the generalizability of trial findings, thus findings should be verified through a larger, multi-centered trial.

Genetics of constant and severe pain in the NAPS2 cohort of recurrent acute and chronic pancreatitis patients.

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function and quality of life. The genetic variants and pain pathways in patients contributing to most severe pain experiences are unknown. We used previously genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European Ancestry for nested genome-wide associated study (GWAS) for pain-severity, chronicity, or both. Lead variants from GWAS were determined using FUMA. Loci with p<1e-5 were identified for post-hoc candidate identification. Transcriptome-wide association studies (TWAS) identified loci in cis and trans to the lead variants. Serum from phenotyped individuals with CP from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) was assessed for BDNF levels using Meso Scale Discovery Immunoassay. We identified four pain systems defined by candidate genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 and HSF22. 2) Neural development and axon guidance tracing genes include: SNPO, RGMA, MAML1 and DOK6 (part of the RET complex). 3) Genes linked to psychiatric stress disorders include TMEM65, RBFOX1, and ZNF385D. 4) Genes in the dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 and RBFOX1. In an independent cohort BDNF was significantly elevated in patients with constant-severe pain. Extension and expansion of this exploratory study may identify pathway- and mechanism-dependent targets for individualized pain treatments in CP patients. PERSPECTIVE: Pain is the most distressing and debilitating feature of chronic pancreatitis. Yet many patients with chronic pancreatitis have little or no pain. The North American Pancreatitis Study II (NAPS2) includes over 1250 pancreatitis patients of all progressive stages with all clinical and phenotypic characteristics carefully recorded. Pain did not correlate well with disease stage, inflammation, fibrosis or other features. Here we spit the patients into groups with the most severe pain and/or chronic pain syndromes and compared them genetically with patients reporting mild or minimal pain. Although some genetic variants associated with pain were expressed in cells (1) of the pancreas, most genetic variants were linked to genes expressed in the nervous system cells associated with (2) neural development and axon guidance (as needed for the descending inhibition pathway), (3) psychiatric stress disorders, and (4) cells regulating sensory nerves associated with BDNF and neuropathic pain. Similar and overlapping genetic variants in systems 2 -4 are also seen in pain syndromes form other organs. The implications for treating pancreatic pain are great in that we can no longer focus on just the pancreas. Furthermore, new treatments designed for pain disorders in other tissues may be effective in some patient with pain syndromes from the pancreas. Further research is needed to replicate and extend these observations so that new, genetics-guided rational treatments can be developed and delivered.

Steady Moderate Exercise Confers Resilience Against Neurodegeneration and Neuroinflammation in a Mouse Model of Parkinson’s Disease

Intensive aerobic exercise slows the progression of movement disorders in Parkinson's disease (PD) and is therefore recommended as an important component of treatment for PD patients. Studies in animal models of PD have shown that vigorous exercise has neuroprotective effects, and emerging evidence suggests that it may be a disease-modifying treatment in humans. However, many people with PD may not be able to participate in vigorous exercise because of multiple medical conditions that severely limit their physical activity. In this study, we have shown that chronic MPTP treatment in sedentary mice resulted in loss of dopaminergic neurons in the SNpc, decreased levels of neurotrophins, BDNF and GDNF, and increased levels of inflammatory markers and pro-inflammatory changes in immunocompetent cells. Moderate exercise, initiated both before and after chronic MPTP treatment, significantly attenuated the loss of dopaminergic neurons and increased BDNF and GDNF levels even above those in sedentary control mice. No signs of inflammation were observed in MPTP-treated mice, either when training began before or after MPTP treatment. Training induced beneficial changes in the dopaminergic system, increased levels of neurotrophins and suppression of inflammation were similar for both steady moderate (present data) and intense training (our previously published data). This suggests that there is a kind of saturation when the percentage of rescued dopaminergic neurons reaches the highest possible value, and therefore further increases in exercise intensity do not enhance neuroprotection. In conclusion, our present results compared with the previous data show that increasing exercise intensity beyond the level used in this study does not increase the neuroprotective effect of aerobic training in a mouse model of Parkinson's disease.

Lipidomics Analysis Reveals the Effects of Docosahexaenoic Acid from Different Sources on Prefrontal-Cortex Synaptic Plasticity

Background: Docosahexaenoic Acid (DHA) is an extensively used nutrition supplement in dairy food because of its beneficial effects on cognition. To find an effective DHA intervention for the synapses in the cortex during this period, this study aimed to use targeted lipidomics to evaluate the lipid composition of prefrontal-cortex (PFC) tissue in different DHA interference methods. Methods: Analyzed samples were taken from interfering feeding Bama pigs (BPs) (3 months) fed with soybean oil (Group B), blended oil (Group M), naturally DHA-supplemented milk with blended oil (Group OM), and DHA from fish oil (FO) with blended oil (Group Y). We also examined the protein expression levels of BDNF, GAP43, and MBP. Results: The lipidomics analysis identified 80 different related negative-ion lipid content and filtered the biomarker lipids in PFC tissue. We observed significant lipid composition changes between group Y and other groups, especially for content levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), and sphingomyelin (SM). The same observations were made from mRNA and protein expressions related to lipid transportation, phosphatidylserine (PS) synthetase, and synaptic plasticity in PFC tissues between group Y and other groups, including the mRNA expression levels of CD36, BDNF, and PTDSS1. The analysis of protein expression levels showed that the metabolism mode of DHA intervention from FO benefited the PFC, PS metabolism, and PFC synaptic plasticity of infants. Conclusions: The results highlight further prospects for the DHA intervention mode, which provides new routes for other studies on polyunsaturated-fatty-acid (PUFA) interference for infants.

Assessment of the Impact of Different Types and Intensities of Physical Exercise on the Quality of Life of Patients with Alzheimer’s Disease: A Literature Review

Objective Alzheimer’s Disease (AD) is the most common form of dementia, representing a global health challenge. The aim of this review is to assess the impact of different types and intensities of physical exercise on cognitive functions, biomarkers, and the quality of life of AD patients. Methods Studies from PubMed, Scopus, Cochrane Library, and Web of Science (2000–2024) were analyzed, focusing on the effects of aerobic, resistance, and combined exercises on memory, executive functions, biomarkers (amyloid beta, tau protein, BDNF), daily living abilities (ADL), and quality of life. The review included 42 studies, including randomized controlled trials and meta-analyses. Results Moderate-intensity aerobic and combined exercises improve memory and executive functions, while resistance training increases hippocampal volume, supporting spatial memory. High-intensity exercises boost BDNF levels, and moderate-intensity exercises reduce neurodegenerative biomarkers and improve ADL. Conclusions Moderate aerobic and combined exercises are effective in preventing and supporting AD therapy. Further research is needed to standardize exercise protocols and evaluate their long-term effects.

GsMTx-4 combined with exercise improves skeletal muscle structure and motor function in rats with spinal cord injury.

Motor dysfunction and muscle atrophy are typical symptoms of patients with spinal cord injury (SCI). Exercise training is a conventional physical therapy after SCI, but exercise intervention alone may have limited efficacy in reducing secondary injury and promoting nerve regeneration and functional remodeling. Our previous research found that intramedullary pressure after SCI is one of the key factors affecting functional prognosis. It has been reported that GsMTx-4, a specific blocker of the mechanosensitive ion channels Piezo1, can protect the integrity of the neuromuscular junction and promote nerve regeneration, and thus has the potential as a therapeutic agent for SCI. In this study, we observed the combined and separate therapeutic effect of GsMTx-4 and exercise on the structure of the soleus muscle and motor function in rats with SCI. At 42 days post-injury, compared with SCI rats, the Basso-Beattie-Bresnahan score (P = 0.0007) and Gait Symmetry (P = 0.0002) were significantly improved after combination therapy. On histology of rat soleus muscle, compared with SCI rats, the combined treatment significantly increased the wet weight ratio, muscle fiber cross-sectional area and acetylcholinesterase (all P<0.0001). On histology of rat spinal tissue, compared with SCI rats, the combined treatment significantly increased neuron counts and BDNF levels, and significantly reduced the percentage of TUNEL-positive cells (all P<0.0001). On physiology of rat soleus muscle, compared with SCI rats, the combined treatment increased the succinate dehydrogenase expression (P<0.0001), while the expression of α-glycerophosphate dehydrogenase (P<0.0001) and GDF8 protein (P = 0.0008) decreased. Results indicate the combination therapy effectively improves histopathology of spinal cord and soleus muscle in SCI rats, enhancing motor function. This study was conducted on animal models, it offers insights for SCI treatment, advancing understanding of lower limb muscle pathology post-SCI. Further research is needed for clinical validation in the future.

Association of inflammation cytokines with cognitive function in first-episode major depressive disorder.

Abnormal cognitive functioning is a core symptom of Major Depressive Disorder (MDD) and is strongly correlated with MDD prognosis. Current studies suggest that the occurrence of MDD may be related to oxidative stress-induced inflammation, hypothalamic-pituitary-adrenal axis disorders, diminished monoamine function and microbe-brain-gut axis, among other pathways. In recent years, the relationship between the immune-inflammatory response and MDD has been a hot topic of research, but how the relationship between immunoinflammation and cognitive function is manifested in MDD is still unclear. In this study, we examined cognitive function characteristics, serum inflammatory factors, brain-derived neurotrophic factor, and their correlations before and after pharmacological treatment(paroxetine hydrochloride tablets) in patients with first-episode major depressive disorder, aiming to identify objective biomarkers for cognitive function assessment. We included 22 patients with first-episode major depressive disorder and 27 healthy volunteers from the community during the same period. The Hamilton Depression Scale-17 (HAMD-17) assessed the severity of depressive symptoms at baseline and after 8 weeks of treatment. The Repeatable Battery for the Assessment of Neuropsychological Status(RBANS) evaluated cognitive function, and serum samples were collected to determine levels of inflammatory and neurotrophic factors at these two time points. For healthy volunteers, only HAMD-17 scale scores, RBANS scale scores, and serum samples were taken at baseline. Spearman's correlation analyzed the relationship between inflammatory factors, neurotrophic factors, and cognitive function. Multiple linear regression determined factors affecting cognitive function in first-time patients. Baseline findings indicated that patients' IL-6 and TNF-α levels exceeded those of healthy individuals, while their IFN-α levels were below; their scores in language, attention, delayed memory, and the RBANS scale were also lower than healthy counterparts. Post-treatment, patients' BDNF, IL-6, and TNF-α levels remained higher than those of healthy subjects, and their IFN-α levels were still lower; their language and attention scores were also inferior. Association analyses revealed an association between BDNF and visuospatial/constructional ability scores and language scores in patients with MDD at baseline, and a positive relationship between TNF-α and attention score. Multiple regression analysis indicated an association between TNF-α levels and attention scores in MDD patients at baseline. Our study concludes that TNF-α and BDNF correlate with cognitive function in MDD at baseline, and furthermore, TNF-α could potentially serve as an objective biomarker to support the assessment of attentional function at baseline.

Exploring the Different Impacts of Ketamine on Neurotrophic Factors and Inflammatory Parameters in a Cecal Ligation and Puncture-Induced Sepsis Model.

Given ketamine's conflicting impacts on the central nervous system, investigating its effects within an inflammatory context becomes crucial. This study aimed to assess the impact of varying ketamine doses on neurotrophin and inflammatory cytokine levels within the brains of rats submitted to the sepsis model. Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Intraperitoneal ketamine injections (5, 15, or 25mg/kg) or saline were administered daily for seven days, thirty days post-CLP. Rats were euthanized thirty minutes following the last injection for analysis of IL-1β, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels in the frontal cortex, hippocampus, and striatum. CLP-induced elevated IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and hippocampus of rats, with reduced BDNF levels across all structures examined. Furthermore, reduced NGF and GDNF levels were observed solely in the hippocampus. Ketamine at 5mg/kg normalized CLP-induced alterations and, in Sham animals, increased BDNF and NGF levels in the frontal cortex and/or hippocampus. At 15mg/kg, ketamine elevated BDNF and NGF levels in Sham animals, while at 25mg/kg, it exacerbated the inflammatory response initiated by CLP. These findings suggest variable effects of ketamine within a context of systemic inflammation, emphasizing the importance of considering individual inflammatory backgrounds when utilizing ketamine.

Peripheral blood age-sensitive immune markers in multiple sclerosis: relation to sex, cytomegalovirus status, and treatment.

Immunosenescence is accelerated by chronic infectious and autoimmune diseases and could contribute to the pathobiology of multiple sclerosis (MS). How MS and disease-modifying therapies (DMTs) impact age-sensitive immune biomarkers is only partially understood. We analyzed 771 serum samples from 147 healthy controls and 289 people with MS (PwMS) by multiplex immunoassays. We determined cytomegalovirus (CMV) serostatus and collected retrospective clinical information. We performed unsupervised and multivariable analyses. Unsupervised analyses revealed that MS immune profile was characterized by low relative levels of anti-inflammatory/neuroprotective factors IL-4, IL-10, TNF, and β-NGF but high levels of growth factors EGF and bFGF. Serum levels of IL-4, β-NGF, IL-27, BDNF, and leptin were significantly influenced by sex and/or CMV status. IL-4 and β-NGF levels were lower in untreated PwMS compared to controls, while EGF and bFGF levels were influenced by age and markedly elevated in PwMS in multivariable analysis. Samples from treated PwMS, but not untreated PwMS, showed lower levels of BDNF and TNF than controls. Initiation of high efficacy DMTs, but not low efficacy DMTs, was associated with reduced levels of bFGF and EGF. Samples associated with distinct DMTs exhibited specific profiles for age-sensitive immune markers. Finally, lower levels of IL-6, TNF, IL-10, and β-NGF were observed at baseline in PwMS who subsequently experienced clinical failure after DMTs initiation. Age, sex, CMV status, and specific DMTs significantly influence levels of age-sensitive immune biomarkers associated with MS and must be considered when investigating inflammation-related biomarkers. This work was supported by a Grant for Multiple Sclerosis Innovation by Merck KGaA (ID: 10.12039/100009945).

The Role of SIRT1-BDNF Signaling Pathway in Fluoride-Induced Toxicity for Glial BV-2 Cells.

Chronic fluorosis is often accompanied by neurological symptoms, leading to attention, memory and learning ability decline and causing tension, anxiety, depression, and other mental symptoms. In the present study, we analyzed the molecular mechanisms of SIRT1-BDNF regulation of PI3K-AKT, MAPK, and FOXO1A in F-treated BV2 cells. The cytotoxic effect of sodium fluoride (NaF) on BV2 cells was assessed using Cell Counting Kit-8 (CCK-8), crystal violet, and 5-ethynyl-2'-deoxyuridine (EdU) staining. Cell cycle progression and apoptosis were evaluated through flow cytometry and western blotting. Reactive oxygen species (ROS) levels, oxidative stress, and inflammatory markers were measured by ROS staining, microplate reader assays, and western blotting. The role of SIRT1 in fluoride-induced toxicity for glial cells was determined using the SIRT1 activator SRT1720. The experiments demonstrated that NaF was toxic to BV2 cells, inhibited their proliferative ability, halted their cell cycle progression, triggered cellular apoptosis, promoted cellular oxidative stress (detected by ROS, SOD, MDA, GSH-Px, T-AOC) and associated protein NQO-1 and HO-1, and elevated inflammatory mediator associated protein IL-1and IL-6 expression). The fluoride-exposed groups had reduced SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein expression levels, and increased FOXO1A protein expression. SRT1720 mitigated the harmful effects of NaF, stimulated cell proliferation and cell cycle progression, decreased apoptosis, reduced oxidative stress and inflammatory factors, elevated SIRT1, BDNF, TrkB, PI3K, AKT, and MAPK protein levels, and suppressed FOXO1A protein expression. The results indicate that NaF potentially harms glial cells by suppressing SIRT1 activation, and SIRT1 significantly mitigated the damage. Furthermore, the SIRT1 signaling pathway might regulate the nerve damage caused by fluoride poisoning and may be a protective factor in treating fluoride-induced brain injury.

Investigating metabolic characteristics of type 2 diabetes mellitus-related cognitive dysfunction and correlating therapeutic effects of Di Dang Tang in animal models.

Di Dang Tang is a classic formula from Shang Han Lun, originally used to treat conditions such as blood stasis and heat accumulation. It is widely applied in the treatment of diabetes and its complications, but its effects on Type 2 Diabetes Mellitus-related Cognitive Dysfunction (T2DM-CD) remain unclear. The study aimed to investigate the metabolic characteristics of patients with T2DM-CD. Additionally, it sought to evaluate the effects of Di Dang Tang on cognitive function in T2DM-CD model rats by targeting the metabolic pathways identified in the clinical analysis, exploring the underlying mechanisms through animal experiments. Fasting venous serum was collected from patients with Type 2 Diabetes Mellitus (T2DM) to detect metabolism-related products, and KEGG annotation analysis was performed. Separately, thirty rats were randomly divided using a random number table method, with six rats selected as the blank control group. Twenty-four successfully modeled rats were then randomly divided into the model group and three Di Dang Tang groups (low, medium, and high doses). After administering the medication, the relevant indicators in the rats were assessed. Clinical metabolomics detected 32 key differential metabolites between the T2DM-CD and the blank control groups. Between the T2DM-CD and T2DM groups, 29 key differential metabolites were identified. In animal experiments, blood glucose levels in the model group were significantly higher compared to the blank control group at the same time points, whereas the high dose groups of Di Dang Tang exhibited reduced blood glucose levels at weeks 6 and 8 relative to the model group. In the Morris water maze test, the model group had longer escape latencies than the blank control group. The medium and high dose groups of Di Dang Tang showed shorter latencies. Additionally, compared to the model group, the Di Dang Tang groups spent more time and covered more distance in the target quadrant but had reduced average proximity and fewer platform entries. HE staining observation of the hippocampal CA1 area showed no apparent pathological changes in the blank group, obvious pathological damage in the model group, and no significant pathological changes in the medium and high dose groups of Di Dang Tang. Compared to the blank control group, the model group showed significant increases in the levels of Arachidonic Acid (AA), Ceramide (Cer), Glutamate (Glu), TNF- α, IL-1β, TG, and LDL-C, and a significant decrease in HDL-C levels. Compared to the model group, the groups of Di Dang Tang significantly modulated the levels of the above indicators. In Western Blot (WB) assays, compared to the blank control group, the model group rats exhibited significantly higher levels of cPLA2, PKC, ERK, and JNK , and significantly lower levels of claudin-5, NMDA, CaMKII, CREB, and BDNF. The Di Dang Tang groups significantly altered the levels of the above indicators compared to the model group. Amino acid metabolism, sphingolipid signaling pathways, glycerophospholipid metabolism, and various signaling pathways play significant roles in the pathogenesis of T2DM-CD. Di Dang Tang can improve learning and memory abilities in T2DM model rats and ameliorate cognitive impairments, potentially by regulating metabolic levels and inflammatory responses.

Dose-Dependent Effect of a New Biotin Compound in Hippocampal Remyelination in Rats.

Demyelination is commonly observed in neurodegenerative disorders, including multiple sclerosis (MS). Biotin supplementation is known to stabilize MS progression. To reduce the effective dose of biotin, we synthesized a new and superior form of biotin, a complex of magnesium ionically bound to biotin (MgB) and compared its dose-dependent effect with biotin alone after inducing demyelination using lysolecithin (LPC) in rats. Myelination was assessed using luxol fast blue staining and immunostaining against MBP protein, revealing that the most significant remyelination occurred in the MgB groups. Additionally, both biotin and MgB-treated animals showed dose-dependent improvements in spatial memory. Moreover, we detected a decrease in inflammatory proteins in both treatment groups, which was more prominent in high-dose MgB-treated animals and correlated with decreased expression of NF-κB p65, OP, and MMP-9 proteins. Further analysis of biotin-related proteins demonstrated that both biotin and, notably, MgB reversed the demyelination-dependent reduction of these proteins. Furthermore, biotin, particularly MgB, improved neuronal transmission proteins, Synapsin-1, PSD-93, and PSD-95. Additionally, both treatment groups exhibited increased BDNF, GAP43, and ICAM levels, with significant increments observed in high-dose MgB-treated animals. Increased GFAP, indicative of reactive gliosis, was observed in LPC-treated animals, and this effect was notably reversed by high-dose MgB treatment. The current data emphasize the dose-dependent beneficial effect on the remyelination process. Furthermore, the combination of biotin with Mg resulted in a more potent effect compared to biotin by itself. The strong influence of MgB encourages proof-of-concept studies using MgB in patients with MS.

BDNF levels in serum and CSF are associated with clinicoradiological characteristics of aggressive disease in MS patients

BackgroundBDNF has increasingly gained attention as a key molecule controlling remyelination with a prominent role in neuroplasticity and neuroprotection. Still, it remains unclear how BDNF relates to clinicoradiological characteristics particularly at the early stage of the disease where precise prognosis for the further MS course is crucial.MethodsBDNF, NfL and GFAP concentrations in serum and CSF were assessed in 106 treatment naïve patients with MS (pwMS) as well as 73 patients with other inflammatory/non-inflammatory neurological or somatoform disorders using a single molecule array HD-1 analyser. PwMS were evaluated for highly active profiles by applying the aggressive disease course criteria proposed by ECTRIMS. Serum/CSF values were logarithmically transformed and compared across groups using one-way ANOVA, while correlations were calculated using Pearson’s correlations. ROC analysis and AUC comparisons for diagnostic performance of the three biomarkers were computed in an explorative analysis.ResultsSerum BDNF (sBDNF) concentrations were higher in treatment naïve pwMS with disease onset after the age of 40 years (p = 0.029), in pwMS with ≥2 gadolinium-enhancing lesions (p = 0.009) and with motor, cerebellar, cognitive or sphincter symptoms at onset (p = 0.036). BDNF correlated positively with NfL (r = 0.198, p = 0.014) and GFAP (r = 0.253, p = 0.002) in serum, but not in CSF. Neurological patients with an acute inflammatory relapse showed significantly higher sBDNF levels (p = 0.03) compared to somatoform controls, while patients without acute relapse did not differ from somatoform controls (p = 0.4). Better diagnostic performance was found for sBDNF than sNfL and sGFAP in differentiating between patients with vs. without 2 or more gadolinium-enhancing lesions (p < 0.05) and for sBDNF as compared to sNfL for separating patients with disease onset after vs. before age of 40 years.ConclusionIn pwMS, BDNF serum levels differ depending on disease-related characteristics, suggesting that not only inflammatory activity but also remyelination capacities may vary with disease severity. BDNF is increased when other biomarkers of neuroaxonal damage and neurodegeneration, such as NfL and GFAP, are elevated, possibly as a compensatory mechanism, and reflect possibly further pathophysiological aspects in MS beyond NfL and GFAP, probably including an apoptotic role for BDNF in neuroinflammation.

Circadian rhythm disruptions exacerbate inner ear damage in a murine endolymphatic hydrops model.

Meniere's disease (MD) is an inner ear disease characterized by endolymphatic hydrops (EH). Maintaining a regular daily routine is crucial for MD patients. However, the relationship between circadian rhythms and MD remains unclear. Therefore, we investigated the effect of circadian rhythm on endolymphatic hydrops and its underlying mechanisms. Mice with endolymphatic hydrops were subjected to chronic jet lag (CJL) conditions to simulate the MD patients under circadian rhythm disruptions. We assessed whether this disruption would exacerbate inner ear damage with endolymphatic hydrops. RNA-seq of the inner ear and bioinformatic analysis were performed. Then, the expression of PER2, AQP2, AQP4, AQP5, and BDNF were assessed, and the morphological changes were evaluated in the inner ear. Our findings showed circadian rhythm disruption affected the cochlear internal clock genes in the inner ear, particularly in mice with EH. EH mice under CJL conditions exhibited exacerbated hearing impairment and an increased severity of EH. GO enrichment analysis revealed that the regulation of fluid homeostasis and neurotransmitter release at synapses were significantly enriched. Disruption of circadian rhythms disturbed the expression pattern of PER2, reduced BDNF levels, and affected the expression of aquaporins in the cochlea. Moreover, the disruption of circadian rhythm compromised inner hair cell synapses and auditory nerve fibers. This study indicated that disruption of circadian rhythms may exacerbate inner ear damage in endolymphatic hydrops mice by affecting the aquaporins and compromising synapses and auditory nerves in the inner ear. BDNF and PER2 may play a central role in these pathophysiological processes.

The impact of the interaction between BDNF rs7103411 gene polymorphism and social activities on mild cognitive impairment in community-dwelling elderly adults.

To investigate the correlation between BDNF gene polymorphism, BDNF levels, and susceptibility to mild cognitive impairment (MCI). In this study, we investigated 107 elderly adults individuals from a community in Zhongshan, Guangdong Province, with an average age of 73.17 ± 7.081 years. The participants included 52 patients with Mild Cognitive Impairment due to Alzheimer's Disease and 55 cognitively normal elderly adults control subjects. The two groups were matched based on gender, age, and education level. We assessed their cognitive functions and analyzed their genotypes and serum BDNF levels. Analysis of covariance (ANCOVA) was used to evaluate the differences in serum BDNF levels between the MCI group and the control group. Multivariate linear regression was utilized to analyze the association between BDNF levels and susceptibility to MCI, as well as cognitive functions. Multivariate logistic regression was employed to investigate the association between BDNF gene polymorphisms and the risk of developing MCI, along with their interactions. The ANCOVA analysis indicated that there was no significant difference in serum BDNF levels between the MCI group and the control group (P > 0.05). Correlation analysis revealed a negative correlation between Mini-Mental Status Examination (MMSE) total scores and MCI (r = -0.461, P = 0.001), with significant correlations observed in orientation (r = -0.420, P = 0.002). Multiple linear regression analysis showed that specific polymorphisms, including rs7103411 (CT+TT vs. CC), rs6265 (CT and CT+TT vs. CC), rs11030104 (AG and AG+GG vs. AA), and rs988748 (CG+CC vs. GG), were significantly associated with decreased serum BDNF levels (P < 0.05). Multivariate logistic regression showed that rs7103411 polymorphism was associated with susceptibility to MCI; individuals with the CT or CC genotype had a 0.370 times lower risk of developing MCI compared to those with the TT genotype (OR = 0.370, 95% CI: 0.141-0.970, P = 0.043). A significant interaction was found between rs7103411 and social activity, which influenced the risk of developing MCI. Specifically, individuals with the CT or TT genotype of rs7103411 who engaged in social activities had a significantly lower risk of developing MCI (OR = 0.32, 95% CI: 0.117-0.878, P = 0.027). This study indicates that BDNF rs7103411、rs6265、rs11030104 and rs988748 are associated with decreased serum BDNF levels in MCI patients. Individuals carrying the TT genotype in the BDNF rs7103411 gene are associated with an increased susceptibility to MCI. Individuals with the rs7103411 CT or TT genotype who participated in social activities showed a significantly reduced risk of developing MCI, suggesting that the interaction between the BDNF rs7103411 genotype and social activity can help reduce the risk of MCI.