Brain-derived Neurotrophic Factor Research Articles

Bibliometric analysis of research on spinal cord and sacral neuromodulation in spinal cord injury.

Qualitative studies. Spinal cord injury (SCI) is one of the most devastating injuries to the central nervous system that places a major burden on society. Neuromodulation technology involving spinal cord stimulation (SCS) and sacral nerve modulation (SNM) is a promising technique for patients with SCI. However, there has been no bibliometric analysis of research in this field to date. Not applicable. Systematic analyses of countries, institutions, authors, journals, co-cited documents, keywords, genes and diseases were performed. Related gene and disease data from the citexs platform were also reviewed. A total of 7437 articles on SCS and SNM in SCI were retrieved from the Web of Science database. The search time was limited to 1985-01-01 to 2022-12-31. We identified a significant increase in research output on SCS and SNM in SCI in recent years, with a concentrated period of high publication activity. Multiple publications were identified on neuropathic pain, electronic stimulation, TNF, BDNF and STAT3 gene expression, indicating that complications and potential therapeutic strategies for SCI are a key focus in the field. Our study provides insights that may help to advance scientific research and potentially improve outcomes in patients with SCI.

Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression

BackgroundDepression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood.MethodsPeriodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques.ResultsUltrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls.ConclusionsThe combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation.Graphical

Effectiveness of Tri-Kaysorn-Mas Extract in Ameliorating Cognitive-like Behavior Deficits in Ovariectomized Mice via Activation of Multiple Mechanisms.

Postmenopausal women have a higher probability of experiencing cognitive alterations compared to men, suggesting that the decline in female hormones may contribute to cognitive deterioration. Thailand traditionally uses Tri-Kaysorn-Mas (TKM), a blend of three medicinal herbs, as a tonic to stimulate appetite and relieve dyspepsia. Due to its antioxidant and anti-acetylcholinesterase activities, we investigated the effects of TKM (50 and 100 mg/kg/day, p.o., for 8 weeks) on cognitive deficits and their underlying causes in an ovariectomized (OVX) mouse model of menopause. OVX mice showed cognitive impairment in the Y-maze, novel object recognition task (NORT), and Morris water maze (MWM) behavioral tests, along with atrophic changes to the uterus, altered levels of serum 17β-estradiol, and down-regulated expression of estrogen receptors (ERα and ERβ). These behavioral effects were reversed by TKM. TKM decreased malondialdehyde (MDA) levels and mitigated oxidative stress in the brain by enhancing the activity of superoxide dismutase (SOD) and catalase (CAT) and by up-regulating the antioxidant-related gene Nrf2 while down-regulating Keap1. TKM also counteracted OVX-induced neurodegeneration by enhancing the expression of the neurogenesis-related genes BDNF and CREB. The results indicate that TKM extract alleviates oxidative brain damage and neurodegeneration while enhancing cognitive behavior in OVX mice, significantly improving cognitive deficiencies related to menopause/ovariectomy through multiple targets.

Comparison of Neural Recovery Effects of Botulinum Toxin Based on Administration Timing in Sciatic Nerve-Injured Rats.

This study aimed to assess the effects of the timing of administering botulinum neurotoxin A (BoNT/A) on nerve regeneration in rats. Sixty 6-week-old rats with a sciatic nerve injury were randomly divided into four groups: the immediately treated (IT) group (BoNT/A injection administered immediately post-injury), the delay-treated (DT) group (BoNT/A injection administered one week post-injury), the control group (saline administered one week post-injury), and the sham group (only skin and muscle incisions made). Nerve regeneration was assessed 3, 6, and 9 weeks post-injury using various techniques. The levels of glial fibrillary acid protein (GFAP), astroglial calcium-binding protein S100β (S100β), growth-associated protein 43 (GAP43), neurofilament 200 (NF200), and brain-derived neurotrophic factor (BDNF) in the IT and DT groups were higher. ELISA revealed the highest levels of these proteins in the IT group, followed by the DT and control groups. Toluidine blue staining revealed that the average area and myelin thickness were higher in the IT group. Electrophysiological studies revealed that the CMAP in the IT group was significantly higher than that in the control group, with the DT group exhibiting significant differences starting from week 8. The findings of the sciatic functional index analysis mirrored these results. Thus, administering BoNT/A injections immediately after a nerve injury is most effective for neural recovery. However, injections administered one week post-injury also significantly enhanced recovery. BoNT/A should be administered promptly after nerve damage; however, its administration during the non-acute phase is also beneficial.

Neuroinflammatory Biomarkers and Their Associations With Cognitive, Affective, and Functional Outcomes 3 to 12 Months After a Traumatic Brain Injury: A Pilot Study.

Neuroinflammation is an important feature of traumatic brain injury (TBI) that remains poorly understood in the 3- to 12-month period post-TBI. The purpose of our pilot study was to examine the relationships between biomarkers of neuroinflammation and functional outcomes in TBI patients 3 to 12months postinjury. TBI patients (n =36) 3 to 12months post-TBI were recruited from a South Florida TBI clinic from May 2022 to June 2023. The Disability Rating Scale, Satisfaction with Life Scale, NIH Toolbox Sorting Working Memory, Neuro-Quality of Life Cognitive Function, Anxiety, Depression, and Sleep assessments were performed. Multiple plasma biomarkers were assayed. Analysis of variance was used to compare between-group results. Linear regression was performed to analyze relationships between biomarkers and outcomes. Brain-derived neurotrophic factor concentrations were higher as postinjury time interval increased and were associated with cognitive battery outcomes. S-100β and glial fibrillary acidic protein were associated with anxiety score and hospital length of stay; S-100β was also associated with depression. Interleukin 6 was associated with cognitive function score and time since injury. We found S-100β, glial fibrillary acidic protein, Interleukin 6, and brain-derived neurotrophic factor to play a larger role in the TBI recovery period than other biomarkers examined. Clinicians should continue to monitor for symptoms post-TBI, as the neuroinflammatory process continues to persist even into the later rehabilitation stage.

Evidence for the Contribution of the miR-206/BDNF Pathway in the Pathophysiology of Depression.

Depression is a complex disorder with substantial impacts on individual health and has major public health implications. Depression results from complex interactions between genetic and environmental factors. Epigenetic mechanisms, including DNA methylation, microRNAs (miRNAs), and histone modifications, can produce heritable phenotypic changes without a change in DNA sequence and recently were proven to mediate lasting increases in the risk of depression following exposure to adverse life events. Of these, miRNAs are gaining attention for their role in the pathogenesis of many stress-associated mental disorders, including depression. One such miRNA is microRNA-206 (miR-206), which is a critical candidate for increasing the susceptibility to stress. Although miR-206 is thought to be a typical muscle-specific miRNA, it is expressed throughout the brain, particularly in the hippocampus and prefrontal cortex. Until now, only a few studies have been conducted on rodents to understand the role of miR-206 in stress-related abnormalities in neurogenesis. However, the precise underlying molecular mechanism of miR-206-mediated depression-like behaviors remains largely unknown. Here, we reviewed recent advances in the field of biomedical and clinical research on the role of miR-206 in the pathogenesis of depression from studies using different tissues and various experimental designs and described how abnormalities in miR-206 expression in these tissues can affect neuronal functions. Moreover, we focused on studies investigating the brain-derived neurotrophic factor (BDNF) as a functional target of miR-206, where miR-206 has been implicated in the pathogenesis of depression by suppressing the expression of the BDNF. In summary, these studies confirm the existence of a tight correlation between the pathogenesis of depression and the miR-206/BDNF pathway.

Regulation and Crosstalk of Cells and Factors in the Pancreatic Cancer Microenvironment.

Pancreatic cancer is a highly malignant form of cancer that distinguishes itself from other gastrointestinal tumors through significant fibrosis and unique perineural invasion. These characteristics underscore the complexity of neural regulation within the pancreatic cancer Tumor Microenvironment (TME). This review aimed to explore the regulatory mechanisms and crosstalk among stromal cells and their factors within the pancreatic cancer microenvironment. We begin by reviewing the major components of the pancreatic cancer microenvironment, analyzing interactions among crucial cell types, such as Cancer-associated Fibroblasts (CAFs) and immune cells, and revealing the dynamic changes between tumor cells and surrounding nerves, immune, and stromal cells. We discuss the role of neural factors, including the Nerve Growth Factor (NGF) and Brain-derived Neurotrophic Factor (BDNF), in the progression of pancreatic cancer and the mechanisms by which the sympathetic and parasympathetic nervous systems regulate tumor cell growth, migration, and invasion. Interactions among stromal cells, cytokines, and neural factors in the pancreatic cancer microenvironment promote fibrosis and perineural invasion. A deeper understanding of the regulation and crosstalk among components in the pancreatic cancer microenvironment offers new perspectives for inhibiting fibrosis and perineural invasion in pancreatic cancer.

KIT-13, a novel plasmalogen derivative, attenuates neuroinflammation and amplifies cognition.

Plasmalogens (Pls) are specialized phospholipids integral to brain health, whose decline due to aging and stress contributes to cognitive impairment and neuroinflammation. This study explores the potential of a novel Pls derivative, KIT-13 (1-O-octadecyl-2-arachidonoyl-sn-glycerol-3-phosphoethanolamine), in mitigating neuroinflammation and enhancing cognition. When administered to mice, KIT-13 exhibited potent memory enhancement attributed to upregulated brain-derived neurotrophic factor (BDNF), a key player in cognitive processes. In vitro experiments with neuronal cells revealed KIT-13's ability to induce robust cellular signaling, surpassing natural plasmalogens. KIT-13 also promoted neurogenesis and inhibited apoptosis of neuronal-like cells, highlighting its potential in fostering neuronal growth and plasticity. Additionally, KIT-13 treatments reduced pro-inflammatory cytokine expression and attenuated glial activation in the brain. KIT-13's superior efficacy over natural Pls positions it as a promising therapeutic candidate for neurodegenerative conditions such as Alzheimer's disease, characterized by cognitive decline and neuroinflammation. This study presents KIT-13 as an innovative approach for addressing cognitive impairment and neuroinflammatory pathologies.

The Effects of Red Palm Oil, Koja Bay Leaves, and Passion Fruit Seeds Formulation on Antioxidant Activity, Antihyperlipidemia, BDNF, and Lipase Enzyme Activity on Sprague-Dawley Rats.

Local wisdom food ingredients in North Sumatra, Indonesia, are a source of phenolics which have antioxidant, antihyperlipidemia, neuronal survival, and growth. Administering products with antioxidant properties can provide a supporting effect in preventing inflammation and neurodegenerative process. The main objective of this study was to analyze the formulation of red palm oil (Elaeis guineensis Jacq), koja bay leaves (Murraya koenigii L Spreng), and passion fruit seeds (Passiflora edulis Sims) to improve lipid profile, antioxidant activity, Brain-Derived Neurotrophic Factor (BDNF), and lipase enzyme activity of Sprague-Dawley rats. This study was an in vivo and pre-post experimental study, starting with analyzing flavonoid of the three extract ingredients, then tested by giving it to rats for 14 days and ending with induction administration of lipopolysaccharide (LPS) for two days. This pre-post study on animals involved 36 rats divided into 6 groups. At the end of the study, termination and examination of malondialdehyde, lipid profile, glucose, BDNF, lipase enzyme activity and histopathological examination were carried out. The study results showed that there were significant values in several parameters, which were body weight, LDL, LDL/HDL ratio, BDNF, and lipase enzyme activity especially in the group of rats given LPS and the group with high calories-fat-protein. This study showed that there were significant differences in body weight, LDL levels, and LDL/HDL ratio in each group of rats, especially in the group given the formulation of the three extract ingredients, the significant dose showed in 300mg/kg body weight (p < 0.001). The formulation of red palm oil, koja bay leaves, and passion fruit seeds showed significant reduction in LDL levels, LDL/HDL ratio, BDNF, and lipase enzyme activity.

Cannabidiol Modulation of Nicotine‐Induced Toxicity: Assessing Effects on Behavior, Brain‐Derived Neurotrophic Factor, and Oxidative Stress in C57BL/6 Male Mice

ABSTRACTHigh doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds' potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain‐derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward. Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti‐inflammatory properties, among others. This work aims to examine the potential anxiety‐reducing properties of CBD in a well‐established experimental mouse model of anxiety‐like behavior induced by high doses of nicotine on male C57BL/6 mice. In this context, the open‐field behavioral test was specially conducted to assess CBD's effects on anxiety‐like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood's metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro‐inflammatory cytokine assessments were conducted to evaluate redox status and immune system function. Our research suggests that CBD shows potential in reducing anxiety‐like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue's systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro‐inflammatory cytokines (TNF‐alpha and IL‐6).

Neuroprotective Effects of Dehydroepiandrosterone and Hericium erinaceus in Scopolamine-induced Alzheimer's Diseases-like Symptoms in Male Rats.

The neuroprotective effects of Dehydroepiandrosterone (DHEA) and Hericium erinaceus (H. erinaceus) mushroom extract against scopolamine-induced Alzheimer's disease-like symptoms in male Wistar rats were investigated. Sixty-four male Wistar rats were divided into eight groups (n = 8). Scopolamine (SCO) was intraperitoneally injected at a dose of 1 mg/kg/day for 10 days. The treatment groups orally received DHEA (250 mg/kg/day) and/or H. erinaceus (300 mg/kg/day) for 14 days. Afterward, the Morris water maze (MWM) and novel object recognition tests were implemented. Then, animals were anesthetized and the brain tissue samples were separated. Levels of lipid peroxidation (LPO), total antioxidant capacity (TAC), catalase activity (CAT), and brain-derived neurotrophic factor (BDNF) were determined. Also, histopathological studies were evaluated in the brain tissue samples. Administration of SCO significantly decreased spatial and cognitive memory (p < 0.001). Not only did SCO injection significantly increase the levels of the LPO but also the SCO markedly reduced the levels of the TAC, CAT activity, and the BDNF in the brain tissue. On the other hand, a combination of the DHEA and H. erinaceus showed higher efficacy than the DHEA or H. erinaceus in attenuating behavioral anomalies and improving the antioxidant defense system and BDNF levels. Histological examination was well correlated with biochemical findings regarding SCO neurodegeneration and DHEA and/or H. erinaceus neuroprotection. Interestingly, ADHE and/or H. erinaceus may due to their potential neurotrophic properties be used as a new and beneficial concurrent therapy in the treatment of Alzheimer's disease-like symptoms caused by SCO.

Sex-specific associations of per- and polyfluoroalkyl substances with brain-derived neurotrophic factors (BDNF) in cord serum

Per- and polyfluoroalkyl substances (PFAS) is perceived as an emerging environmental endocrine disruptor, which have been linked to children neurodevelopment. However, the potential mechanisms are not clear. Brain-derived neurotrophic factor (BDNF) is a vital protein in neurodevelopment, and the associations between PFAS exposure and BDNF require exploration. We aimed to explore the relationships between PFAS exposure and the levels of BDNF in cord serum. A total of 1,189 mother-infant dyads from the Sheyang Mini Birth Cohort Study (SMBCS) were enrolled. The levels of 12 PFAS and BDNF were measured in cord serum. We utilized generalized linear models (GLMs), quantile-based g-computation (QGC) models, and Bayesian Kernel Machine Regression (BKMR) models to explore the relationships between single and mixed PFAS exposure and BDNF concentration. Additionally, the potential sex differences were explored by sex-stratified analysis. Median concentrations of the included 10 PFAS ranged from 0.04 to 3.97μg/L. In the single chemical models, four PFAS congeners, namely perfluorononanoic acid (PFNA), perfluorooctane sulfonic acid (PFOS), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), were negatively associated with BDNF levels in cord serum among females only (β: -0.116 to -0.062, p<0.05). In the BKMR models of total mother-infant dyads and female fetuses, the significant negative relationships between PFAS mixtures and BDNF were observed, and PFUnDA was identified as an important contributor (Posterior inclusion probability, PIP=0.8584 for the total subjects; PIP=0.8488 for the females). PFOS was another important driver based on the mixture approaches. We found that PFNA, PFOS, PFDA, and PFUnDA were associated with decreased BDNF concentration in the females, although the causal inference might be limited. PFAS mixtures were also negatively linked with BDNF levels in the total mother-infant pairs and female fetuses. The adverse effect of PFAS exposure on fetal BDNF levels might be sex-specific.

Activity in the dorsal hippocampus-mPFC circuit modulates stress-coping strategies during inescapable stress

Anatomical connectivity and lesion-deficit studies have shown that the dorsal and ventral hippocampi contribute to cognitive and emotional processes, respectively. However, the role of the dorsal hippocampus (dHP) in emotional or stress-related behaviors remains unclear. Here, we showed that neuronal activity in the dHP affects stress-coping behaviors in mice via excitatory projections to the medial prefrontal cortex (mPFC). The antidepressant ketamine rapidly induced c-Fos expression in both the dorsal and ventral hippocampi. The suppression of GABAergic transmission in the dHP-induced molecular changes similar to those induced by ketamine administration, including eukaryotic elongation factor 2 (eEF2) dephosphorylation, brain-derived neurotrophic factor (BDNF) elevation, and extracellular signal-regulated kinase (ERK) phosphorylation. These synaptic and molecular changes in the dHP induced a reduction in the immobility time of the mice in the tail-suspension and forced swim tests without affecting anxiety-related behavior. Conversely, pharmacological and chemogenetic potentiation of inhibitory neurotransmission in the dHP CA1 region induced passive coping behaviors during the tests. Transneuronal tracing and electrophysiology revealed monosynaptic excitatory connections between dHP CA1 neurons and mPFC neurons. Optogenetic stimulation of dHP CA1 neurons in freely behaving mice produced c-Fos induction and spike firing in the mPFC neurons. Chemogenetic activation of the dHP-recipient mPFC neurons reversed the passive coping behaviors induced by suppression of dHP CA1 neuronal activity. Collectively, these results indicate that neuronal activity in the dHP modulates stress-coping strategies to inescapable stress and contributes to the antidepressant effects of ketamine via the dHP-mPFC circuit.

Safety and Effectiveness of Acute Intermittent Hypoxia during a Single Treatment at Different Hypoxic Severities

PurposeExamine the cardiovascular, muscular function, cognitive, and neural plastic responses to determine the safety and effectiveness of acute Intermittent hypoxia (AIH) at a low, high, and control fractional inspired oxygen (FiO2) dosage MethodsThirteen human participants performed 30-min of AIH in 60-s intervals at FiO2’s of 0.21 (AIH21), 0.15 (AIH15), and 0.09 (AIH9). Heart rate variability (root mean squared of successive differences; RMSSD), heart rate, oxygen saturation (SpO2), blood pressure, muscular strength, neuromuscular activation, cerebral hemodynamic responses, cognition, symptomology, and brain-derived neurotrophic factor (BDNF) responses were measured before (Pre-AIH), after (post-AIH), and at 20-min of recovery (Recovery-AIH) ResultsThere were no differences between AIH protocols for heart rate, RMSSD, blood pressure, or SpO2. Muscular strength improved Post-AIH for AIH15 (10%) and AIH9 (14%) and remained elevated (6%) at Recovery-AIH. Neuromuscular activation increased Pre-AIH to Post-AIH for AIH15 (10%) and AIH9 (11%). Cerebral hemodynamic responses were not impacted between conditions. Both AIH15 and AIH9 increased BDNF Post-AIH (62%) and Recovery-AIH (63%) ConclusionAcute intermittent hypoxia is generally safe and effective at producing neural plastic responses, but further examination of co-occurring cardiovascular diseases is needed. This study provides safety focused findings which will widen the adoption and refinement of AIH protocols

Exploring the translational impact of type 1 diabetes on cerebral neurovascular function through ECoG-LSCI.

Type 1 diabetes mellitus (T1DM) can result in complications such as retinopathy, nephropathy, and peripheral neuropathy, which can lead to brain dysfunction. In this study, we investigated the effects of T1DM on cerebral neurovascular function in mice. Streptozotocin (STZ) is known to induce T1DM in animals; thus, we used an STZ-induced diabetes model to evaluate the effects of hyperglycemia on brain morphology and neurovascular tissue. Neurovascular coupling is the connection between neuronal activity and cerebral blood flow that maintains brain function. The ECoG-LSCI technique combines electrocorticography (ECoG) and laser speckle contrast imaging (LSCI) to detect cortical spreading depression (CSD) as a marker of neurovascular coupling and measure corresponding neurovascular function. Our results suggested that in the STZ group, hyperglycemia affected excitatory neurotransmission and metabolism, leading to reductions in intercellular signaling, somatosensory evoked potential (SSEP) amplitudes, and CSD transmission rates. Western blot data further revealed that brain-derived neurotrophic factor (BDNF) and neuronal nuclear antigen levels were reduced in the STZ group. Abnormalities in glucose metabolism in the brain and increased phosphorylation of AKT and GSK3 are hypothesized to be responsible for these decreases. Overall, this study highlights the importance of glucose metabolism in normal brain physiology and demonstrates that hyperglycemia disrupts neurovascular coupling and affects cerebral neurovascular function and that the degree of CSD is positively correlated with the extent of brain tissue damage. Further research is essential to gain a complete understanding of the related mechanisms and the implications of these findings.

Antidepressant effect of PT-31, an α₂-adrenoceptor agonist, on lipopolysaccharide-induced depressive-like behavior in mice.

Increasing evidence indicates that neuroinflammation, oxidative stress, and neurotrophic factors play a key role in the pathophysiology of major depressive disorder (MDD). In addition, the attenuation of inflammatory response has been considered a putative mechanism for MDD treatment. PT-31 is an imidazolidine derivative and a putative α₂-adrenoceptor agonist that has previously demonstrated antinociceptive activity. The present study aimed to investigate the effect of PT-31 on depressive-like behavior and lipopolysaccharide-induced neurochemical changes. To this end, mice received intraperitoneally saline or lipopolysaccharide (600 µg/kg), and 5 h postinjection animals were orally treated with saline, PT-31 (3, 10, and 30 mg/kg), or fluoxetine (30 mg/kg). Mice were subjected to the open field test (OFT) 6 and 24 h after lipopolysaccharide administration and to the tail suspension test (TST) 24 h postlipopolysaccharide. Subsequently, animals were euthanized, and brains were dissected for neurochemical analyses. The administration of lipopolysaccharide-induced sickness- and depressive-like behaviors, besides promoting an increase in myeloperoxidase activity and a reduction in brain-derived neurotrophic factor (BDNF) levels. Noteworthy, PT-31 3 mg/kg attenuated lipopolysaccharide-induced decreased locomotor activity 6 h after lipopolysaccharide in the OFT. All tested doses of PT-31 significantly reduced the immobility time of animals in the TST and attenuated lipopolysaccharide-induced increased myeloperoxidase activity in the cortex of mice. Our results demonstrate that PT-31 ameliorates behavioral changes promoted by lipopolysaccharide in OFT and TST, which is possibly mediated by attenuation of the inflammatory response.

Acupuncture for overactive bladder in adults: Study protocol for a randomized controlled trial

BackgroundOveractive bladder (OAB) is a prevalent condition that substantially degrades patient quality of life. Acupuncture is recognized as an effective therapeutic approach for various urological diseases. However, there is limited evidence validating the effectiveness and safety of acupuncture for OABs. ObjectiveTo assess the therapeutic efficacy of acupuncture for OAB and to investigate the potential mechanisms by analyzing its effects on relevant urinary biomarkers. MethodsThis is a randomized, participants and outcome assessors blinded, sham acupuncture controlled trial. A total of 110 patients with OABs will be randomly divided in a 1:1 ratio between the acupuncture and sham acupuncture groups. Participants in the acupuncture group will undergo 30-min authentic acupuncture, while their counterparts in the sham acupuncture group will undergo sham acupuncture needling non-acupoints superficially three times weekly for a duration of 8 weeks. The two co-primary outcomes will be the change in the mean number of micturitions per 24 h from baseline to the end of the 8-week treatment and 20-week follow-up. The secondary outcomes will encompass the change in Overactive Bladder Symptom Score, Overactive Bladder Questionnaire Short Form, and average 24 h values of urgency, daytime micturition, nocturia, and mean volume voided per micturition from baseline to weeks 8 and 20. Urinary nerve growth factor, brain-derived neurotrophic factor, and monocyte chemoattractant protein-1 levels will be measured at baseline and week 8. Adverse events will also be documented. DiscussionThe results of this trial provide evidence for the effectiveness and safety of acupuncture in the management of OAB.

Molecular and Functional Alterations in the Cerebral Microvasculature in an Optimized Mouse Model of Sepsis-Associated Cognitive Dysfunction.

Systemic inflammation has been implicated in the development and progression of neurodegenerative conditions such as cognitive impairment and dementia. Recent clinical studies indicate an association between sepsis, endothelial dysfunction, and cognitive decline. However, the investigations of the role and therapeutic potential of the cerebral microvasculature in sepsis-induced cognitive dysfunction have been limited by the lack of standardized experimental models for evaluating the alterations in the cerebral microvasculature and cognition induced by the systemic inflammatory response. Herein, we validated a mouse model of endotoxemia that recapitulates key pathophysiology related to sepsis-induced cognitive dysfunction, including the induction of an acute systemic hyperinflammatory response, blood-brain barrier (BBB) leakage, neurovascular inflammation, and memory impairment after recovery from the systemic inflammation. In the acute phase, we identified novel molecular (e.g., upregulation of plasmalemma vesicle-associated protein, PLVAP, a driver of endothelial permeability, and the procoagulant plasminogen activator inhibitor-1, PAI-1) and functional perturbations (i.e., albumin and small-molecule BBB leakage) in the cerebral microvasculature along with neuroinflammation. Remarkably, small-molecule BBB permeability, elevated levels of PAI-1, intra-/perivascular fibrin/fibrinogen deposition, and microglial activation persisted 1 month after recovery from sepsis. We also highlight molecular neuronal alterations of potential clinical relevance following systemic inflammation including changes in neurofilament phosphorylation and decreases in postsynaptic density protein 95 and brain-derived neurotrophic factor, suggesting diffuse axonal injury, synapse degeneration, and impaired neurotrophism. Our study serves as a standardized mouse model to support future mechanistic studies of sepsis-associated cognitive dysfunction and to identify novel endothelial therapeutic targets for this devastating condition.

Brain and Lung Biomarker Responses to Hyperoxic Hypobaric Decompression.

INTRODUCTION: Biomarker responses to intensive decompression indicate systemic proinflammatory responses and possible neurological stress. To further investigate responses, 12 additional brain and lung biomarkers were assayed.METHODS: A total of 15 healthy men (20 to 50 yr) undertook consecutive same-day ascents to 25,000 ft (7620 m), following denitrogenation, breathing 100% oxygen. Venous blood was sampled at baseline (T0), after the second ascent (T8), and next morning (T24). Soluble protein markers of brain and lung insult were analyzed by enzyme-linked immunosorbent assay with plasma microparticles quantified using flow cytometry.RESULTS: Levels of monocyte chemoattractant protein-1 and high mobility group box protein 1 were elevated at T8, by 36% and 16%, respectively, before returning to baseline. Levels of soluble receptor for advanced glycation end products fell by 8%, recovering by T24. Brain-derived neurotrophic factor rose by 80% over baseline at T24. Monocyte microparticle levels rose by factors of 3.7 at T8 and 2.7 at T24 due to early and late responses in different subjects. Other biomarkers were unaffected or not detected consistently.DISCUSSION: The elevated biomarkers at T8 suggest a neuroinflammatory response, with later elevation of brain-derived neurotrophic factor at T24 indicating an ongoing neurotrophic response and incomplete recovery. A substantial increase at T8 in the ratio of high mobility group box protein 1 to soluble receptor for advanced glycation end products suggests this axis may mediate the systemic inflammatory response to decompression. The mechanism of neuroinflammation is unclear but elevation of monocyte microparticles and monocyte chemoattractant protein-1 imply a key role for activated monocytes and/or macrophages.Connolly DM, Madden LA, Edwards VC, Lee VM. Brain and lung biomarker responses to hyperoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(9):667-674.

Activation of ACE2/Ang-(1–7)/Mas axis improves cognitive dysfunction induced by isoflurane in mice via inhibiting oxidative stress

BackgroundLong-term inhalation anesthesia is known to be associated with postoperative cognitive dysfunction. Our previous studies have confirmed that oxidative stress damage contributes to its mechanistic connection. Angiotensin-converting enzyme 2 (ACE2)/Angiotensin-(1–7)/Mas axis plays a crucial role in balancing the classic Renin-Angiotensin System (RAS) and regulating oxidative stress. This research aims to investigate the involvement of the ACE2/Angiotensin-(1–7)/Mas axis in the development of cognitive impairment induced by long-term isoflurane anesthesia. Methods3-month-old male C57BL/6 mice were randomly assigned to four groups: Control + Vehicle (C + Veh), Anesthesia + Vehicle (A + Veh), Control + Diminazene aceturate (C + DIZE), and Anesthesia + Diminazene aceturate (A + DIZE). Long-term isoflurane exposure was utilized to induce cognitive impairment. DIZE was administered intraperitoneally to mice 10 days prior to anesthesia to intervene ACE2. Cognitive function was administered using Y-maze and fear conditioning test. Flow Cytometry was used to measure the levels of ROS. Western blot was used to determine the expression levels of ACE2 and Mas, as well as the cognitive proteins such as phosphorylated N-methyl-D-aspartate receptor subtype 2B (p-NR2B) and Brain-Derived Neurotrophic Factor (BDNF). ResultsWe successfully constructed a long-term isoflurane anesthesia-mediated cognitive dysfunction model. Following long-term isoflurane anesthesia, there was a decrease in the levels of ACE2 and Mas in the hippocampus, accompanied by increased oxidative stress and significant cognitive impairment. Treatment with the ACE2 activator DIZE effectively restored the levels of ACE2 and Mas and decreased the content of ROS. Notably, DIZE treatment ameliorated cognitive dysfunction induced by long-term isoflurane exposure. ConclusionsThe findings suggest that the activation of the ACE2/Ang-(1–7)/Mas axis could reduce oxidative stress and improve cognitive impairment. ACE2/Ang-(1–7)/Mas axis may play a prophylactic role in mitigating isoflurane-induced cognitive decline and other cognitive impairments related to oxidative stress.