Brain-derived Neurotrophic Factor Expression Research Articles

Investigating the influence of estrous cycle-dependent hormonal changes on neurogenesis in adult mice

ObjectiveNeurogenesis is the process of generating new neurons from neural stem cells (NSCs) in the adult brain. Sex hormones play an essential role in the development of the brain. The aim of this study was to evaluate the neurogenic changes in the brain at different phases of the estrous cycle in adult mice. Materials and methodsFemale NMRI mice were divided into four groups: 1- Estrous, 2- Proestrous, 3- Metestrous, and 4- Diestrous. Different stages of the estrous cycle were determined by staining of vaginal smears. The level of estrogen, progesterone, prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) hormones was evaluated by the enzyme-linked immunosorbent assay (ELISA) method. The expression of brain-derived neurotrophic factor) BDNF), nerve growth factor (NGF), ciliary neurotrophic factor(CNTF)) genes in hippocampal and the expression of glial fibrillary acidic protein (GFAP) in subventricular zone (SVZ) tissue were evaluated. ResultsThe serum estrogen and FSH increased significantly in Proestrous group (p < 0.001). Also, progesterone and prolactin hormones were significantly increased in the Diaestrus group (p < 0.001). The expression levels of BDNF, NGF, and CNTF significantly increased in the hippocampal tissue of Proestrous and Diaestrus groups (p < 0.001). The number of GFAP+ cells in SVZ of the Proestrous and Diestrous groups had a significant increase (p < 0.05, p < 0.01, p < 0.001). ConclusionOur data showed that Changes in sex hormones, especially estrogen in the estrous cycle, can cause the production of new neurons and astrocytes in the hippocampus and SVZ. Therefore, the increase in neurotrophic factors in the Proestrus and Diestrus leads to neurogenesis in adult mice brains.

Functional neurological disorder and gut microbiome: Casual or causal relationship?

Functional neurological disorder (FND), or conversion disorder, is a psychosomatic condition that affects the voluntary motor and/or sensory functions of the patient. Its origin is not yet fully understood, but the main risk factors related to this disorder include exposure to recent psychological stressors and previous experience of aversive episodes during childhood, such as abuse, family dysfunction, and neglect. The symptoms of FND result from complex interactions involving the central nervous system and also the endocrine and immune systems. In this work, we hypothesized the relationship between the gut microbiome and the pathophysiology of FND because both share several common features, such as the effects of neurotransmitters, the hippocampal expression of brain-derived neurotrophic factor, and the inflammatory responses. Based on these common aspects, we suggested that stress, gut microbiome, and inflammation factors induce chronic and systemic inflammation of the brain causing neurological disorders, including FND. More specific studies are warranted to validate the casual or causal relationship between FND and the gut microbiome.

Accelerated BDNF expression in visceral white adipose tissues following high-fat diet feeding in mice.

Brain-derived neurotrophic factor (BDNF) is expressed in the white adipose tissues (WATs), and the expression increases during high-fat diet (HFD) feeding, implicating its role in obesity. Here, we focused on BDNF expression in epididymal WAT (eWAT), a visceral adipose tissue, in mice. During 2 weeks of HFD feeding, Bdnf mRNA expression in eWAT slightly increased, but a robust increase was observed after 8 weeks of HFD feeding. This upregulation of Bdnf mRNA was correlated with significant induction of hypoxia-inducible factor 1α (Hif1α) and platelet-derived growth factor subunit B (Pdgfb) mRNA in eWAT following 8 weeks of HFD feeding. Furthermore, the increased expression of the M1 macrophage markers was strongly correlated with the elevation of Bdnf mRNA in the eWAT. Notably, 8 weeks of HFD feeding significantly elevated Tnfα mRNA expression in eWAT, while no such induction was observed in inguinal WAT (iWAT). In contrast, the expression of Adipoq (adiponectin), implicated in improved insulin sensitivity and anti-inflammatory effects, was significantly upregulated in iWAT, but not in eWAT. Thus, our study may show the role of BDNF in eWAT in obesity models, potentially contributing to the pathological state of visceral adipose tissues.

The extracellular vesicle of depressive patient-derived Escherichia fergusonii induces vagus nerve-mediated neuroinflammation in mice

BackgroundGut microbiota dysbiosis is closely associated with psychiatric disorders such as depression and anxiety (DA). In our preliminary study, fecal microbiota transplantation from volunteers with psychological stress and subclinical symptoms of depression (Vsd) induced DA-like behaviors in mice. Escherichia fergusonii (Esf) was found to be more abundant in the feces of Vsd compared to healthy volunteers. Therefore, we investigated the effect of Esf on DA-like behavior and neuroinflammation in mice with and without celiac vagotomy.Methods and resultsOrally gavaged Esf increased DA-like behaviors, tumor necrosis factor (TNF)-α, and toll-like receptor-4 (TLR4) expression, and NF-κB+Iba1+ and lipopolysaccharide (LPS)+Iba1+ cell populations, while decreasing serotonin, 5-HT1A receptor, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex. However, celiac vagotomy attenuated Esf-induced DA-like behavior and neuroinflammation. Orally gavaged extracellular vesicle (EV) from Vsd feces (vfEV) or Esf culture (esEV) induced DA-like behavior and inflammation in hippocampus, prefrontal cortex and colon. However, celiac vagotomy attenuated vfEV- or esEV-induced DA-like behaviors and inflammation in the brain alone, while vfEV- or esEV-induced blood LPS and TNF-α levels, colonic TNF-α expression and NF-κB-positive cell number, and fecal LPS level were not. Although orally gavaged fluorescence isothiocyanate-labeled esEV was translocated into the blood and hippocampus, celiac vagotomy decreased its translocation into the hippocampus alone.ConclusionsesEVs may be translocated into the brain via the vagus nerve and bloodstream, subsequently inducing TNF-α expression and suppressing serotonin, its receptor, and BDNF expression through the activation of TLR4-mediated NF-κB signaling, thereby contributing to DA pathogenesis.

Zeaxanthin and Lutein Ameliorate Alzheimer's Disease-like Pathology: Modulation of Insulin Resistance, Neuroinflammation, and Acetylcholinesterase Activity in an Amyloid-β Rat Model.

Alzheimer's disease (AD) is characterized by impaired insulin/insulin-like growth factor-1 signaling in the hippocampus. Zeaxanthin and lutein, known for their antioxidant and anti-inflammatory properties, have been reported to protect against brain damage and cognitive decline. However, their mechanisms related to insulin signaling in AD remain unclear. This study investigated the efficacy and mechanisms of zeaxanthin, lutein, and resveratrol in modulating an AD-like pathology in an amyloid-β rat model. Rats were administered hippocampal infusions of 3.6 nmol/day amyloid-β (Aβ)(25-35) for 14 days to induce AD-like memory deficits (AD-CON). Normal control rats received Aβ(35-25) (Normal-CON). All rats had a high-fat diet. Daily, AD rats consumed 200 mg/kg body weight of zeaxanthin (AD-ZXT), lutein (AD-LTN), and resveratrol (AD-RVT; positive-control) or resistant dextrin as a placebo (AD-CON) for eight weeks. The AD-CON rats exhibited a higher Aβ deposition, attenuated hippocampal insulin signaling (reduced phosphorylation of protein kinase B [pAkt] and glycogen synthase kinase-3β [pGSK-3β]), increased neuroinflammation, elevated acetylcholinesterase activity, and memory deficits compared to the Normal-CON group. They also showed systemic insulin resistance and high hepatic glucose output. Zeaxanthin and lutein prevented memory impairment more effectively than the positive-control resveratrol by suppressing acetylcholinesterase activity, lipid peroxidation, and pro-inflammatory cytokines (TNF-α, IL-1β). They also potentiated hippocampal insulin signaling and increased brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CTNF) mRNA expression to levels comparable to the Normal-CON rats. Additionally, zeaxanthin and lutein improved glucose disposal, reduced hepatic glucose output, and normalized insulin secretion patterns. In conclusion, zeaxanthin and lutein supplementation at doses equivalent to 1.5-2.0 g daily in humans may have practical implications for preventing or slowing human AD progression by reducing neuroinflammation and maintaining systemic and central glucose homeostasis, showing promise even when compared to the established neuroprotective compound resveratrol. However, further clinical trials are needed to evaluate their efficacy and safety in human populations.

Ameliorating Effect of Standardized Rice Bran Supplement on Depressive-Like Behaviors in Ovariectomized Mice.

Menopausal depression, often associated with hormonal fluctuations such as decreased estrogen levels, imposes significant mental health burdens. Despite the antidepressant biological properties of standardized rice bran supplement (RBS), its impact on menopausal depression and underlying mechanisms remains largely unexplored. In this study, we investigated the antidepressant effects of RBS in a mouse model of estrogen deficiency-induced depression. Ovariectomized (OVX) mice received oral doses of RBS (250 and 1000 mg/kg) and 17β estradiol over a 20-week period. RBS administration resulted in decreased immobility time in the tail suspension and forced swim tests, along with increased locomotor activity in the open field test. Furthermore, RBS enhanced nitric oxide production and neuronal nitric oxide synthase (nNOS) expression in the hippocampi of OVX mice. Additionally, RBS administration phosphorylated extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and tropomyosin receptor kinase B and increased the protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. These findings suggest that RBS alleviated depressive behaviors in OVX mice by augmenting hippocampal nNOS expression and activating the ERK-CREB-BDNF signaling pathway. Therefore, based on these results, we propose that RBS is a promising agent to treat menopausal depression, a challenging condition.

Anti-NMDAR1 antibody impairs dendritic branching in immature cultured neurons.

Anti-N-methyl D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by IgG antibodies targeting NMDAR. The prevalence is remarkably higher in women and some develop the condition during pregnancy. While immunotherapies have shown good outcomes for pregnant mothers and their infants, the impact on early neurodevelopment remains elusive. This study investigates the effects of anti-NMDAR antibody on the development of primary cortical cultures. Anti-NMDAR antibody was administered to the cultures at day in vitro 5 for the following 5 days to assess dendritic branching and arbor complexity, and at day in vitro 14 for measuring the expression of brain-derived neurotrophic factor (BDNF) and synaptic proteins. Immature cultured neurons treated with anti-NMDAR antibody exhibited impaired dendritic branching and arbor complexity. Interestingly, BDNF expression was unaffected in mature neurons. Additionally, GluN1 expression, a mandatory NMDAR subunit, was significantly reduced, while no significant alterations were observed in PSD-95, gephyrin and synaptophysin expression. These findings shed light on the structural and synaptic impacts of anti-NMDAR antibody on immature neurons, providing evidence for their consequences in early neuronal development.

Exploring the impact of acetylsalicylic acid and conditioned medium obtained from mesenchymal cells, individually and in combination, on cognitive function, histological changes, and oxidant-antioxidant balance in male rats with hippocampal injury.

The hippocampus is susceptible to damage, leading to negative impacts on cognition. Conditioned medium (CM) obtained from adipose tissue-derived mesenchymal stem cells (MSCs) and acetylsalicylic acid (ASA) have shown neuroprotective effects independently. This study explored the synergistic potential of ASA and CM from adipose-derived MSCs against hippocampal injury. Adult male Wistar rats received bilateral hippocampal ethidium bromide (EB) injections to induce hippocampal damage. Rats were treated with ASA and/or CM derived from adipose tissue MSCs every 48h for 16 days. Behavioral tests (open field test, Morris water maze, novel object recognition, and passive avoidance), oxidative stress, Western blot analysis of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) expression, and hippocampal histological investigation were conducted. Administration of EB caused impairments in spatial, recognition, and passive avoidance memory, as well as heightened oxidative stress, reduced BDNF/CDNF expression, and pyramidal cell loss in the hippocampal CA1 region. Administration of ASA, CM, or a combination of both mitigated these hippocampal damages and cognitive deficits, elevated BDNF and CDNF levels, and alleviated the CA1 necrosis caused by EB. Moreover, co-administering ASA and CM resulted in greater improvements in spatial memory compared to administering ASA alone, suggesting possible synergistic interactions. The ability of ASA, CM obtained from adipose tissue-derived MSCs, and their combination therapy to alleviate hippocampal injuries highlights their promising therapeutic potential as a neuroprotection strategy against brain damage. Our findings provide preliminary evidence of the potential synergistic effects of ASA and CM, which warrants further investigations.

Modulation of Brain-derived Neurotrophic Factor Expression by Physical Exercise in Reserpine-induced Pain-depression Dyad in Mice.

Pain accompanied by depressive symptoms is a common reason for seeking medical assistance, and many chronic pain patients experience comorbid depression. The brain-derived neurotrophic factor (BDNF) is a well-known neurotrophin expressed throughout the nervous system, playing a crucial role in neuronal growth and neuroplasticity. This study aimed to examine the effects of exercise on BDNF expression in the nervous system and reserpine (RSP)-induced pain-depression dyad. RSP (1 mg/kg) was subcutaneously administered once daily for three days in mice. The exercise was performed using a rota-rod tester for seven consecutive days following RSP administration. Pain responses were evaluated using von Frey filaments, and depression-like behaviors were assessed through forced swimming and open field tests. Immunofluorescence staining was performed to examine the changes in BDNF expression in the dorsal root ganglion (DRG), spinal cord, and hippocampus. Administration of RSP reduced mechanical paw withdrawal threshold, increased immobility time in the forced swimming test, and decreased movement in the open field test. The immunoreactivity of BDNF was increased in the DRG and spinal dorsal regions, and decreased in the hippocampus after RSP administration. Physical exercise significantly reduced the RSP-induced mechanical hypersensitivity and depression-like behaviors. In addition, exercise suppressed not only the increased expression of BDNF in the DRG and spinal dorsal regions but also the decreased expression of BDNF in the hippocampus induced by RSP administration. These findings suggest that repetitive exercise could serve as an effective and non-invasive treatment option for individuals experiencing both pain and depression by modulating BDNF expression.

Coenzyme Q10 ameliorates cyclophosphamide-induced chemobrain by repressing neuronal apoptosis and preserving hippocampal neurogenesis: Mechanistic roles of Wnt/ β-catenin signaling pathway

Deterioration in the neurocognitive function of cancer patients referred to as “Chemobrain” is a devastating obstacle associated with cyclophosphamide (CYP). CYP is an alkylating agent, clinically utilized as an efficient anticancer and immunosuppressant. Coenzyme Q10 (CoQ10) is a worthwhile micronutrient with diverse biological activities embracing antioxidant, anti-apoptotic, and neuroprotective effects. The current experiment was designed for investigating the neuroprotective capability of CoQ10 versus CYP-elicited chemobrain in rats besides elucidating the causal molecular mechanisms. Male Sprague Dawley rats received CoQ10 (10 mg/kg, orally, once daily, for 10 days) and/or a single dose of CYP (200 mg/kg i.p. on day 7). CoQ10 counteracted CYP-induced cognitive and motor dysfunction as demonstrated by the findings of neurobehavioral tests (passive avoidance, Y maze, locomotion, and rotarod tests). Histopathological analysis further affirmed the neuroprotective abilities of CoQ10. CoQ10 effectually diminished CYP-provoked oxidative injury by restoring the antioxidant activity of catalase (CAT) enzyme while reducing malondialdehyde (MDA) levels. Besides, CoQ10 efficiently repressed CYP-induced neuronal apoptosis by downregulating the expression of Bax and caspase-3 while upregulating the Bcl-2 expression. Moreover, CoQ10 hampered CYP-provoked upregulation in acetylcholinesterase (AChE) activity. Furthermore, CoQ10 considerably augmented hippocampal neurogenesis by elevating the expressions of brain-derived neurotrophic factor (BDNF) and Ki-67. These promising neuroprotective effects can be credited to upregulating Wnt/β-catenin pathway as evidenced by the elevated expressions of Wnt-3a, β-catenin, and Phoshpo-glycogen synthase kinase-3 β (p-GSK-3β). Collectively, these findings proved the neuroprotective capabilities of CoQ10 against CYP-induced chemobrain through combating oxidative injury, repressing intrinsic apoptosis, boosting neurogenesis, and eventually upregulating the Wnt/β-catenin pathway.

Repurposing Anakinra for Alzheimer's Disease: The In Vitro and In Vivo Effects of Anakinra on LPS- and AC-Induced Neuroinflammation.

Alzheimer's disease is a significant global health issue, and studies suggest that neuroinflammation plays a vital role in the advancement of this disease. In this study, anakinra has been shown to display a time- and concentration-dependent antineuroinflammatory effect. In the in vitro studies, it diminished the gene expressions of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) synthase 2 stimulated by lipopolysaccharide (LPS). Anakinra also reduced the LPS-induced production of NO and reactive oxygen species. Thus, the hypertrophic state of LPS-activated BV2 microglial cells was reversed by anakinra. Furthermore, acrylamide (ACR)-induced activation of nuclear transcription factor-κB, TNF-α, and interleukin-1β was downregulated, while cAMP response element binding protein and brain-derived neurotrophic factor expression levels were markedly enhanced in ACR-treated zebrafish larvae. It was also observed that anakinra improved the uncoordinated swimming behaviors in ACR-exposed zebrafish larvae. Overall, anakinra demonstrated potential antineuroinflammatory and antioxidative effects.

Faecalibacterium prausnitzii, FOS and GOS loaded synbiotic reverses treatment-resistant depression in rats: Restoration of gut-brain crosstalk

Alterations in commensal gut microbiota, such as butyrate-producing bacteria and its metabolites, have been linked to stress-related brain disorders, including depression. Herein, we investigated the effect of Faecalibacterium prausnitzii (ATCC-27766) administered along with fructooligosaccharides (FOS) and galactooligosaccharides (GOS) in a rat model of treatment-resistant depression (TRD). The behavioral changes related to anxiety-, anhedonia- and despair-like phenotypes were recorded employing elevated plus maze, sucrose-preference test, and forced-swim test, respectively. Rats exposed to unpredictable chronic mild-stress (UCMS) and adrenocorticotropic hormone (ACTH) injections exhibited a TRD-like phenotype. Six-week administration of F. prausnitzii and FOS + GOS ameliorated TRD-like conditions in rats. This synbiotic treatment also restored the decreased levels of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate in the fecal samples of TRD rats. Synbiotic-recipient TRD rats displayed an increased abundance of Lactobacillus helveticus, Lactobacillus hamsteri, and Ruminococcus flavefaciens. Moreover, more mucus-producing goblet cells were seen in the colon of synbiotic-treated rats, suggesting improved gut health. The synbiotic treatment effectively modulated neuroinflammation by reducing proinflammatory cytokines (IFN-γ, TNF-α, CRP, and IL-6). It normalized the altered levels of key neurotransmitters such as serotonin, gamma-aminobutyric acid, noradrenaline, and dopamine in the hippocampus and/or frontal cortex. The enhanced expression of brain-derived neurotrophic factor, tryptophan hydroxylase 1, and serotonin transporter-3 (SERT-3), and reduced levels of indoleamine 2,3-dioxygenase 1 (IDO-1) and kynurenine metabolite were observed in the synbiotic-treated group. We suggest that F. prausnitzii and FOS + GOS-loaded synbiotic may reverse the TRD-like symptoms in rats by positively impacting gut health, neuroinflammation, neurotransmitters, and gut microbial composition.

Kappa Opioid Receptor Activation Induces Epigenetic Silencing of Brain-Derived Neurotropic Factor via HDAC5 in Depression.

Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of Bdnf transcripts II, IV, and Bdnf CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, norbinaltorphimine. Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at Bdnf II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, norbinaltorphimine. Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of Bdnf expression in the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.

Developing a novel hypothesis to enhance mental resilience via targeting Faecalibacterium prausnitzii in gut-brain axis

Social stress (SS) can lead to mental disorders (MD) in some people, such as depression and anxiety, while others who are resilient can handle SS without showing signs of mental illness. Resilience is characterized by human capacity to adapt to life’s adverse events without losing function or developing a mental disorder. Exploring molecular processes can help elucidate resilience mechanisms that counteract the pathophysiology of depression. Gut microbiome plays an essential role in the homeostasis of human body, especially the central nervous system (CNS). Therefore, it may support the counterbalance of certain disorders, such as depression, through the microbiota-gut-brain (MGB) axis. Short-chain fatty acids (SCFAs) produced by the gut microbiota, such as butyrate, increase the transmission activity of neurotransmitters, brain-derived neurotrophic factor (BDNF) expression and the regulation of microglia maturation enhances resilience in response to stress. Probiotics can be engineered to yield more butyrate. However, the overproduction of SCFAs is not necessarily beneficial and may lead to known side effects, such as intestinal dysbiosis or metabolic dysfunction. Herein, as we hypothesized the potential effect of the microbiome in resilience promotion, we have designed a cortisol-sensitive operon that allows gut microbiota to regulate the production of SCFAs according to the environmental demands which produces butyrate only when responding to stress. Amongst gut bacteria, Faecalibacterium prausnitzii (F. prausnitzii) has large amounts of butyrate and can be manipulated by designed plasmid, a process which makes it a suitable candidate to be translated into clinic.

A study on factors related to sleep disorders and serum BDNF expression levels in patients with primary Sjӧgren's syndrome.

We aimed to assess the sleep quality of patients with primary Sjögren's syndrome (pSS) and the associated factors. Moreover, Preliminary exploration of the clinical significance of serum brain-derived neurotrophic factor (BDNF) in pSS patients with sleep disorders. A self-report survey was administered to 111 pSS patients and 40 healthy individuals using the Pittsburgh Sleep Quality Index (PSQI) for sleep quality. General clinical information,the sleep quality and mental conditions were collected using on-site questionnaires and various scales. 40 healthy controls from the health examination center of the same hospital, who were age and sex matched. Detection of serum BDNF levels by ELISA method . Independent samples t tests, Chi-square analysis, logistic regression were used to analyze these data. Patients with pSS had higher scores on the PSQI than the healthy individuals. Abnormal sweating, high PHQ-9 and ESSPRI scores were independent risk factors for sleep disorders. pSS patients had lower serum BDNF than the healthy individuals, The area under the curve (AUC) of predicting sleep disorder in pSS patients using detection of serum BDNF level was 0.8470, and the sensitivity and specificity were 0.951 and 0.727, which were superior to PHQ-9 and GAD-7. Compared with the healthy individuals, pSS patients had a higher prevalence of sleep disorders and lower serum BNDF. Serum BDNF level demonstrated greater predictive advantage for sleep disorder in pSS patients.

Role of Lactobacillus plantarum-Derived Extracellular Vesicles in Regulating Alcohol Consumption.

Alcohol Use Disorder (AUD), characterized by repeated alcohol consumption and withdrawal symptoms, poses a significant public health issue. Alcohol-induced impairment of the intestinal barrier results in alterations in intestinal permeability and the composition of the intestinal microbiota. Such alterations lead to a reduced relative abundance of intestinal lactic acid bacteria. However, the role of gut microbiota in alcohol consumption is not yet fully understood. In this study, we explore the mechanism by which gut microbiota regulates alcohol consumption, specifically using extracellular vesicles derived from Lactobacillus plantarum (L-EVs). L-EVs were administered to Sprague-Dawley rats either through intraperitoneal injection or microinjection into the ventral tegmental area (VTA), resulting in a significant reduction in alcohol consumption 72 hours after withdrawal. The observed reduction was akin to the effect of an intra-VTA microinjection of Brain-Derived Neurotrophic Factor (BDNF). Intriguingly, the microinjection of K252a (a Trk B antagonist) into the VTA blocked the reducing effect of L-EVs on alcohol consumption. The intraperitoneal injection of L-EVs restored the diminished BDNF expression in the VTA of alcohol-dependent rats. Furthermore, L-EVs rescued the low BDNF expression in alcohol-incubated PC12 cells. In conclusion, our study demonstrates that L-EVs attenuated alcohol consumption by enhancing BDNF expression in alcohol-dependent rats, thus suggesting the significant therapeutic potential of L-EVs in preventing excessive alcohol consumption.

Prophylactic effects of Tibetan goat kefir on depression-like behaviors in chronic unpredictable stress model through the gut-brain axis.

Depression is a common psychological disorder, and traditional therapeutic drugs often result in side effects such as emesis, dry mouth, headache, dysentery and constipation. Probiotics and goat milk have garnered widespread attention for their ability to modulate immune function and regulate the endocrine system, and for their anti-inflammatory effects. In this work, the effects of Tibetan goat kefir on the behavior, immune status, neuroendocrine response and gut microbiological composition of chronic unpredictable mild stress (CUMS) mouse models were evaluated. The results indicated that Tibetan kefir goat milk significantly alleviated behavioral despair in mice. Furthermore, the results demonstrated that Tibetan kefir goat milk mitigated the inflammatory response in the mice and moderated the hyperactivity of the hypothalamic-pituitary-adrenal axis and the expression of brain-derived neurotrophic factor. Meanwhile, chronic stress-induced gut microbial abnormalities were restored. In addition, the correlation between gut microbiota and nervous system was evaluated. These results explained the potential mechanism of Tibetan kefir in the antidepressant effect on the CUMS model and enriched diets for depressed patients. © 2024 Society of Chemical Industry.

Platelet-rich plasma protects hippocampal neurons and memory functions in a rat model of vascular dementia.

Platelet-rich plasma (PRP) is a promising biomaterial rich in bioactive growth factors, offering potential as a therapeutic agent for various diseases. However, its effectiveness in central nervous system disorders like vascular dementia (VaD) remains underexplored. This study investigated the potential of PRP to mitigate VaD progression in vivo. A rat model of VaD was established via bilateral common carotid artery occlusion and hypovolemia operation. Rats were randomly assigned to receive either PRP or platelet-poor plasma (PPP)-the latter being a byproduct of PRP preparation and used as a reference standard-resulting in the groups designated as 'operated group (OP)+PRP' and 'OP+PPP', respectively. PRP or PPP (500 μl) was administered intraperitoneally on the day of the operation and postoperative days 2, 4, 6, and 8. Cognitive function was assessed using the Y-maze, Barnes maze, and passive avoidance tests. On postoperative day 8, hippocampal samples were subjected to histological and semi-quantitative analyses. OP exhibited significant memory decline compared to controls, while the 'OP+PRP' group showed notable improvement. Histological analysis revealed increased neuronal loss and neuroinflammation in OP hippocampi, mitigated in 'OP+PRP'. Semi-quantitative analysis showed decreased expression of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) in OP, restored in 'OP+PPP' and further in 'OP+PRP'. These results highlight PRP's protective effects against VaD-induced hippocampal damage and cognitive impairment, partially attributed to BDNF/TrkB pathway upregulation.

Green Tea Polyphenol Nanoparticles Reduce Anxiety Caused by Tobacco Smoking Withdrawal in Rats by Suppressing Neuroinflammation.

Repeated exposure to tobacco smoke causes neuroinflammation and neuroplasticity, which correlates with smoking withdrawal-induced anxiety. The purpose of this study was to investigate the anticipated involvement of antioxidant-rich nanoparticles (NPs) prepared by oxidation-triggered polymerization of green tea catechins in impacting these effects in a rat model of tobacco smoke exposure. Exposure to tobacco smoke was carried out for 2 h a day, 5 days a week, for a total of 36 days. Weekly behavioral tests were conducted prior to recommencing the exposure. Following a 20-day exposure period, rats were administered either distilled water or green tea (GT) NPs (20 mg/kg, orally) for an additional 16 days. Our findings revealed that tobacco smoke exposure induced anxiety-like behavior indicative of withdrawal, and this effect was alleviated by GT NPs. Tobacco smoke exposure caused a marked increase in the relative mRNA and protein expression of nuclear factor-kappa B (NF-κB) and reduced the relative mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus (HIP) and hypothalamus (HYP) brain subregions. The intervention of GT NPs effectively inhibited these effects. Our findings demonstrate the potent protective role of GT NPs in reducing withdrawal-induced anxiety-like behavior, neuroinflammation, and neuroplasticity triggered by tobacco smoke exposure.

Ketamine alleviates PTSD-like effect and improves hippocampal synaptic plasticity via regulation of GSK-3β/GR signaling of rats

BackgroundEach year, 3–4% of the global population experiences post-traumatic stress disorder (PTSD), a chronic mental disorder with significant social and economic repercussions. Although it has been shown that ketamine can effectively alleviate PTSD symptoms in individuals, the specific mechanism of action underlying its anti-PTSD effects remains unclear. In this study, we investigated how a single, low dose of ketamine affected the glycogen synthase kinase 3β (GSK-3β)/glucocorticoid receptor (GR) signaling pathway in a single prolonged stress (SPS)-induced PTSD rat model. MethodsAfter establishing the model, stress-related behavioral alterations in the rats were assessed following intraperitoneal injections of ketamine (10 mg/kg) and GSK-3β antagonist SB216763 (5 mg/kg). In the hippocampus, alterations in the expression of specific proteins implicated in PTSD development, such as GR, brain-derived neurotrophic factor (BDNF), GSK-3β, and phosphorylated glycogen synthase kinase 3β (p-GSK-3β), were assessed. We also measured changes in the mRNA expression levels of GR, BDNF, GSK-3β, FK501 binding protein 51 (FKBP5), and corticotropin-releasing hormone (CRH), as well as synaptic ultrastructure, in the hippocampus, and measured changes in corticosterone levels in the blood. ResultsSPS induced anxiety-like and depression-like behaviors in rats and induced morphological changes in synapse, which were accompanied by higher GSK-3β protein expression and conversely, decreased expression of GR, BDNF, p-GSK-3β, FKBP5 and CRH. Intraperitoneal administration of ketamine (10 mg/kg) after SPS prevented SPS-induced anxiety-like behaviors. Most importantly, ketamine attenuated SPS-induced dysfunctions in GSK-3β/GR signaling and synaptic deficits. Furthermore, treatment with a GSK-3β inhibitor played the same effect as ketamine on behavioral changes of SPS model rats. ConclusionSingle doses of ketamine effectively ameliorate SPS-induced anxiety-like symptoms, potentially by improving synaptic plastic in the hippocampus by regulating GSK-3β/GR signaling.