Brain-derived Neurotrophic Factor mRNA Levels Research Articles

High-Caloric Diets in Adolescence Impair Specific GABAergic Subpopulations, Neurogenesis, and Alter Astrocyte Morphology

We compared the effects of two different high-caloric diets administered to 4-week-old rats for 12 weeks: a diet rich in sugar (30% sucrose) and a cafeteria diet rich in sugar and high-fat foods. We focused on the hippocampus, particularly on the gamma-aminobutyric acid (GABA)ergic system, including the Ca2+-binding proteins parvalbumin (PV), calretinin (CR), calbindin (CB), and the neuropeptides somatostatin (SST) and neuropeptide Y (NPY). We also analyzed the density of cholinergic varicosities, brain-derived neurotrophic factor (BDNF), reelin (RELN), and cyclin-dependent kinase-5 (CDK-5) mRNA levels, and glial fibrillary acidic protein (GFAP) expression. The cafeteria diet reduced PV-positive neurons in the granular layer, hilus, and CA1, as well as NPY-positive neurons in the hilus, without altering other GABAergic populations or overall GABA levels. The high-sugar diet induced a decrease in the number of PV-positive cells in CA3 and an increase in CB-positive cells in the hilus and CA1. No alterations were observed in the cholinergic varicosities. The cafeteria diet also reduced the relative mRNA expression of RELN without significant changes in BDNF and CDK5 levels. The cafeteria diet increased the number but reduced the length of the astrocyte processes. These data highlight the significance of determining the mechanisms mediating the observed effects of these diets and imply that the cognitive impairments previously found might be related to both the neuroinflammation process and the reduction in PV, NPY, and RELN expression in the hippocampal formation.

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

Objective: Although the role of brain-derived neurotrophic factor (BDNF) in allergic rhinitis and/or nasal polyps (NPs) development has been studied, the contribution of BDNF in non-allergic NPs has not been evaluated yet. This study was to investigate the possible role of BDNF in non-allergic NPs pathogenesis.
 Methods: The study was carried out at The Second Hospital of Shandong University from December 2020 to November 2021. The non-allergic NPs patients (n=26) and the control group (n=22) were included. Lund-Mackay CT scores, nasal endoscopy scores, and pulmonary function testing were evaluated before surgery. Tissue and serum levels of BDNF, eosinophil cationic protein (ECP), and cytokeratins 5 (CK5) were assessed between different groups.
 Result: The BDNF level in serum and tissue, CK5 count, and eosinophil infiltration in tissue were higher in non-allergic NPs. The eosinophils infiltration, ECP mRNA expression level, as well as BDNF mRNA level were increased in the BDNFhigh subgroup compared with BDNFlow subgroup. Significantly negative correlations between BDNF count and the situation of airway obstruction were found in non-allergic NPs.
 Conclusion: BDNF may have both local and systemic effects in non-allergic NPs pathogenesis. BDNF may be a possible therapeutic target or an indicator for eosinophilic NPs management.
 doi: https://doi.org/10.12669/pjms.40.5.7907
 How to cite this: Zhou X, Zhang Q, Wan Y, Shi L. Up-regulation of systemic and local BDNF in non-allergic Nasal Polyps in China. Pak J Med Sci. 2024;40(5):---------. doi: https://doi.org/10.12669/pjms.40.5.7907
 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Total Saponins of Panax Notoginseng Modulate the Astrocyte Inflammatory Signaling Pathway and Attenuate Inflammatory Injury Induced by Oxygen- Glucose Deprivation/Reperfusion Injury in Rat Brain Microvascular Endothelial Cells.

Reperfusion after cerebral ischemia causes brain injury. Total saponins of Panax notoginseng (PNS) have potential roles in protecting against cerebral ischemia-reperfusion injury. However, whether PNS regulates astrocytes on oxygen-glucose deprivation/reperfusion (OGD/R) injury in rat brain microvascular endothelial cells (BMECs) and its mechanism still need further clarification. Rat C6 glial cells were treated with PNS at different doses. Cell models were established by exposing C6 glial cells and BMECs to OGD/R. Cell viability was assessed, and levels of nitrite concentration, inflammatory factors (iNOS, IL-1β, IL-6, IL-8, TNF-α), and oxidative stress-related factors (MDA, SOD, GSH-Px, T-AOC) were subsequently measured through CCK8, Grice analysis, Western blot, and ELISA, respectively. The co-cultured C6 and endothelial cells were treated with PNS for 24 hours before model establishment. Then transendothelial electrical resistance (TEER), lactate dehydrogenase (LDH) activity, brain-derived neurotrophic factor (BDNF) content, and mRNA and protein levels and positive rates of tight junction proteins [Claudin-5, Occludin, ZO-1] were measured by a cell resistance meter, corresponding kits, ELISA, RT-qPCR, Western blot, and immunohistochemistry, respectively. PNS had no cytotoxicity. PNS reduced iNOS, IL-1β, IL-6, IL-8, and TNF-α levels in astrocytes, promoted T-AOC level and SOD and GSH-Px activities, and inhibited MDA levels, thus inhibiting oxidative stress in astrocytes. In addition, PNS alleviated OGD/R injury, reduced Na-Flu permeability, and enhanced TEER, LDH activity, BDNF content, and levels of tight junction proteins Claudin-5, Occludin, ZO-1 in the culture system of astrocytes and rat BMECs after OGD/R. PNS repressed astrocyte inflammation and attenuated OGD/R injury in rat BMECs.

C-terminal peptide of preproorexin enhances brain-derived neurotrophic factor expression in rat cerebrocortical cells and recognition memory in mice

During the production of orexin A and B from preproorexin, a common precursor protein, in hypothalamic orexin neurons, C-terminal peptide (herein called preproorexin C-peptide) is concomitantly produced via post-translational processing. The predicted three-dimensional structure of preproorexin C-peptide is similar among mammalian species, suggestive of a conserved function in the mammalian brain. However, C-peptide has long been regarded as a non-functional peptide. We herein examined the effects of rat and/or mouse preproorexin C-peptide on gene expression and cell viability in cultured rat cerebrocortical cells and on memory behavior in C57BL/6J mice. Rat and mouse C-peptides both increased brain-derived neurotrophic factor (Bdnf) mRNA levels. Moreover, C-peptide enhanced high K+-, glutamate-, and BDNF-induced increases in Bdnf mRNA levels without affecting forskolin-induced Bdnf expression. H-89, a protein kinase A inhibitor, blocked C-peptide-induced Bdnf expression, whereas rolipram, a phosphodiesterase inhibitor, enhanced this effect. Intracellular cyclic AMP concentrations were elevated by C-peptide. These results demonstrate that preproorexin C-peptide promoted Bdnf mRNA expression by a cyclic AMP-dependent mechanism. Eleven amino acids at the N terminus of rat preproorexin C-peptide exerted similar effects on Bdnf expression as full-length preproorexin C-peptide. Preproorexin C-peptide also exerted protective effects against CoCl2-induced neuronal cell death. An intracerebroventricular injection of mouse preproorexin C-peptide induced c-fos and Bdnf expression in the cerebral cortex and hippocampus and enhanced novel object recognition memory in mice. Collectively, the present results show that preproorexin C-peptide is a functional substance, at least in some pharmacological and neuronal settings.

Upregulation of brain-derived neurotrophic factor by Shiikuwasha (Citrus depressa Hayata)

BackgroundA reduction in the brain-derived neurotrophic factor (BDNF) level in the brain causes depression, whereas an increase in its level has therapeutic benefits against depression. BDNF is synthesized in various peripheral tissues and transported to the brain via the peripheral circulation across the blood–brain barrier. Therefore, substances that upregulate peripheral BDNF level may be used to prevent and treat depression. Previously, we demonstrated that Citrus unshiu peel (Chinpi) and C. natsudaidai increased BDNF level in a human renal adenocarcinoma cell line ACHN, which has BDNF-producing ability. Here, we evaluated whether Shiikuwasha (C. depressa Hayata), a citrus species cultivated in East Asia, can upregulate BDNF level in ACHN cells.MethodsWe evaluated the effects of test samples on BDNF production by measuring BDNF level in the medium of ACHN cells after a 24 h cultivation in the presence of test samples. The BDNF mRNA level was measured by quantitative reverse transcription-polymerase chain reaction, and the phosphorylation level of cyclic adenosine monophosphate response element-binding protein (CREB), a transcription factor regulating BDNF expression, was determined using Western blotting.ResultsWe found that methanol extracts of Shiikuwasha peel, pulp, and seed increased the BDNF level in the culture medium of ACHN cells. Shiikuwasha peel and pulp extracts also upregulated BDNF mRNA level and phosphorylation of CREB.ConclusionsThese results suggest that Shiikuwasha includes the candidate antidepressant substances with peripheral BDNF-upregulation effect.

Sex difference affects fear extinction but not lithium efficacy in rats following fear-conditioning with respect to the hippocampal level of BDNF

In rodents, exposure to electrical shock and creating a strong fear memory using fear-conditioning model can induce PTSD-like behavior. In this study, we induced a fear-conditioning model in rats and investigated freezing (PTSD-like) behavior, 21 days after three shocks exposure (0.6 mA, 3 s, 30 seconds interval) in both male and female rats. Lithium was injected intraperitoneally (100 mg/kg) in three protocols: (1) 1 h after fear-conditioning (2) 1 h, 24 h, and 48 h after fear-conditioning (3), 1 h, 24 h, 48 h, 72 h, and 96 h after fear-conditioning. Extinction training (20 sounds without shocks, 75 dB, 3 s, 30 seconds interval) was performed in three protocols: (1) 1 h after fear-conditioning (one session), (2) 1 h, 24 h, and 48 h after fear-conditioning (three sessions), (3), 1 h, 24 h, 48 h, 72 h, and 96 h after fear-conditioning (five sessions). Forced swim test (FST) and hot plate were used to assess behavior. Results showed that lithium in all protocols had no effect on freezing behavior, FST, and pain subthreshold in all rats. Extinction training decreased freezing behavior, with more efficacy in females. In males, only 5-session training was effective, while in females all protocols were effective. Extinction training also altered pain perception and the results of FST, depending on the sessions and was different in males and females. Brain-derived neurotrophic factor (BDNF) mRNA level was increased in females following 3 and 5 sessions, and in males following 5 sessions extinction training. In conclusion, we suggested that there is a sex difference for the effect of extinction training on freezing behavior and BDNF mRNA level in a rat model of fear-conditioning.

Improving behavioral deficits induced by perinatal ethanol and stress exposure in adolescent male rat progeny via maternal melatonin treatment.

Early-life stressful situations and binge drinking have been thus far acknowledged as two burdensome conditions that potentially give rise to negative outcomes and then synergistically affect brain development. In this context, the hippocampus, with the greatest number of glucocorticoid receptors (GCRs) in the brain, is responsible for regulating negative responses to stress. Prolonged glucocorticoid (GC) exposure can accordingly cause oxidative stress (OS), leading to cognitive and emotional dysfunction. Against this background, melatonin, as a powerful antioxidant and hypothalamus-pituitary-adrenal (HPA) axis regulator, was administered in this study to ameliorate cognitive impairments induced by perinatal ethanol and stress exposure in adolescent male rat progeny. Wistar rat dams were exposed to ethanol (4 g/kg) and melatonin (10 mg/kg) from gestational day (GD) 6 to postnatal day (PND) 14 and then limited nesting material (LNS) from PND0 to PND14 individually or in combination. Maternal behavior was then investigated in mothers. Afterward, the plasma corticosterone (CORT) concentration, the OS marker, the corticotropin-releasing hormone receptor type 1 (CRHR1) expression, and the GCR and brain-derived neurotrophic factor (BDNF) levels were measured in the male pups. Moreover, behavioral tasks, including the elevated plus maze (EPM), the Morris water maze (MWM), the novel object recognition (NORT), and the object-location memory (OLM) tests were completed and assessed. The quantity and quality of maternal care significantly decreased in the mothers with dual exposure to ethanol and stress. The plasma CORT concentration in the progeny also dropped in the Ethanol + LNS group, but the risk-taking behavior elevated significantly. The ethanol and stress exposure further revealed a significant fall in the GCR and CRHR1 expression levels, compared with stress alone. The results of learning and memory tasks also indicated a significant reduction in spatial learning and memory among animals exposed to ethanol and stress. The BDNF mRNA levels correspondingly increased in the Ethanol + LNS group, compared with LNS alone. In the presence of ethanol and stress, the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities correspondingly declined. On the other hand, the malondialdehyde (MDA) levels augmented in the hippocampus of the animals with ethanol and LNS dual exposure, as compared with the control group. Melatonin treatment (MT) thus improved nursing behaviors in dams, prevented OS, enhanced the CRHR1 and GCR expression, and reduced the BDNF levels to the similar ones in the control group. The animals in the Ethanol + LNS + MT group ultimately showed an ameliorated performance at behavioral tasks, including the memory and risk-taking behavior. It was concluded that MT could prevent stress response and memory impairments arising from dual exposure to ethanol and stress by inhibiting OS.

Neurobehavioral impairments in ciprofloxacin- treated osteoarthritic adult rats.

<p>Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinolone-induced neurotoxic adverse events have been reported in a few case reports, all the preclinical studies on its neuropsychiatric side effects involved only healthy animals. This study firstly investigated the behavioral effects of CIP in an osteoarthritis rat model with joint destruction and pain, which can simulate inflammation-associated musculoskeletal pain. Furthermore, effects of CIP on regional brain-derived neurotrophic factor (BDNF) expression were examined given its major contributions to the neuromodulation and plasticity underlying behavior and cognition.&nbsp;</p>. <p>Fourteen days after induction of chronic osteoarthritis, animals were administered vehicle, 33 mg/kg or 100 mg/kg CIP for five days intraperitoneally. Motor activity, behavioral motivation, and psychomotor learning were examined in a reward-based behavioral test (Ambitus) on Day 4 and sensorimotor gating by the prepulse inhibition test on Day 5. Thereafter, the prolonged BDNF mRNA and protein expression levels were measured in the hippocampus and the prefrontal cortex.&nbsp;</p>. <p>CIP dose-dependently reduced both locomotion and reward-motivated exploratory activity, accompanied with impaired learning ability. In contrast, there were no significant differences in startle reflex and sensory gating among treatment groups; however, CIP treatment reduced motor activity of the animals in this test, too. These alterations were associated with reduced BDNF mRNA and protein expression levels in the hippocampus but not the prefrontal cortex.&nbsp;</p>. <p>This study revealed the detrimental effects of CIP treatment on locomotor activity and motivation/learning ability during osteoarthritic condition, which might be due to, at least partially, deficient hippocampal BDNF expression and ensuing impairments in neural and synaptic plasticity.</p>.

ABA Supplementation Rescues IRS2 and BDNF mRNA Levels in a Triple-Transgenic Mice Model of Alzheimer's Disease.

Insulin resistance underlies Alzheimer's disease (AD) by affecting neuroinflammation and brain-derived neurotrophic factor (BDNF) expression. Here, we evaluated the effect of early and late-start abscisic acid (ABA) intervention on hippocampal BDNF, tumor necrosis factor α (TNFα), and insulin receptors substrates (IRS) 1/2 mRNA levels in a triple-transgenic mice model of AD. Transgenic mice displayed lower BDNF and IRS2, equal IRS1, and higher TNFα expression compared to wild-type mice. Late ABA treatment could rescue TNFα and increased IRS1/2 expression. However, early ABA administration was required to increase BDNF expression. Our data suggests that early intervention with ABA can prevent AD, via rescuing IRS1/2 and BDNF expression.

High blood levels of brain-derived neurotrophic factor (BDNF) mRNA in early psychosis are associated with inflammatory markers

The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism (SNP) rs6265C > T, Val66Met, affects BDNF secretion and has been related to inflammatory processes. Both the rs6265 and BDNF protein levels have been widely investigated in neuropsychiatric disorders with conflicting results. In the present study we examined BDNF mRNA expression in blood considering the SNP rs6265 and its relationship with inflammatory markers in the early stages of psychosis. The rs6265 genotype and blood BDNF mRNA levels were measured in 34 at-risk mental states (ARMS) individuals, 37 patients with first-episode psychosis (FEP) and 42 healthy controls (HCs) by quantitative PCR and reverse transcription (RT)-qPCR using validated TaqMan assays. We also obtained measures of interleukin-6 (IL6) mRNA levels, fibrinogen, neutrophil-to-lymphocyte ratio (NLR) and high-sensitivity C-reactive protein. We identified that BDNF mRNA levels were associated with the rs6265 genotype in an allele-dose-dependent manner, with low expression levels associated with the T allele (Met substitution). Thus, we controlled for the rs6265 genotype in all analyses. Blood BDNF mRNA levels differed between diagnostic groups: patients with FEP exhibited higher blood BDNF mRNA levels than ARMS individuals, and the lowest levels were observed in HC. In addition, we observed significant correlations between BDNF mRNA levels and inflammatory markers (IL6 mRNA levels and NLR), controlled by the rs6265 genotype, in ARMS and FEP groups. This exploratory study suggests that the rs6265 genotype is associated with differential blood mRNA expression of BDNF that increases with illness progression and correlated with inflammation in the early stages of psychosis.

Chronic haloperidol administration downregulates select BDNF transcript and protein levels in the dorsolateral prefrontal cortex of rhesus monkeys.

Post-mortem studies in the prefrontal cortex and hippocampal formation from schizophrenia patients have revealed significant disruptions in the expression molecules associated with cytoarchitecture, synaptic structure, function, and plasticity, known to be regulated in part by brain derived neurotrophic factor (BDNF). Interestingly, several studies using postmortem brain tissue from individuals diagnosed with schizophrenia have revealed a significant reduction in BDNF mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC), hippocampus and related areas; however, differentiating the effects of illness from antipsychotic history has remained difficult. We hypothesized that chronic antipsychotic treatment may contribute to the altered BDNF mRNA and protein expression observed in post-mortem brains of individuals diagnosed with schizophrenia. To address the influence of antipsychotic administration on BDNF expression in the primate brain, rhesus monkeys orally administered haloperidol, clozapine, or vehicle twice daily for 180 days. We found BDNF splice variants 4 and 5 in the DLPFC and variant 2 in the EC were significantly down-regulated following chronic administration of haloperidol. In addition, proBDNF and mature BDNF expression in the DLPFC, but not the EC, were significantly reduced. Based on the known regulation of BDNF expression by BDNF-AS, we assessed the expression of this lncRNA and found expression was significantly upregulated in the DLPFC, but not EC. The results of the present study provide evidence of haloperidol-induced regulation of BDNF mRNA and protein expression in the DLFPC and suggest an important role for BDNF-AS in this regulation. Given the role of BDNF in synaptic plasticity, neuronal survival and maintenance, aberrant expression induced by haloperidol likely has significant ramifications for neuronal populations and circuits in primate cortex.

Synergistic therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) and voluntary exercise with running wheel in a rat model of ischemic stroke

BackgroundMesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke.MethodsWistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 105 cells/5 μl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups.ResultsSB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05).ConclusionsThis study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery and synergistically promotes endogenous neurogenesis and angiogenesis after cerebral ischemia, possibly through a mechanism involving the up-regulation of BDNF and VEGF.

Increase in Effect of Citrus natsudaidai on Brain-Derived Neurotrophic Factor.

The increase in brain-derived neurotrophic factor (BDNF) in the brain is beneficial for the treatment of depression, Alzheimer's disease (AD), and Parkinson's disease (PD); BDNF can cross the blood-brain barrier. Therefore, foods that elevate BDNF concentration in peripheral tissues may increase BDNF in the brain and thereby induce preventive and therapeutic effects against depression, AD, and PD. In this study, we aimed to determine whether Citrus natsudaidai extracts can increase BDNF concentration using the human kidney adenocarcinoma cell line ACHN, which has BDNF-producing and -secreting abilities. As test samples, methanol extracts of C. natsudaidai peel and pulp, and their n-hexane, ethyl acetate, n-butanol, and water fractions were prepared. The BDNF concentrations in culture medium of ACHN cells were assayed after 24 h cultivation in the presence of test samples. Compared with that of control (non-treated) cells, the BDNF concentration increased in the culture medium of ACHN cells treated with the methanol extract of C. natsudaidai peel and its hexane, butanol, and water fractions, as well as the butanol and water fractions of the pulp extract. Quantitative reverse transcription-polymerase chain reaction analysis revealed that ACHN cells treated with the butanol fractions of the peel and pulp extracts showed elevated levels of BDNF mRNA compared with those of non-treated cells. C. natsudaidai may increase BDNF concentration by acting on peripheral tissues and could be a medication for the prevention and treatment of depression, AD, and PD.

Heat shock factor HSF1 regulates BDNF gene promoters upon acute stress in the hippocampus, together with pCREB.

Heat shock factor 1 (HSF1) is a master stress-responsive transcriptional factor, protecting cells from death. However, its gene regulation in vivo in the brain in response to neuronal stimuli remains elusive. Here, we investigated its direct regulation of the brain-derived neurotrophic factor (BDNF) gene (Bdnf) in response to acute neuronal stress stimuli in the brain. The results of immunohistochemistry and chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) showed that administration of kainic acid (a glutamate receptor agonist inducing excitotoxity) to young adult mice induced HSF1 nuclear translocation and its binding to multiple Bdnf promoters in the hippocampus. Footshock, a physical stressor used for learning, also induced HSF1 binding to selected Bdnf promoters I and IV. This is, to our knowledge, the first demonstration of HSF1 gene regulation in response to neuronal stimuli in the hippocampus in vivo. HSF1 binding sites (HSEs) in Bdnf promoters I and IV were also detected when immunoprecipitated by an antibody of phosphorylated (p)CREB (cAMP-responsive element-binding protein), suggesting their possible interplay in acute stress-induced Bdnf transcription. Interestingly, their promoter binding patterns differed by KA and footshock, suggesting that HSF1 and pCREB orchestrate to render fine-tuned promoter control depending on the types of stress. Further, HSF1 overexpression increased Bdnf promoter activity in a luciferase assay, while virus infection of constitutively active-form HSF1 increased levels of BDNF mRNA and protein in vitro in primary cultured neurons. These results indicated that HSF1 activation of Bdnf promoter was sufficient to induce BDNF expression. Taken together, these results suggest that HSF1 promoter-specific control of Bdnf gene regulation plays an important role in neuronal protection and plasticity in the hippocampus in response to acute stress, possibly interplaying with pCREB.

Mast Cell Specific Receptor Mrgprb2 Regulating Experimental Colitis is Associated with the Microbiota-Gut-Brain Axis.

Ulcerative colitis (UC) patients have disturbances in the microbiota-gut-brain axis, and mast cells are important components of this axis. The mast cell-specific receptor Mrgprb2 has effects on host defense against bacterial infection and neurogenic inflammation, which may help mast cells act on the axis. This study analyzed how Mrgprb2 participates in the pathogenesis of UC by affecting the microbiota-gut-brain axis. Mrgprb2 knockout (b2KO) mice and wild-type (WT) mice were fed 2% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days, which was then replaced with normal water for 14 days. This cycle was repeated three times. Feces were collected on Days 21, 42, and 63 for intestinal microbiota analysis, and mice were euthanized on Day 64. Hypothalamus, amygdala and colon tissues were removed and analyzed. Compared with WT mice, B2KO mice exhibited increased weight loss, colon shortening and colonic pathological damage after colitis induction. Analysis of the intestinal microbiota showed that b2KO mice with colitis had a significant decrease in the abundance and diversity, as well as an increase in Allobaculum and a decrease in norank_f__Muribaculaceae and Ileibacterium. In colon tissues, the expression of mucin 2 (MUC2) and junctional adhesion molecule A (JAM-A) in b2KO mice was reduced, and oxidative stress levels were higher. B2KO mice with colitis had higher corticotropin-releasing hormone (CRH), corticotropin-releasing hormone receptor 1 (CRHR1), neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) mRNA levels in hypothalamus tissues and glucocorticoid receptor mRNA levels in the amygdala. In the microbiota-gut-brain axis, Mrgprb2 was involved in regulating the intestinal microbiota composition, intestinal barrier and oxidative stress levels, and was related to stress regulation, which might help to explain the pathogenesis of UC.

Biphasic Response of Astrocytic Brain-Derived Neurotrophic Factor Expression following Corticosterone Stimulation.

Novel research studies indicate multivarious interactions of glucocorticoid hormones (GCs) with the brain-derived neurotrophic factor (BDNF), regulating important aspects of neuronal cell physiology. While there is recent evidence of the chronic effects of GC stimulation on BDNF levels, as well as of the role of BDNF stimulation in the type of genomic effects following activation of GC-sensitive receptors, no data exist concerning the acute effects of GC stimulation on BDNF/TrkB gene expression. To address this question, we conducted a chrono-pharmacological study on rodent glial cells, astrocytes, which express the BDNF receptor, TrkB, following corticosterone administration. mRNA levels of BDNF and TrkB were estimated 1, 6, 12 and 24 h post-treatment. Selective inhibitors for GC-sensitive receptors and TrkB were used to decipher the molecular pathways of the effects observed. Our data support a biphasic response of BDNF expression after corticosterone stimulation. This response is characterized by a rapid TrkB phosphorylation-dependent upregulation of BDNF mRNA within the first hour, followed by a glucocorticoid receptor (GR)-dependent downregulation of BDNF mRNA, evident at 6, 12 and 24 h, with a direct impact on the protein levels of mature BDNF. Finally, a second pulse of corticosterone administration 1 h prior to the 6, 12 or 24 h timepoints normalized BDNF expression for the corresponding timepoint (i.e., mRNA levels became indifferent from baseline). These results present for the first time a biphasic regulation of the neurotrophin system based on glucocorticoid rhythmicity, further indicating complex trophic responses to temporal hormonal mechanisms in the brain microenvironment.

Study of the mechanism by which MSCs combined with LITUS treatment improve cognitive dysfunction caused by traumatic brain injury

Traumatic brain injury (TBI) substantially affects the quality of life of patients, and an effective therapy is unavailable. Previous studies have shown that mesenchymal stem cells (MSCs) and low-intensity transcranial ultrasound (LITUS) are effective treatments for neurological damage, inflammation, edema and cognitive impairment caused by TBI. However, it is unclear whether the combination of the two treatments exerts an additive effect. In this study, a rat TBI model was established using the controlled cortical impact (CCI) method. Neurological function was assessed by determining the rat modified neurological score (mNSS), and cognitive function was assessed using the Y-maze. Pathological changes in the injured tissue were observed using hematoxylin-eosin (HE) staining and immunohistochemistry (IHC), and western blot was performed to detect the expression levels of Nestin, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), growth-associated protein-43 (GAP-43), postsynaptic density protein (PSD-95), brain-derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), and aquaporin-4 (AQP-4). Real-time fluorescence quantitative polymerase chain reaction (RT–PCR) was performed to detect the expression levels of GAP-43, PSD-95, BDNF, TNF-α, and AQP-4 mRNA to investigate whether MSCs combined with LITUS exert an additive therapeutic effect of alleviating the cognitive dysfunction caused by TBI and the possible mechanisms involved. Rats exhibited cognitive dysfunction 28 days after TBI, and MSCs combined with LITUS treatment ameliorated the cognitive deficits caused by TBI via increasing Nestin, NSE, GAP-43, PSD-95, and BDNF expression and attenuating the inflammatory response and edema caused by TBI via reducing TNF-α and AQP-4 expression. According to these results, MSCs combined with LITUS is more effective than MSCs alone for the treatment of TBI, and the mechanism may be the promotion of neuronal proliferation and differentiation, and the attenuation of the inflammatory response and edema, which ameliorates the spatial learning memory impairment caused by TBI. MSCs combined with LITUS treatment represents a new approach for the clinical treatment of patients with TBI.

The role of MeCP2 and the BDNF/TrkB signaling pathway in the stress resilience of mice subjected to CSDS.

There is accumulating evidence to support the idea that brain-derived neurotrophic factor (BDNF) is involved in stress resilience. However, the precise molecular mechanisms underlying resilience in major depressive disorder (MDD) remain unknown. The objective of this study was to explore the role of methyl CpG binding protein 2 (MeCP2) and the BDNF/tropomyosin-receptor-kinase B (TrkB) signaling pathway in the stress resilience to chronic social defeat stress (CSDS) in mice. We found that the overexpression of MeCP2 inhibited BDNF transcription, resulting in BDNF mRNA and protein downregulation in neuro-2a cells. The overexpression of MeCP2 increased S80-MeCP2 and decreased S421-MeCP2, BDNF, the ratio of S133-cyclic AMP response element binding protein (CREB)/CREB and p-TrkB/TrkB expression in neuro-2a cells. In addition, using the CSDS mouse model, we found that MeCP2 mRNA levels were decreased in the medial prefrontal cortex (mPFC) of resilient mice and increased in the hippocampus of susceptible mice. BDNF exon IV promoter and BDNF mRNA levels were decreased in the mPFC and hippocampus of susceptible mice. Finally, MeCP2 and S80-MeCP2 protein levels were increased in the mPFC and hippocampus of susceptible mice, whereas the protein expression of S421-MeCP2 and BDNF, the ratio of S133-CREB/CREB, and the levels of p-TrkB/TrkB were decreased in susceptible mice. These data suggest that the overexpression of MeCP2 inhibits BDNF transcription in neuro-2a cells. The inhibition of MeCP2 expression and activation of the BDNF/TrkB signaling pathway may confer stress resilience in CSDS mice.

Panaxydol Derived from Panax notoginseng Promotes Nerve Regeneration after Sciatic Nerve Transection in Rats.

Peripheral nerve regeneration is a coordinated process of Schwann cell (SC) reprogramming and intrinsic neuronal growth program activation. Panaxydol (PND) is a strong biologically active traditional Chinese medicine monomer extracted from Panax notoginseng rhizomes. In vitro, PND protects neurons and SCs from injury and stimulates the expression and secretion of neurotrophic factors (NTFs) by SCs. We hypothesized that PND may also promote peripheral nerve regeneration in adult animals. PND (10 mg/kg body weight) was injected intraperitoneally into the Sprague-Dawley (SD) rats for two consecutive weeks after sciatic nerve transection. The morphology of the repaired sciatic nerve was evaluated after 16 weeks, and sensory and motor function recovery was evaluated using functional and behavioral techniques. PND was biologically safe at an injection dose of 10 mg/kg/day. After 14 days, it significantly increased the myelination of regenerated nerve fibers, and promoted sensory and motor function recovery. In the early stage of injury, PND significantly upregulated the mRNA expression of brain-derived neurotrophic factor (BDNF) and its receptors in distal injured nerves, which may represent a possible mechanism by which PND promotes nerve regeneration in vivo. Our study demonstrated that PND leads to sensory and motor recovery in a sciatic nerve transection model rat. Furthermore, we showed that BDNF mRNA level was significantly increased in the injured distal nerve, potentially contributing to the functional recovery. Further research is warrantied to examine whether direct injection is a more efficient method to increase BDNF expression compared to an exogenous BDNF administration.

AT1R‐mediated neurodegeneration is part of the etiology of hypertension‐associated cognitive impairment

Hypertension has now been closely associated to cognitive impairment, due to its contribution to cerebrovascular dysfunction. To investigate whether there is neuronal mechanism, hypertension was induced in C57BL/6j male mice (6 months) by DOCA‐salt treatment (1.5 mg/g, s.c., 28 days). Firstly, behavioral study, which contains object location behavioral task, novel object recognition, Barnes maze, and nesting score test, was performed to assess cognitive function, meanwhile, blood pressure (BP) was monitored by tail‐cuff device. In NT (non‐transgenic) mice, DOCA+1%NaCl increases BP significantly, before vs. after DOCA (systolic BP): 114.8 ±0.94 vs. 133.7 ±3.3 mmHg. In whole, compared to sham controls, the treated NT mice performed worse in all four behavioral tests, indicating cognition decline after DOCA‐salt treatment. Later, brain tissues were collected to evaluate possible degenerative alterations in neurons by transmission electron microscope (TEM) imaging, Golgi‐Cox staining, fluorescence‐activated cell sorting (FACS) and qRT‐PCR. It was shown via the TEM that DOCA‐salt hypertension induces mitochondrial damage and morphological changes in prefrontal cortical neurons, meanwhile, Golgi‐Cox staining revealed decreased numbers of dendritic spines, suggesting the onset of neurodegeneration in DOCA‐salt hypertension. In both prefrontal cortex and hippocampus, the mRNA levels of BDNF (brain‐derived neurotrophic factor) and PI4KIIIβ (phosphatidylinositol 4‐kinase IIIβ) were found to be significantly lower in hypertensive NT mice. Using FACS, neurons were sorted from those regions, then analyzed via qRT‐PCR, which identified that the downregulated expression of PI4KIIIβ takes place in neurons. Using laser speckle contrast imaging system, we detected only decreased functional hyperemia, but no impairment in basal cerebral blood flow of the hypertensive mice, suggesting that the neurodegeneration is not caused by cerebral ischemia. We previously demonstrated that neuronal angiotensin type 1 receptors (AT1R) plays a pivotal role in the maintenance of neurogenic hypertension, and here we hypothesized that activation of AT1R could also exacerbate hypertension‐induced reduction in neuronal function. Particularly, in the hippocampal CA1 of adult mice, treatment of angiotensin II (Ang‐II, 500 nM, bath application) induces a significant inhibition in the induction of long‐term potentiation (LTP), while pre‐treatment with losartan (5 μM, 15 min), the AT1R antagonist, can efficiently block this Ang‐II‐induced inhibition, supporting the involvement of neuronal AT1R. Indeed, in mice with selective deletion of neuronal AT1aR, DOCA‐salt‐induced neurodegeneration was attenuated, as evidenced by significantly higher mRNA levels of cortical BDNF and PI4KIIIβ, compared with the NT. In summary, our data suggest that neuron‐expressing AT1R participates in the development of hypertension‐associated cognitive impairment, independently of vascular AT1R.