Brain-derived Neurotrophic Factor Protein Expression Research Articles

Neuroprotective efficacy of nano-CoQ against propionic acid toxicity in rats: Role of BDNF and CREB protein expressions.

Propionic acid (PRA) is used as a food preservative. This study was aimed to investigate the neuroprotective effect of acetyl-l-carnitine (ALC) and nano-Coenzyme Q (N-CoQ) on brain intoxication induced by PRA in rats. Rats were divided into five groups: group I: control; group II: received PRA; group III: received ALC; group IV: received N-CoQ; and group V: received ALC and N-CoQ for 5 days. The antioxidants in question markedly ameliorated serum interleukin-1β and tumor necrosis factor-α, and brain NO, lipid peroxide, glutathione, and superoxide dismutase levels as well as protein expression of brain-derived neurotrophic factor (BDNF) and P-cyclic-AMP response element-binding protein (CREB) that were altered by a toxic dose of PRA, as well as histopathological alterations, including improvement of the cerebellum architecture. Interestingly, the combination therapy of ALC and N-CoQ achieved the most neuroprotective effect compared with monotherapies. The current study established that N-CoQ is considered as a useful tool to prevent brain injury induced by PRA. BDNF and CREB proteins are involved in both PRA neurotoxicity and treatment.

An enriched environment increases the expression of fibronectin type III domain-containing protein 5 and brain-derived neurotrophic factor in the cerebral cortex of the ischemic mouse brain.

Many studies have shown that fibronectin type III domain-containing protein 5 (FDNC5) and brain-derived neurotrophic factor (BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an environment that provides animals with multi-sensory stimulation and movement opportunities. An enriched environment has been shown to promote the regeneration of nerve cells, synapses, and blood vessels in the animal brain after cerebral ischemia; however, the exact mechanisms have not been clarified. This study aimed to determine whether an enriched environment could improve neurobehavioral functions after the experimental inducement of cerebral ischemia and whether neurobehavioral outcomes were associated with the expression of FDNC5 and BDNF. This study established ischemic mouse models using permanent middle cerebral artery occlusion (pMCAO) on the left side. On postoperative day 1, the mice were randomly assigned to either enriched environment or standard housing condition groups. Mice in the standard housing condition group were housed and fed under standard conditions. Mice in the enriched environment group were housed in a large cage, containing various toys, and fed with a standard diet. Sham-operated mice received the same procedure, but without artery occlusion, and were housed and fed under standard conditions. On postoperative days 7 and 14, a beam-walking test was used to assess coordination, balance, and spatial learning. On postoperative days 16-20, a Morris water maze test was used to assess spatial learning and memory. On postoperative day 15, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex were analyzed by western blot assay. The results showed that compared with the standard housing condition group, the motor balance and coordination functions (based on beam-walking test scores 7 and 14 days after operation), spatial learning abilities (based on the spatial learning scores from the Morris water maze test 16-19 days after operation), and memory abilities (based on the memory scores of the Morris water maze test 20 days after operation) of the enriched environment group improved significantly. In addition, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex increased in the enriched environment group compared with those in the standard housing condition group. Furthermore, the Pearson correlation coefficient showed that neurobehavioral functions were positively associated with the expression levels of FDNC5 and BDNF (r = 0.587 and r = 0.840, respectively). These findings suggest that an enriched environment upregulates FDNC5 protein expression in the ipsilateral cerebral cortex after cerebral ischemia, which then activates BDNF protein expression, improving neurological function. BDNF protein expression was positively correlated with improved neurological function. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval Nos. 20160858A232, 20160860A234) on February 24, 2016.

Transient Forebrain Ischemia Induces Differential Bdnf Transcript Expression and Histone Acetylation Patterns in the Rat Hippocampus.

Forebrain ischemia induces delayed, selective neuronal death in hippocampal CA1. It has been established that BDNF (brain-derived neurotrophic factor) is an important factor in ischemic injury. However, the exact mechanism of BDNF expression in the hippocampus after ischemia is unclear. We found that the decrease of BDNF protein expression in hippocampal CA1 was associated with a decrease of Bdnf transcript IV expression in the same region of the rats after ischemia/reperfusion (I/R). In hippocampal CA3 and DG, the results showed increased expression of BDNF protein and transcripts I, IIc, III, IV, VI, and X1. Furthermore, at the Bdnf promoters, I/R led to decreased H3K27ac, increased H3K9ac, and H3K14ac in CA1; increased H3K9ac, H3K14ac, and H3K27ac in CA3; no significant change of H3K9ac, H3K14ac, and H3K27ac in DG. HDAC inhibitor SAHA increased the expression of Bdnf transcripts IV, VI, and X1 in CA1. These findings suggest a potential of modulation Bdnf transcript expression to resolve ischemic brain injury through histone acetylation patterns at the Bdnf promoters.

Effects of Deoxyschisandrin on Visceral Sensitivity of Mice with Inflammatory Bowel Disease.

The aims of this study were to build an IBD mouse model and further to observe the effects of deoxyschisandrin on IBD and visceral sensitivity and to evaluate the relevance of brain-derived neurotrophic factor (BDNF) to intestinal hypersensitivity of IBD mice. The results showed that deoxyschisandrin could depress the contraction of isolated smooth muscle, modulate gastrointestinal function, and efficiently decrease the disease activity index (DAI) of IBD mice, which proved that deoxyschisandrin had antidiarrheal effects on the animals. In the colorectal distention (CRD) experiment, visceral sensibility was increased in the model group. However, abdominal withdrawal reflex (AWR) scores were decreased after deoxyschisandrin intervention, indicating that deoxyschisandrin could reduce the visceral hypersensitivity of IBD mice. Both IHC observation and western blotting analysis showed that BDNF protein expression increased evidently in colon of IBD mice. After the intervention of deoxyschisandrin, colon mucosa BDNF protein expression in IBD mice decreased, indicating that deoxyschisandrin could decrease mouse intestinal sensitivity by reducing colon mucosa BDNF expression. In conclusion, deoxyschisandrin possessed antidiarrheal effects and visceral hypersensitivity inhibitory effects in the mice with IBD induced by TNBS, which was related to the reduction in BDNF expression in the colon.

Brain-derived Neurotrophic Factor and TrkB Levels in Mice that Lack Vesicular Zinc: Effects of Age and Sex

In certain neurons, zinc ions are stored in synaptic vesicles by zinc transporter 3 (ZnT3). Vesicular zinc can then be released synaptically to modulate myriad targets. In vitro evidence indicates that these targets may include brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB). But the effects of vesicular zinc on BDNF and TrkB in the intact brain are unclear. Studies of mice that lack ZnT3 – and, as a result, vesicular zinc – have shown abnormalities in BDNF and TrkB levels, but results have been mixed and are therefore difficult to interpret. This might be caused by differences in the age or sex of mice tested. In the present study, we measured BDNF and TrkB levels in the hippocampus and neocortex, comparing wild type and ZnT3 knockout mice of both sexes at two ages (5 and 12 weeks). We also examined BDNF mRNA expression and protein levels at an intermediate age (8–10 weeks). We found that, regardless of age or sex, BDNF and TrkB protein levels did not differ between wild type and ZnT3 knockout mice. There were sex-specific differences in BDNF protein and mRNA expression, however. BDNF protein levels increased with age in female mice but not in males. And in females, but not males, ZnT3 KO mice exhibited great hippocampal BDNF mRNA expression than wild type mice. We conclude that, at least in naïve mice housed under standard laboratory conditions, elimination of vesicular zinc does not affect BDNF or TrkB protein levels.

Aluminium-induced synaptic plasticity injury via the PHF8-H3K9me2-BDNF signalling pathway.

Aluminium is an environmental neurotoxin that comes extensively in contact with human being. The molecular mechanism of aluminium toxicity remains unclear. A number of studies have indicated that exposure to aluminium can impair learning and memory function. The purpose of this study was to investigate the mechanism of long-term potentiation(LTP) injury and the related signalling pathway activated by aluminium exposure. The results showed that aluminium treatment produced dose-dependent inhibition of LTP and reduced the activity of Histone H3K9 demethylation (H3K9me2) demethylase and the expression of the PHD (plant homeodomain) finger protein 8 (PHF8). Interestingly, there was no statistically significant difference in the expression of the PHF8 gene, suggesting that aluminium exposure only affects the translation process. Decrease in brain-derived neurotrophic factor (BDNF) expression may be related to the effect of aluminium. With correlation analysis between the hippocampal standardised field excitatory postsynaptic potential (fEPSP) amplitude and the expression of various proteins in the aluminium-exposed rat, the hippocampal standardised fEPSP amplitude was positively correlated with the expression of hippocampal PHF8 and BDNF proteins, and negatively correlated with the expression of hippocampal H3K9me2 protein. The correlation between H3K9me2 and BDNF was also considered negative. The results suggest that changes in synaptic plasticity might be related to changes in these proteins, which were induced by aluminium exposure. In conclusion, chronic aluminium exposure may inhibit PHF8 and prevent it from functioning as a demethylase. This may block H3K9me2 demethylation, decrease BDNF protein expression, and lead to LTP impairment.

The effects of eicosapentaenoic acid dietary supplementation on behavioral parameters and expression of hippocampal brain-derived neurotrophic factor in an animal model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a trauma- and stressor-related disorder, characterized by bi-directional symptomatic manifestations of increase in both hyperarousal/hypervigilance and numbing/avoidance. In our previous reports, we have proposed an animal model of PTSD using avoidance/escape task sessions in the shuttle box after delivering an inescapable foot-shock traumatization in the same box (Wakizono et al., 2007), and demonstrated the efficacy of 2-week administration of antidepressant on the hyperarousal/hypervigilant behavioral parameters (Sawamura et al., 2004) in the model. In this study, we observed a partial but significant efficacy of oral supplementation of eicosapentaenoic acid (EPA) for five weeks on the numbing/avoidance behavior in the experimental model. Additionally, western blot analyses using brain-derived neurotrophic factor (BDNF) monoclonal antibody revealed a decreased expression of BDNF protein, in the hippocampal region of the rats, due to foot-shock traumatization and a significantly increased expression of BDNF protein after oral EPA supplementation. The results indicate a possibility that alteration of the numbing/avoidance behavior parallels the expression of hippocampal BDNF in the rat brain. The present study suggests a possibility that EPA supplementation in the treatment of PTSD ameliorates persistent numbing/avoidance symptoms. (185 words).

MiR-15a regulates oxygen glucose deprivation/reperfusion (OGD/R)-induced neuronal injury by targeting BDNF.

Multiple microRNAs (miRs) have also been implicated in ischemic brain injury. This research intended to probe the regulatory function and the mechanism of miR-15a on the ischemic brain injury induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in neurons of rats. The OGD/R model was established with the cortical neurons separated from rats. After transfection with miR-15a mimic negative control (NC), miR-15a mimic, miR-15a inhibitor NC and miR-15a inhibitor, the OGD/R-induced apoptosis were detected. Using bioinformatic softwares including TargetScan, miRanda, and miRWalk to predict the underlying targets of miR-15a, and the binding of miR-15a with brain-derived neurotrophic factor (BDNF) were validated with double-fluorescein reporter assay system. The expression levels of BDNF mRNA and protein were detected with qRT-PCR and western blot. The effect of miR-15a on PI3K/AKT pathway in neurons submitted to OGD/R was also investigated. The findings showed that miR-15a may mediate the apoptosis of neurons submitted to OGD/R, and lower expression of Bcl-2 and higher expression of Bax and cleaved caspase-3 were observed. BDNF was screened as the candidate target, and the direct binding of miR-15a with 3'-UTR of BDNF were verified. Further research showed that miR-15a downregulated the expression of BDNF mRNA and protein, thus exerted negative regulatory effect on the OGD/R injury. PI3K/AKT pathway may be related to the regulatory effect of miR-15a. Our findings contribute to uncovering novel pathogenesis for ischemic brain injury.

Vitamin E attenuates alterations in learning, memory and BDNF levels caused by perinatal ethanol exposure

ABSTRACT Objective: Alcohol exposure during pregnancy affects the developing fetus and causes a variety of physical and neurological abnormalities. Here we aim to study the effects of vitamin E on spatial learning and memory deficits and on changes in hippocampal brain-derived neurotrophic factor (BDNF) levels following perinatal ethanol exposure in rats. Method: Pregnant Wistar rats received ethanol (4 g/kg) and vitamin E (doses of 100, 200, and 400 mg/kg) on day 0 of gestation (GD) until weaning (28 days). On postnatal days (PND) 29, the performance of spatial learning and memory of rats were measured using the Morris water maze (MWM). The expression of BDNF protein levels in the hippocampus was assayed using BDNF ELISA kits. Results: Ethanol exposed group showed higher escape latency during training, reduced time spent in the target quadrant, higher escape location latency and average proximity in probe test. Vitamin E with doses of 100, 200 and 400 mg/kg significantly reduced escape latency during training. Also, vitamin E (400 mg/kg) significantly increased time spent in target quadrant, decreased escape location latency and average proximity in probe test. Maternal ethanol treatment significantly reduced the expression of BDNF protein in the hippocampus of offspring, whereas administration of vitamin E (400 mg/kg) significantly increased hippocampal BDNF in ethanol-treated rats. Discussion: Vitamin E administration dose-dependently ameliorate learning and memory deficits induced by perinatal ethanol exposure and increased hippocampal BDNF levels. BDNF may be implicated in the beneficial effects of vitamin E on learning and memory in the perinatal ethanol-exposed rat.

Melatonin ameliorates cuprizone-induced reduction of hippocampal neurogenesis, brain-derived neurotrophic factor, and phosphorylation of cyclic AMP response element-binding protein in the mouse dentate gyrus.

IntroductionThe aim of this study was to investigate the effects of cuprizone on adult hippocampal neurogenesis in naïve mice. Additionally, we also studied how melatonin affects the neuronal degeneration induced by cuprizone.MethodsEight‐week‐old male C57BL/6J mice were randomly divided into three groups: (a) the control group, (b) the group treated with cuprizone only, and (c) the group treated with both cuprizone and melatonin. Cuprizone was administered with food at 0.2% ad libitum for 6 weeks. Melatonin was also administered with tap water at 6 g/L ad libitum for 6 weeks; the animals were then euthanized for immunohistochemistry with Ki67, doublecortin (DCX), glucose transporter 3 (GLUT3), and phosphorylation of cyclic adenosine monophosphate (AMP) response element binding (pCREB); double immunofluorescence of neuronal nuclei (NeuN) and myelin basic protein (MBP); and Western blot analysis of brain‐derived neurotrophic factor (BDNF) expression to reveal the effects of cuprizone and melatonin on cell damage and hippocampal neurogenesis.ResultsAdministration of cuprizone significantly decreased the number of differentiating (DCX‐positive) neuroblasts and proliferating (Ki67‐positive) cells in the dentate gyrus. Moreover, cuprizone administration decreased glucose utilization (GLUT3‐positive cells) and cell transcription (pCREB‐positive cells and BDNF protein expression) in the dentate gyrus. Administration of melatonin ameliorated the cuprizone‐induced reduction of differentiating neuroblasts and proliferating cells, glucose utilization, and cell transcription.ConclusionThe results of the study suggest that cuprizone treatment disrupts hippocampal neurogenesis in the dentate gyrus by reducing BDNF levels and decreasing the phosphorylation of CREB. These effects were ameliorated by melatonin treatment.

5-HT6 receptor agonist and antagonist improve memory impairments and hippocampal BDNF signaling alterations induced by MK-801

The aim of the present study was to investigate and compare the effects of acute and chronic (21-day) administration of agonist (WAY-181187) and antagonist (SB-742457) of the 5-hydroxytryptamine 6 receptor (5-HT6R) on MK-801-induced memory impairments in novel object recognition (NORT) and Y-maze continuous spontaneous alternation tests (Y-CAT). Further, the expression of the brain-derived neurotrophic factor (BDNF) in rat hippocampus was measured after 21-day administration to investigate BDNF participation in the pro-cognitive effects of 5-HT6R ligands. We found that acute administration of WAY-181187, as well as SB-742457, reversed the effects of MK-801 in NORT and Y-CAT, and that this influence persisted after prolonged application in NORT but not in Y-CAT. Both 5-HT6R ligands increased hippocampal BDNF protein expression, but WAY-181187 was much more potent than SB-742457 and alleviated the MK-801-induced inhibition of BDNF signaling pathways better, which seems to translate into a stronger WAY-181187 effect in behavioral tests. Collectively, both the 5-HT6R agonist and the antagonist, administered acutely and chronically, prevent memory impairments and alterations in BDNF signaling induced by MK-801 in rats. The present results confirm the pro-cognitive properties of both types of 5-HT6R ligands and suggest that BDNF pathways may be involved in their mechanism of action.

Ginsenoside Rb1 pretreatment reverses hippocampal changes in BDNF/TrkB mRNA and protein in rats subjected to acute immobilization stress.

PurposeEpisodes of acute emotional or physical stress can have significant adverse effects on the hippocampus. Ginsenoside Rb1, the most predominant ginsenoside present in Panax species, has been reported to show a neuroprotective effect. The purpose of this study was to investigate the influence of ginsenoside Rb1 on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in rats subjected to acute immobilization stress.MethodsWistar rats were divided into controls treated with saline only (N), rats exposed to stress only (M), and rats pretreated with Rb1 (40 mg.kg (−1)) thirty minutes prior to stress exposure (R). In the model, animals were restrained in a plastic immobilizer for 2 h of acute immobilization stress at room temperature. ELISA was used to determine plasma levels of CORT and ACTH. The effect of Rb1 pretreatment on the expression of BDNF and TrkB was determined by immunofluorescence, real-time PCR, and Western blotting analysis.ResultsThe R group showed significantly increased plasma CORT and ACTH levels compared to the N and M groups. Acute stress stimulation suppressed BDNF and TrkB protein and mRNA expression in the hippocampus; otherwise, Rb1 pretreatment reversed the decreases.ConclusionThe results from this study demonstrate that Rb1 pretreatment reverses the decreases in hippocampal BDNF/TrkB and increases the plasma levels of CORT and ACTH, indicating a potential neuroprotective effect of Rb1 against acute stress.

Isoflurane produces antidepressant effects inducing BDNF-TrkB signaling in CUMS mice.

The volatile anesthetic isoflurane is suggested to produce a rapid and robust antidepressive effect in preliminary clinical trials. Recently, isoflurane was found to activate the tropomyosin receptor kinase B (TrkB) signaling which is the underlying mechanism of the rapid antidepressant ketamine. Our study investigated the effect of isoflurane anesthesia on chronic unpredictable mild stressed (CUMS) model in mice and verified the role of brain-derived neurotrophic factor (BDNF)/TrkB/ the mammalian target of rapamycin (mTOR) signaling in the antidepressant effect of isoflurane. We employed the CUMS model of depression to assess the rapid antidepressant effect of isoflurane by the forced swimming test (FST), the sucrose preference test (SPT), and the novelty suppressed feeding test (NSFT). The protein expression of BDNF and TrkB/protein kinase B (PKB or Akt)/mTOR was determined through Western blot. The dendritic spine density in the hippocampus and medial prefrontal cortex (PFC) was measured by the Golgi staining. A brief burst-suppressing isoflurane anesthesia rapidly reversed the behavioral deficits caused by CUMS procedure, normalized the expression of BDNF and further activated the TrkB signaling pathway in CUMS-induced stressed mice in both prefrontal cortex (PFC) and hippocampus (HC). All of those behavioral and proteomic effects were blocked by K252a, a selective receptor inhibitor of TrkB. Isoflurane significantly promoted the formation of dendritic spines in both medial prefrontal cortex (mPFC), CA1, CA3, and DG of the hippocampus. Our study indicates that isoflurane exerts a rapid antidepressant-like effect in CUMS depression animal model, and the activation of BDNF/TrkB signaling pathway plays an indispensable role in the biological and behavioral antidepressant effects of isoflurane. A single exposure to isoflurane could repair synaptic damage caused by chronic stimulation.

Baicalin regulates depression behavior in mice exposed to chronic mild stress via the Rac/LIMK/cofilin pathway

BackgroundDepression is a common disease that endangers people’s physical and mental health. Traditional Chinese medicine has advantages in treating the emotional and cognitive symptoms of depressive disorders. ObjectiveTo study the effects of baicalin on the behavior and to clarify the underlying mechanism through evaluation of the Rac1-LIMK1-cofilin pathway. MethodsA chronic mild stress (CMS) model of depression was used. Baicalin was administered to the mice for the intervention, and the positive control group was treated with fluoxetine. Behavioral tests were conducted to observe the degree of depressive disorders. Synaptophysin (SYP), postsynaptic density protein-95 (PSD95), brain-derived neurotrophic factor (BDNF), tyrosine kinase receptors (TrkB), Rac1 and cofilin expression was determined using Western blot analysis, and mRNA was quantified using real-time PCR. ResultsMice in the CMS group showed an increase in depression-like behavior (p < 0.01), while mice in the baicalin and fluoxetine groups showed a decrease in depression-like behavior (p < 0.01), compared with the control group. Electron microscopy showed ultrastructural changes in the hippocampal CA3 area of the CMS group, which were alleviated by baicalin treatment. SYP, PSD95, BDNF, TrkB, Rac1 and cofilin protein expression levels were decreased in the CMS group compared with the control group, while these levels were increased in the baicalin and fluoxetine groups (p < 0.01). There was no significant difference among the baicalin and fluoxetine groups (p > 0.05). ConclusionBaicalin markedly alleviated depression-like behavioral changes, exerted effects on SYP, PSD95, BDNF, and TrkB expression, activated the Rac1-cofilin pathway, and subsequently improve synaptic plasticity.

Inhibition of microRNA-103a inhibits the activation of astrocytes in hippocampus tissues and improves the pathological injury of neurons of epilepsy rats by regulating BDNF

BackgroundThe aim of this study is to explore the effect of microRNA-103a (miR-103a) on astrocytes activation and hippocampal neuron injury in epilepsy rats by targeting brain-derived neurotrophic factor (BDNF).MethodsThe epilepsy rat model was induced by intraperitoneal injection of lithium chloride-pilocarpine. Successful modeled rats were intralateroventricularly microinjected with miR-103a inhibitors, inhibitors negative control (NC), siRNA-NC and BDNF-siRNA, respectively. The RT-qPCR and western blot analysis were used to detect the expression of miR-103a, BDNF and glial fibrillary acidic protein (GFAP) in hippocampus tissues of rats. TUNEL staining was used to detect the apoptosis of hippocampal neurons. The RT-PCR and ELISA was used to detect the levels of TNF-α and IL-6 in hippocampal tissues and in serum, respectively.ResultsIncreased expression of miR-103a, GFAP, and number of apoptotic neurons, decreased expression of BDNF and number of surviving neurons were found in hippocampus tissues of epilepsy rats. After miR-103a inhibitors interfered with epilepsy rats, there showed decreased expression of miR-103a and GFAP, increased expression of BDNF and decreased number of apoptotic neuron as well as increased number of surviving neurons. Compared with miR-103a inhibitors alone, epilepsy rats treated with BDNF-siRNA combined with miR-103a inhibitors significantly increased expression of GFAP in hippocampal tissues of epilepsy rats, increased number of apoptotic neurons and significantly decreased the number of surviving neurons.ConclusionOur study provides evidence that the inhibition of miR-103a can inhibit the activation of astrocytes in hippocampus tissues and improve the pathological injury of neurons of epilepsy rats by regulating BDNF gene.

The Chinese Herbal Formula PAPZ Ameliorates Behavioral Abnormalities in Depressive Mice.

Major depressive disorder (MDD) is a chronic mental disorder characterized by mixed symptoms and complex pathogenesis. With long history of practical application, traditional Chinese medicine (TCM) offers many herbs for the treatment and rehabilitation of chronic disease. In this study, we developed a modified Chinese herbal formula using Panax ginseng, Angelica Sinensis, Polygala tenuifolia Willd, and Ziziphi spinosae Semen (PAPZ), based on an ancient TCM prescription. The antidepressant effects of PAPZ were investigated with a corticosterone (CORT) model of depression in mice. Our results showed that administration of PAPZ ameliorated depression-like phenotypes in the CORT model. An anatomic study showed that chronic PAPZ administration upregulated the protein expression of brain-derived neurotrophic factor (BDNF) in hippocampal tissue. The enzyme activity of superoxide dismutase was enhanced in hippocampal tissue, in line with a decreased malondialdehyde level. Taken together, these findings suggested that PAPZ has therapeutic effects in a mice depression model through increasing protein expression of BDNF and improving the anti-oxidation ability of the brain.

Effects of α7 nicotinic receptor positive allosteric modulator, PNU120596, on BDNF, NKCC1, and KCC2 expressions following LPS‐induced depressive‐like behavior in mice

Previous evidence indicates that neuroinflammation plays a critical role in the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain‐derived neurotrophic factor (BDNF), Na‐K‐Cl cotransporter‐1 (NKCC1), and K‐Cl cotransporter‐2 (KCC2). However, the role of microglial α7 nicotinic acetylcholine receptors (nAChRs), exhibiting anti‐inflammatory function during the activation, on these mediators is unknown. The objective of the present study was to determine the effects of PNU120596 on BDNF, NKCC1, and KCC2 expressions in lipopolysaccharide (LPS)‐induced mouse model of MDD using Western blot analysis, immunofluorescence staining, and real‐time polymerase chain reaction. We also examined the pharmacological interaction between PNU120596 and ANA12, an antagonist of TrkB which is the primary receptor for BDNF, on LPS‐induced depressive‐like behavior using forced swim test (FST), tail suspension test (TST), and Y‐maze test. Systemic administration of LPS (1 mg/kg, i.p.) significantly increased BDNF protein expression and mRNA ratio of NKCC1 to KCC2, and decreased KCC2 mRNA expression in the hippocampus and prefrontal cortex, the brain regions implicated in MDD. The PNU120596 (1 or 4 mg/kg, i.p.) dose‐dependently prevented the LPS‐induced dysregulated BDNF, NKCC1, and KCC2 expressions in these brain regions. Combination treatment with PNU120596 (1 mg/kg, i.p.) and ANA12 (0.25 mg/kg, i.p.) prevented LPS‐induced increased immobility time during FST and TST and LPS‐induced decreased spontaneous alternations (%) during Y‐maze test. Overall, our results suggest that PNU120596 prevented LPS‐induced depressive‐like behavior by decreasing neuronal excitability by targeting microglial α7 nAChR in the hippocampus and prefrontal cortex. (Supported in part by grant from Saudi Arabian Cultural Mission, USA).Support or Funding InformationSupported in part by grant from Saudi Arabian Cultural Mission, USA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

GSTO1 acts as a mediator in sodium fluoride-induced alterations of learning and memory related factors expressions in the hippocampus cell line

The mechanism of GSTO1, as a high-risk factor for neurological damage, in sodium fluoride (NaF)-induced learning and memory impairment remained still unclear. Hence, in this study, we used the siRNA-GSTO1 HT22 model to explore the effect of NaF and siRNA-GSTO1 on the viability, and proliferation rate of HT22 cells, as well as the mRNA and protein expression levels of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), neural cell adhesion molecule (NCAM), stem cell factor (SCF) and brain-derived neurotrophic factor (BDNF). The results of MTT showed that 10−3, 10−4, and 10−5 moL/L sodium fluoride (NaF) exposure could significantly promote the proliferation of HT22 cells at 24 h, 36 h, and 48 h, respectively. In addition, our results showed that exposure to 10−3, 10−4, and 10−5 moL/l NaF increased GSTO1 mRNA and protein expression, but decreased CREB and BDNF expression levels in a dose and time-dependent manner. The mRNA and protein expressions of GSTO1, CREB and BDNF were significantly decreased in the siRNA-GSTO1 and NaF + siRNA-GSTO1 group (P < 0.05). We have shown that various NaF doses affected the learning and memory ability by down-regulation the expressions of CREB, BDNF, NCAM and SCF. In summary, we concluded that GSTO1 plays a mediator role in NaF-induced neurological damage.

Downregulated hippocampal expression of brain derived neurotrophic factor and tyrosine kinase B in a rat model of comorbid epilepsy and depression

ABSTRACTObjective: To investigate the expression of brain-derived neurotrophic factor(BDNF) and tyrosine kinase B (TrkB) protein in the hippocampus of model rats of comorbid epilepsy and depression.Methods: A rat model of epilepsy was established using lithium chloride.pilocarpine. Among these epileptic rats, those with comorbid depression were selected by a battery of behavioral tests starting on the 14th day after establishing the epilepsy model. A depression group was established by unpredicted chronic mild stress (UCMS) and separate housing. These treatment groups were compared to an untreated control group. Thirteen rats per group were examined by immunofluorescence staining with optical density quantitation to determine the distribution of BDNF- and TrkB-positive cells in the hippocampus and by western blotting to estimate total protein expression levels during the 4th week after establishing the models. Immunofluorescence staining for NeuN was also conducted in hippocampus to evaluate neuronal survival. Depression-like behaviors were also assessed.Results: Compared to the untreated control group and the epilepsy alone group, the comorbid group exhibited lower average optical densities of BDNF- and TrkB-immunopositive cells as well as lower total BDNF and TrkB protein expression levels (all P = 0.000). The comorbid group exhibited lower behavioral scores compared to all other groups (all P=0.000). Numbers of NeuN–positive cells were lower in the hippocampus of all three experimental groups compared to the untreated control group (all P = 0.000).Conclusions: These results suggest that hypofunctional BDNF-TrkB signaling may contribute to depression in epilepsy.Abbreviations: BDNF: Brain-derived neurotrophic factor; TrkB: tyrosine kinase B; UCMS: unpredicted chronic mild stress; PBS: phosphate-buffered saline; HS: Hippocampal sclerosis

Ojayeonjonghwan, an oriental medicine composed of five seeds, protects against vasomotor and neurological disorders in estrogen-deficient rats.

Menopausal symptoms impair the quality of life of many women, and although conventional treatments are often effective, their use is limited by adverse effects. Ojayeonjonghwan, OJa, is a traditional Oriental medicine that is used for both male and female reproductive health and has a long history of safe use. We evaluated the effectiveness of two variations of OJa (OJa1 and OJa2) for treating menopausal symptoms in ovariectomized (OVX) rats. Both OJa preparations were effective for relieving indicators of hot flashes and depression, and for preventing loss of bone mineral density and lean body mass. Only OJa 2 prevented memory dysfunction. These results show that the traditional Oriental medicine, Ojayeonjonghwan, has the potential to relieve menopausal symptoms in women and should be further evaluated in human clinical trials as an alternative to convention therapies in women for whom conventional therapies are not indicated or found to be ineffective.