BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury.

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

Synergistic Effect of the Long-Term Overexpression of Bcl-2 and BDNF Lentiviral in Cell Protecting against Death and Generating TH Positive and CHAT Positive Cells from MSC.

Mesenchymal stem cells (MSC) are potentially a good material for transplantation in many diseases, including neurodegenerative diseases. The main problem with using them is the low percentage of surviving cells after the transplant procedure and the naturally poor ability of MSC to spontaneously differentiate into certain types of cells, which results in their poor integration with the host cells. The aim and the novelty of this work consists in the synergistic overexpression of two genes, BCL2 and BDNF, using lentiviral vectors. According to our hypothesis, the overexpression of the BCL2 gene is aimed at increasing the resistance of cells to stressors and toxic factors. In turn, the overexpression of the BDNF gene is suspected to direct the MSC into the neural differentiation pathway. As a result, it was shown that the overexpression of both genes and the overproduction of proteins is permanent and persists for at least 60 days. The synergistically transduced MSC were significantly more resistant to the action of staurosporine; 12 days after transduction, the synergistically transduced MSC had a six-times greater survival rate. The overexpression of the Bcl-2 and BDNF proteins was sufficient to stimulate a significant overexpression of the CHAT gene, and under specific conditions, the TH, TPH1, and SYP genes were also overexpressed. Modified MSC are able to differentiate into cholinergic and dopaminergic neurons, and the release of acetylcholine and dopamine may indicate their functionality.

Myokine Responses to Exercise in a Rat Model of Low/High Adaptive Potential.

Introduction: Assuming myokines underlie some of the health benefits of exercise, we hypothesised that 'high responder trainer' (HRT) rats would exhibit distinct myokine profiles to 'low responder trainers' (LRT), reflecting distinct health and adaptive traits. Methods: Blood was collected from LRT and HRT (N=8) rats at baseline (BL), immediately (0h), 1h, and 3h after running; repeated after 3-wks training. Myokines were analysed by ELISA (i.e. BDNF/Fractalkine/SPARC/Irisin/FGF21/Musclin/IL-6). Results: At baseline, Musclin (LRT: 84 ± 24 vs HRT: 26 ± 3 pg/ml, P=0.05) and FGF21 (LRT: 133 ± 34 vs HRT: 63.5 ± 13 pg/ml, P=0.08) were higher in LRT than HRT. Training increased Musclin in HRT (26 ± 3 to 54 ± 9 pg/ml, P<0.05) and decreased FGF21 in LRT (133 ± 34 to 60 ± 28 pg/ml, P<0.05). Training increased SPARC (LRT: 0.8 ± 0.1 to 2.1 ± 0.6 ng/ml, P<0.05; HRT: 0.7 ± 0.06 to 1.8 ± 0.3 ng/ml, P=0.06) and Irisin (LRT 0.62 ± 0.1 to 2.6 ± 0.4 ng/ml, P<0.01; HRT 0.53 ± 0.1 to 2.8 ± 0.7 ng/ml, P<0.01) while decreasing BDNF (LRT: 2747 ± 293 to 1081 ± 330 pg/ml, P<0.01; HRT: 1976 ± 328 to 797 ± 160 pg/ml, P<0.05). Acute exercise response of Musclin (AUC) was higher in LRT vs HRT (306 ± 74 vs. 88 ± 12 pg/ml×3h-1, P<0.01) and elevated in HRT after training (221 ± 31 pg/ml×3h-1, P<0.01). Training elevated SPARC (LRT: 2.4 ± 0.1 to 7.7 ± 1.3 ng/ml×3h-1, P<0.05; HRT: 2.5 ± 0.13 to 11.2 ± 2.2 ng/ml×3h-1, P<0.001) and Irisin (LRT: 1.34 ± 0.3 to 9.6 ± 1.7 ng/ml×3h-1, P<0.001; HRT: 1.5 ± 0.5 to 12.1 ± 1.9 ng/ml×3h-1, P<0.0001). Conclusion: Exercise training alters how myokines are secreted in response to acute exercise. Myokine responses were not robustly linked to adaptive potential in aerobic capacity, making them an unlikely regulator of adaptive traits.

Mitochondria transplantation protects traumatic brain injury via promoting neuronal survival and astrocytic BDNF.

Traumatic brain injury (TBI) is one of the leading causes of disability and paralysis around the world. Secondary injury, characterized by progressive neuronal loss and astrogliosis, plays important roles in the post-TBI cognitive impairment and mood disorder. Unfortunately, there still lacks effective treatments, particularly surgery interferences for it. Recent findings of intercellular mitochondria transfer implies a potential therapeutic value of mitochondria transplantation for TBI, which has not been tested yet. In the present study, we demonstrated a quick dysfunction of mitochondria, up-regulation of Tom20 in the injured cortex and subsequent cognitive and mood impairment. Our data demonstrated that mitochondria derived from allogeneic liver or autogeneic muscle stimulated similar microglial activation in brain parenchyma. In vitro experiments showed that exogenous mitochondria could be easily internalized by neurons, astrocytes, and microglia, except for oligodendrocytes. Mitochondria transplantation effectively rescued neuronal apoptosis, restored the expression of Tom20 and the phosphorylation of JNK. Further analysis revealed that mitochondria transplantation in injured cortex induced a significant up-regulation of BDNF in reactive astrocytes, improved animals' spatial memory and alleviated anxiety. In together, our data indicate that mitochondria transplantation may has the potential of clinical translation for TBI treatment, in combination with surgery.

Low-Intensity Pulsed Ultrasound Prompts Both Functional and Histologic Improvements While Upregulating the Brain-Derived Neurotrophic Factor Expression after Sciatic Crush Injury in Rats.

The aim of this study was to determine that low-intensity pulsed ultrasound (LIPUS) at an intensity of 140 mW/cm2 promotes functional and histologic improvements in sciatic nerve crush injury in a rat model and to investigate changes over time in relevant growth factors and receptors, exploring the mechanism of LIPUS in the recovery process after injury. Toe angle in the toe-off phase, regenerative axonal length, myelinated nerve fiber density, diameter of myelinated nerve fiber, axon diameter and myelin sheath thickness were significantly higher in the LIPUS group than in the sham group. Gene and protein expression of brain-derived neurotrophic factor (BDNF) was upregulated in the LIPUS group. In conclusion, LIPUS contributed to rapid functional and histologic improvement and upregulated BDNF expression after sciatic nerve crush injury in rats.

Improvement of Cerebral Ischemia-Reperfusion Injury via Regulation of Apoptosis by Exosomes Derived from BDNF-Overexpressing HEK293.

Brain-derived neurotrophic factor (BDNF) provides neuroprotective effects towards therapeutic cerebral ischemia-reperfusion (I/R) injury. This view has been proposed by more and more evidence. However, due to the lack of permeability of the blood-brain barrier (BBB) as well as the brief half-life in serum, clinical application is not widespread. To study the participation of exosomes containing BDNF in I/R, we isolated exosomes from BDNF-overexpressing HEK293. The protective outcomes of exosomes in hypoxia/reoxygenation (H/R) experiments were determined by the use of SY-5Y cells. Exosome-BDNF therapy restrained H/R-induced apoptosis by inhibition of the reducing levels of oxidative stress and calcium ions in the cells while maintaining stable levels of mitochondrial membrane potential in brain cells damaged by I/R. We then constructed a cerebral I/R injury model using SD rats to find the function of BDNF in exosome-mediated neuroprotection. The in vivo experiments conducted established that exosomes from BDNF-overexpressing HEK293 cells improved cerebral I/R injury by concealing neuronal apoptosis. Findings gained demonstrated that BDNF is a part of preventing cerebral I/R injury due to exosome mediation by regulating the cellular internal environment and inhibiting apoptosis.

PPM1F in Dentate Gyrus Modulates Anxiety-Related Behaviors by Regulating BDNF Expression via AKT/JNK/p-H3S10 Pathway.

Anxiety is a serious psychiatric disorder, with a higher incidence rate in women than in men. Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F), a serine/threonine phosphatase, has been shown to have multiple biological and cellular functions. However, the effects of PPM1F and its neuronal substrates on anxiety remain largely unclear. In this study, we showed that chronic restraint stress (CRS) induced anxiety-related behaviors only in female mice, while acute restraint stress (ARS) produced anxiety-related behaviors in both male and female mice in light-dark and elevated plus maze tests and induced upregulation of PPM1F and downregulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Adeno-associated virus-mediated overexpression of PPM1F or conditional knockout of BDNF in dentate gyrus (DG) led to a more pronounced anxiety-related behavior in female than in male mice as indicated by the behavioral evaluations. Meanwhile, overexpression of PPM1F in the DG decreased total Bdnf exon-specific messenger RNA expression in the hippocampus with the decreased binding activity of phosphorylated H3S10 to its individual promoters in female mice. Furthermore, we identified that overexpression of PPM1F decreased the phosphorylation levels of AKT and JNK in the hippocampus of female mice. These results may suggest that PPM1F regulates anxiety-related behaviors by modulating BDNF expression and H3S10 phosphorylation-mediated epigenetic modification, which may be served as potentially pathological genes associated with anxiety or other mental diseases.

Brain-Derived Neurotrophic Factor Expression and Signaling in Different Perivascular Adipose Tissue Depots of Patients With Coronary Artery Disease.

Background Brain-derived neurotrophic factor (BDNF) is expressed in neuronal and nonneuronal cells and may affect vascular functions via its receptor, tropomyosin-related kinase B (TrkB). In this study, we determined the expression of BDNF in different perivascular adipose tissue (PVAT) depots of patients with established coronary atherosclerosis. Methods and Results Serum, vascular tissue, and PVAT surrounding the proximal aorta (C-PVAT) or internal mammary artery (IMA-PVAT) was obtained from 24 patients (79% men; mean age, 71.7±9.7 years; median body mass index, 27.4±4.8 kg/m2) with coronary atherosclerosis undergoing elective coronary artery bypass surgery. BDNF protein levels were significantly higher in C-PVAT compared with IMA-PVAT, independent of obesity, metabolic syndrome, or systemic biomarkers of inflammation. mRNA transcripts of TrkB, the BDNF receptor, were significantly reduced in aorta compared with IMA. Vessel wall TrkB immunosignals colocalized with cells expressing smooth muscle cell markers, and confocal microscopy and flow cytometry confirmed BDNF receptor expression in human aortic smooth muscle cells. Significantly elevated levels of protein tyrosine phosphatase 1B, a negative regulator of TrkB signaling in the brain, were also observed in C-PVAT. In vitro, inhibition of protein tyrosine phosphatase 1B blunted the effects of BDNF on smooth muscle cell proliferation, migration, differentiation, and collagen production, possibly by upregulation of low-affinity p75 neurotrophin receptors. Expression of nerve growth factor or its receptor tropomyosin-related kinase A did not differ between C-PVAT and IMA-PVAT. Conclusions Elevated expression of BDNF in parallel with local upregulation of negative regulators of neurotrophin signaling in perivascular fat and lower TrkB expression suggest that vascular BDNF signaling is reduced or lost in patients with coronary atherosclerosis.

Gadd45b mediates environmental enrichment-induced neurogenesis in the SVZ of rats following ischemia stroke via BDNF.

Ischemic stroke is a major cause of mortality and disability. Subventricular zone (SVZ) neurogenesis following an ischemic stroke may be beneficial for improving the outcomes. Environmental enrichment (EE) has been reported to increase neurogenesis following stroke. Growth arrest and DNA-damage-inducible protein 45 ß (Gadd45b) is a crucial gene for activity-correlated neurogenesis in the adult hippocampus of mice. This study examined whether Gadd45b inhibition affects adult SVZ neurogenesis after an ischemic injury and explored the role of Gadd45b in EE-induced SVZ neurogenesis in adult male Sprague Dawley rats following middle cerebral artery occlusion (MCAO). Gadd45b expression was silenced by a lentivirus with RNA interference (RNAi). The 5-ethynyl-2-deoxyuridine (EdU) staining test was performed to detect cell proliferation. Gadd45b-RNAi after MCAO decreased SVZ proliferation and differentiation in the infarction boundary following ischemic injury, accompanied by the depressed expression of the brain-derived neurotrophic factor (BDNF). Treatment with EE following ischemic stroke upregulated Gadd45b and BDNF expressions and increased neurogenesis in the SVZ. Inhibition of Gadd45b markedly ameliorated the increased neurogenesis induced by EE. These data indicated that Gadd45b is related to SVZ neurogenesis following ischemic stroke, and Gadd45b mediates EE-induced neurogenesis via BDNF in the SVZ of rats following an ischemia stroke. These results implicate that Gadd45b can be a potential therapeutic target to enhance adult neurogenesis following cerebral ischemia.

ERRγ ligand HPB2 upregulates BDNF-TrkB and enhances dopaminergic neuronal phenotype.

Brain derived neurotrophic factor (BDNF) promotes maturation of dopaminergic (DAergic) neurons in the midbrain and positively regulates their maintenance and outgrowth. Therefore, understanding the mechanisms regulating the BDNF signaling pathway in DAergic neurons may help discover potential therapeutic strategies for neuropsychological disorders associated with dysregulation of DAergic neurotransmission. Because estrogen-related receptor gamma (ERRγ) is highly expressed in both the fetal nervous system and adult brains during DAergic neuronal differentiation, and it is involved in regulating the DAergic neuronal phenotype, we asked in this study whether ERRγ ligand regulates BDNF signaling and subsequent DAergic neuronal phenotype. Based on the X-ray crystal structures of the ligand binding domain of ERRγ, we designed and synthesized the ERRγ agonist, (E)-4-hydroxy-N'-(4-(phenylethynyl)benzylidene)benzohydrazide (HPB2) (Kd value, 8.35 µmol/L). HPB2 increased BDNF mRNA and protein levels, and enhanced the expression of the BDNF receptor tropomyosin receptor kinase B (TrkB) in human neuroblastoma SH-SY5Y, differentiated Lund human mesencephalic (LUHMES) cells, and primary ventral mesencephalic (VM) neurons. HPB2-induced upregulation of BDNF was attenuated by GSK5182, an antagonist of ERRγ, and siRNA-mediated ERRγ silencing. HPB2-induced activation of extracellular-signal-regulated kinase (ERK) and phosphorylation of cAMP-response element binding protein (CREB) was responsible for BDNF upregulation in SH-SY5Y cells. HPB2 enhanced the DAergic neuronal phenotype, namely upregulation of tyrosine hydroxylase (TH) and DA transporter (DAT) with neurite outgrowth, both in SH-SY5Y and primary VM neurons, which was interfered by the inhibition of BDNF-TrkB signaling, ERRγ knockdown, or blockade of ERK activation. HPB2 also upregulated BDNF and TH in the striatum and induced neurite elongation in the substantia nigra of mice brain. In conclusion, ERRγ activation regulated BDNF expression and the subsequent DAergic neuronal phenotype in neuronal cells. Our results might provide new insights into the mechanism underlying the regulation of BDNF expression, leading to novel therapeutic strategies for neuropsychological disorders associated with DAergic dysregulation.

Memantine treatment exerts an antidepressant-like effect by preventing hippocampal mitochondrial dysfunction and memory impairment via upregulation of CREB/BDNF signaling in the rat model of chronic unpredictable stress-induced depression.

Mitochondrial and cognitive dysfunctions have long been associated with major depressive disorders (MDDs). Studies have shown that Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, possesses an antidepressant-like effect. Hence, the NMDA receptor can be a better therapeutic target for MDD. Therefore, the present study was designed to study the impact of Memantine on mitochondrial functional status and depression-like symptoms in the chronic unpredictable stress (CUS) model of depression. CUS for 28 days resulted in depression-like symptoms (as indicated by increased immobility time in the forced swim test) and a decline in the spatial learning and retention memory in the Morris water maze (MWM) test, which was prevented by Memantine (10 mg/kg/day) treatment. We observed elevated plasma corticosterone (CORT) levels, microdialysates glutamate concentration, and synaptosomal calcium (Ca2+) ion levels after 28 days of CUS. Memantine treatment prevented only increased plasma CORT and synaptosomal Ca2+ ion levels. Memantine treatment also restored CUS induced increase in oxidative stress parameters [increased neuronal nitric oxide synthase (nNOS) expression, nitric oxide (NO) levels, lipid peroxidation (LPO) and superoxide dismutase (SOD) activity], decrease in mitochondrial electron transport chain (ETC) enzymes activity and mitochondrial membrane potential (MMP). CUS also reduced the expression of cell survival genes, cyclic-AMP response element-binding protein (CREB), and brain-derived nerve growth factor (BDNF), which was reversed by treatment with Memantine. CUS, however, caused a non-significant decrease in the hippocampal adenosine triphosphate (ATP) levels and a non-significant increase in the expression of pro-apoptotic genes, Caspase 3, and the number of TUNEL positive cells, indicating that hippocampal mitochondrial dysfunction caused due to CUS was not severe enough to affect overall energy production, mitochondrial integrity, and cellular apoptosis status. Thus, Memantine treatment exerts an antidepressant-like effect by preventing CUS induced excitotoxicity, oxidative stress, and enhancing CUS induced decrease in mitochondrial functioning and expression of cell survival genes via upregulation of stress-responsive CREB/BDNF signaling.

Zika virus infection of first trimester trophoblast cells affects cell migration, metabolism and immune homeostasis control.

Zika virus (ZIKV) re-emerged after circulating almost undetected for many years and the last spread in 2015 was the major outbreak reported. ZIKV infection was associated with congenital fetal growth anomalies such as microcephaly, brain calcifications, and low birth weight related to fetal growth restriction. In this study, we investigated the effect of ZIKV infection on first trimester trophoblast cell function and metabolism. We also studied the interaction of trophoblast cells with decidual immune populations. Results presented here demonstrate that ZIKV infection triggered a strong antiviral response in first trimester cytotrophoblast-derived cells, impaired cell migration, increased glucose uptake and GLUT3 expression, and reduced brain derived neurotrophic factor (BDNF) expression. ZIKV infection also conditioned trophoblast cells to favor a tolerogenic response since an increased recruitment of CD14+ monocytes bearing an anti-inflammatory profile, increased CD4+ T cells and NK CD56Dim and NK CD56Bright populations and an increment in the population CD4+ FOXP3+ IL-10+ cells was observed. Interestingly, when ZIKV infection of trophoblast cells occurred in the presence of the vasoactive intestinal peptide (VIP) there was lower detection of viral RNA and reduced toll-like receptor-3 and viperin messenger RNA expression, along with reduced CD56Dim cells trafficking to trophoblast conditioned media. The effects of ZIKV infection on trophoblast cell function and immune-trophoblast interaction shown here could contribute to defective placentation and ZIKV persistence at the fetal-maternal interface. The inhibitory effect of VIP on ZIKV infection of trophoblast cells highlights its potential as a candidate molecule to interfere ZIKV infection during early pregnancy.

Neurotrophic isoindolinones from the fruiting bodies of Hericium erinaceus.

Four compounds, hericerin (1), isohericerinol A (2), N-de-phenylethyl isohericerin (3) and corallocin A (4) were isolated from the fruiting bodies of Hericium erinaceus, a lion's mane mushroom (Hericiaceae). Among them, isohericerinol A (2) was newly reported in nature. Further investigation of the neurotrophic effect of isolated compounds demonstrated that isohericerinol A (2) strongly increased the nerve growth factor (NGF) production in C6 glioma cells followed by corallocin A (4) and hericerin (1). Increased NGF production by these compounds promoted the neurite outgrowth in N2a neuronal cells. Western blot analysis also showed the increased protein expression of NGF, brain-derived neurotrophic factor (BDNF) and synaptophysin (SYP) in C6-N2a cells. Taken together, our present study characterized the neurotrophic constituents of H. erinaceus, which may support the potential use of memory improvement.

Drinking Pattern in Intermittent Access Two-Bottle-Choice Paradigm in Male Wistar Rats Is Associated with Exon-Specific BDNF Expression in the Hippocampus During Early Abstinence.

Outbred rats differentially consume alcohol when having free access to it. Among others, BDNF (brain-derived neurotrophic factor) is believed to control voluntary ethanol intake in rodents. Meanwhile, expression of BDNF exons in brain regions and epigenetic mechanisms underlying alcohol intake pattern remain obscure. The main goal was to study whether voluntary alcohol drinking pattern affects expression of BDNF exons in selected rat brain regions during early abstinence. Intermittent access to 20% ethanol in a two-bottle-choice procedure (IA2BC) was used as a model of voluntary ethanol intake. Male Wistar rats (n = 24) had twenty 24-h sessions of free access to two-bottle choice (water or 20% ethanol) with 24-h withdrawal periods (water only). Control animals had access to water only (n = 11). After finishing IA2BC, the animals were divided according to the compliance of ethanol intake pattern with gradual escalation, a key feature of the paradigm. To access potential behavioral disturbances during the early abstinence, rats were consequently tested in the open field test, the elevated plus-maze, and the sucrose preference test. On the third day after the last drinking session, expression of BDNF exons and polypeptide was measured in the frontal cortex, hippocampus, striatum, and midbrain using quantitative PCR and Western blotting, respectively. Additionally, chromatin immunoprecipitation was performed to analyze enrichment of positive Ph-CREB (Ser133) and negative EZH2 transcriptional regulators as well as markers of active H3K9ac and repressed H3K27me3 chromatin at exon-specific BDNF promoters in brain regions with affected BDNF expression. During the course of the IA2BC, one part of animals demonstrated gradual escalation from low to high alcohol intake and preference of alcohol over water (a typical pattern for IA2BC) while the other one consumed alcohol at a consistently high level (an unusual pattern for IA2BC). Drinking pattern in the IA2BC does not define differences of behavior in any of the tests during early abstinence. Finally, the IA2BC rats with growing alcohol intake showed elevation of BDNF mRNA containing exon VI in the hippocampus associated with an enhanced H3K9ac occupancy at the respective promoter. Thus, rats differentially consuming alcohol in the IA2BC paradigm differ in epigenetically determined expression of BDNF exon VI in the hippocampus during early abstinence.

Bexarotene promotes microglia/macrophages - Specific brain - Derived Neurotrophic factor expression and axon sprouting after traumatic brain injury.

Traumatic brain injury (TBI) has been regarded as one of the leading cause of injury-related death and disability. White matter injury after TBI is characterized by axon damage and demyelination, resulting in neural network impairment and neurological deficit. Brain-derived neurotrophic factor (BDNF) can promote white matter repair. The activation of peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to promote microglia/macrophages towards anti-inflammatory state and therefore to promote axon regeneration. Bexarotene, an agonist of retinoid X receptor (RXR), can activate RXR/PPARγ heterodimers. The aim of the present study was to identify the effect of bexarotene on BDNF in microglia/macrophages and axon sprouting after TBI in mice. Bexarotene was administered intraperitoneally in C57BL/6 mice undergoing controlled cortical impact (CCI). PPARγ dependency was determined by intraperitoneal administration of a PPARγ antagonist T0070907. We found that bexarotene promoted axon regeneration indicated by increased growth associated protein 43 (GAP43) expression, myelin basic protein (MBP) expression, and biotinylated dextran amine (BDA)+ axon sprouting. Bexarotene also increased microglia/macrophages-specific brain derived neurotrophic factor (BDNF) expression after TBI. In addition, bexarotene reduced the number of pro-inflammatory microglia/macrophages while increased the number of anti-inflammatory microglia/macrophages after TBI. Moreover, bexaortene inhibited pro-inflammatory cytokine secretion. In addition, bexarotene treatment improved neurological scores and cognitive function of CCI-injured mice. These effects of bexarotene were partially abolished by T0070907. In conclusion, bexarotene promotes axon sprouting, increases microglia/macrophages-specific BDNF expression, and induces microglia/macrophages from a pro-inflammatory state towards an anti-inflammatory one after TBI at least partially in a PPARγ-dependent manner.

Glucosamine Enhancement of BDNF Expression and Animal Cognitive Function.

Brain-derived neurotrophic factor (BDNF) is an important factor for memory consolidation and cognitive function. Protein kinase A (PKA) signaling interacts significantly with BDNF-provoked downstream signaling. Glucosamine (GLN), a common dietary supplement, has been demonstrated to perform a variety of beneficial physiological functions. In the current study, an in vivo model of 7-week-old C57BL/6 mice receiving daily intraperitoneal injection of GLN (0, 3, 10 and 30 mg/animal) was subjected to the novel object recognition test in order to determine cognitive performance. GLN significantly increased cognitive function. In the hippocampus GLN elevated tissue cAMP concentrations and CREB phosphorylation, and upregulated the expression of BDNF, CREB5 and the BDNF receptor TrkB, but it reduced PDE4B expression. With the in vitro model in the HT22 hippocampal cell line, GLN exposure significantly increased protein and mRNA levels of BDNF and CREB5 and induced cAMP responsive element (CRE) reporter activity; the GLN-mediated BDNF expression and CRE reporter induction were suppressed by PKA inhibitor H89. Our current findings suggest that GLN can exert a cognition-enhancing function and this may act at least in part by upregulating the BDNF levels via a cAMP/PKA/CREB-dependent pathway.

Taurine and Ginsenoside Rf Induce BDNF Expression in SH-SY5Y Cells: A Potential Role of BDNF in Corticosterone-Triggered Cellular Damage.

This study shows that taurine and ginsenoside Rf act synergistically to increase the expression of brain-derived neurotrophic factor (BDNF) in SH-SY5Y human neuroblastoma cells in a dose- and time-dependent manner. The increase of BDNF mRNA by taurine and ginsenoside Rf was markedly attenuated by inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. In addition, taurine and ginsenoside Rf protected cells from corticosterone-induced BDNF suppression and reduced cell viability and lactate dehydrogenase release. The results from this study showed that combined treatment with both taurine and ginsenoside Rf enhanced BDNF expression and protected cells against corticosterone-induced damage.

Involvement of proBDNF in Monocytes/Macrophages with Gastrointestinal Disorders in Depressive Mice.

Major depressive disorders (MDD) are often comorbid with the gastrointestinal (GI) disorders. Brain-derived neurotrophic factor precursor (proBDNF) has been reported to contribute to the development of depression in mouse models. However, the role of proBDNF in depression-associated GI disorders is still unrevealed. Mice experienced unpredictable chronic mild stress (UCMS) procedure and were then intraperitoneally injected with fluoxetine (20 mg/kg). Open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were performed to evaluate the severity of depression. Oral administration of food dye gel and histological staining were performed to assess GI transit and morphological alterations. QPCR was performed to assess the mRNA levels of inflammatory cytokines. Additionally, flow cytometry, immunohistochemistry, and immunofluorescence were performed to examine the expression and cellular localization of proBDNF. It was found that (a) in the peripheral blood, the expression of proBDNF and its receptor pan neurotrophin receptor 75 (p75NTR) in CD11b+ cells in depressive mice was higher than in controls; (b) the GI motility was decreased after the UCMS procedure and partly reversed by fluoxetine treatment; (c) proBDNF/p75NTR was highly expressed in macrophages in the intestinal lamina propria; (d) the upregulated proBDNF/p75NTR and the activated cytokines, including IL (interleukin)-1ß, IL-6, IL-10, and IFN (interferon)-γ, were positively correlated with the depression and GI disorders, and were inhibited by fluoxetine treatment. UCMS procedure upregulated the expression of proBDNF and p75NTR in monocytes/macrophages of peripheral blood and intestinal lamina propria, which may be involved in the pathogenesis of depression-associated GI disorders. Fluoxetine reversed the GI dysfunction, infiltration of macrophages, and upregulation of proBDNF signaling in the depressive mice.

Expression analysis of hippocampal and amygdala CREB-BDNF signaling pathway in nicotine-induced reward under stress in rats.

Extensive research has shown that individuals are more sensitive to develop addiction and drug taking under stress state. The present study includes an expression analysis to identify the possible role of hippocampal and amygdala CREB (cAMP response element-binding protein) and BDNF (Brain-derived neurotrophic factor) activation in nicotine-induced conditioned place preference (CPP) under exposure to acute or sub-chronic stress. Using western-blot technique, CREB phosphorylation was shown to increase in the hippocampus and the amygdala following nicotine-induced CPP. The hippocampal level of BDNF was increased following nicotine administration and in the nicotine-treated animals exposed to acute stress. In animals exposed to acute stress, the amygdala ratios of the pCREB/CREB decreased, while pre-treatment of the animals with nicotine (0.1 mg/kg) decreased this ratio only in the hippocampus. Sub-chronic stress decreased the pCREB/CREB ratios in the hippocampus and the amygdala. Interestingly, sub-chronic stress-induced increase of nicotine reward only decreased the hippocampal pCREB/CREB ratio. The levels of BDNF in the hippocampus and the amygdala decreased under acute stress. Acute stress-induced increase of nicotine reward increased BDNF levels in the hippocampus. Moreover, the animals' exposure to the CPP apparatus without any drug administration increased the ratios of pCREB/tCREB and BDNF/ß-actin in the targeted sites. In summary, the present study indicate that the alterations of the ratio of pCREB/CREB and also the level of BDNF in the hippocampus may be critical for enhancing nicotine reward under stress condition. The evidence from this study suggests the distinct roles of the hippocampus and the amygdala in mediating nicotine reward under stress.

NDRG4 Alleviates Aß1-40 Induction of SH-SY5Y Cell Injury via Activation of BDNF-Inducing Signalling Pathways.

We explored the functions and mechanisms of N-myc downstream-regulated gene 4 (NDRG4) in an amyloid beta 1-40 induced Alzheimer's disease cell model. The levels of total and phosphorylated Tau protein were significantly up-regulated and cell activity was decreased with increasing Aß1-40 treatment in SH-SY5Y cells. The expression of NDRG4 mRNA and protein levels were significantly decreased that induced by Aß1-40 in these cells. NDRG4 overexpression significantly alleviated Aß1-40-induced SH-SY5Y apoptosis rates and caspases-3/7 activities. Equally, Reactive oxygen species, Mitochondrial membrane potential and Microscale malondialdehyde levels were significantly down-regulated, and Superoxide dismutase activity was increased by NDRG4 overexpression. BDNF protein level and phosphorylation levels of AKT and ERK1/2 were enhanced by NDRG4 overexpression. We also determined that the inhibitory effects of NDRG4 on cell apoptosis and Reactive oxygen species release were partially reversed by BDNF silencing, and by application of the PI3K specific inhibitor (LY294002) or ERK inhibitor (PD98059). These data indicate that NDRG4 attenuates Aß1-40-induced cell apoptosis and Reactive oxygen species release release, as well as oxidative stress injury. These effects may be mediated through BDNF-induced PI3K/AKT and MEK/ERK pathways.