Brain-derived Neurotrophic Factor Gene Expression Research Articles

Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter.

Recent increases in fructose consumption have raised concerns about the potential adverse intergenerational effects of excess fructose intake. In the present study, we investigated whether excess maternal fructose intake affects hippocampal function in offspring. Female Sprague-Dawley rats were divided into 3 experimental groups: one group received distilled water, one group received 20% fructose water, and one group received 20% glucose water in addition to standard chow during gestation and lactation. Hippocampal function of offspring was evaluated by using novel object recognition and fear conditioning tests. Impaired cognitive performance was observed in the offspring of fructose-fed dams at postnatal d 60, potentially a result of decreased hippocampal neurogenesis. Real-time PCR analysis demonstrated that offspring from fructose-fed dams exhibited decreased brain-derived neurotrophic factor ( BDNF) gene expression, whereas pyrosequencing assays revealed increased DNA methylation at the BDNF promoter. The potential association between BDNF transcription and levels of DNA methylation was confirmed on the basis of luciferase activity. Furthermore, longitudinal analysis revealed that increased methylation of the BDNF promoter region was maintained at least until rats reached maturity. These results indicate that epigenetic changes associated with BDNF may underlie hippocampal dysfunction that is induced by early-life exposure to excess maternal fructose consumption.-Yamazaki, M., Yamada, H., Munetsuna, E., Ishikawa, H., Mizuno, G., Mukuda, T., Mouri, A., Nabeshima, T., Saito, K., Suzuki, K., Hashimoto, S., Ohashi, K. Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter.

Effect of quercetin on the brain-derived neurotrophic factor gene expression in the rat brain.

Quercetin is a ubiquitous flavonoid found in many plants. Neuroprotective effects of quercetin have been shown in several in vitro and in vivo studies, but its mechanism of action has not been fully defined yet. Brain-derived neurotrophic factor (BDNF) is a fundamental neurotrophin with vital functions in the survival of neuronal cells. In the present study, we aimed to investigate the effects of quercetin on expression of BDNF mRNA in the hippocampus of rat brain. Male rats were daily gavaged with quercetin (10, 20 or 50 mg/kg·bwt) for 30 days. Hippocampal levels of the BDNF transcripts were assessed using quantitative (q) RT-PCR. Quercetin at doses of 20 and 50 mg/kg caused a significant increase in the mRNA expression of BDNF as compared with the control group. Quercetin treatment at a dose of 10 mg/kg failed to cause any significant changes in the levels of BDNF mRNA CONCLUSION: Our findings suggest that the neuroprotective effects of quercetin may be at least partly due to its inducing effects on the expression levels of the BDNF mRNA (Fig. 1, Ref. 40).

Effects of acute voluntary loaded wheel running on BDNF expression in the rat hippocampus.

[Purpose]Voluntary loaded wheel running involves the use of a load during a voluntary running activity. A muscle-strength or power-type activity performed at a relatively high intensity and a short duration may cause fewer apparent metabolic adaptations but may still elicit muscle fiber hypertrophy. This study aimed to determine the effects of acute voluntary wheel running with an additional load on brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus. [Methods]Ten-week old male Wistar rats were assigned randomly to a (1) sedentary (Control) group; (2) voluntary exercise with no load (No-load) group; or (3) voluntary exercise with an additional load (Load) group for 1-week (acute period). The expression of BDNF genes was quantified by real-time PCR. [Results]The average distance levels were not significantly different in the No-load and Load groups. However, the average work levels significantly increased in the Load group. The relative soleus weights were greater in the No-load group. Furthermore, loaded wheel running up-regulated the BDNF mRNA level compared with that in the Control group. The BDNF mRNA levels showed a positive correlation with workload levels (r=0.75), suggesting that the availability of multiple workload levels contributes to the BDNF-related benefits of loaded wheel running noted in this study. [Conclusion]This novel approach yielded the first set of findings showing that acute voluntary loaded wheel running, which causes muscular adaptation, enhanced BDNF expression, suggesting a possible role of high-intensity short-term exercise in hippocampal BDNF activity.

Evaluation of the BDNF, NGF, NT3 and NT4 Genes Expressions in the Brains of Neonatal Mice with Hypothyroidism

Background and Aim: Thyroid is one of the endocrine glands, (T3 and T4) play a significant role in the development of prenatal brain and the following stages. The study aimed to evaluate the effect of hypothyroidism on the amount of expression of NT4, NT3, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in brain of one-day rat neonates with hypothyroidism.Materials and Methods: In total, 25 mature mice of Albino NMRI race were selected after mating, divided into three group, control, as well as low-dose and high-dose intervention groups. Samples of the control group received pure water during pregnancy, whereas subjects of the intervention group with low and high doses of the medication were administered with 20 mg and 100 mg methimazole powder (dissolved in 100 cc water), respectively. After child delivery, blood samples were obtained from mother mice to determine the level of T3 and T4 in blood serum. Following that, the brain of one-day mice were removed by surgery and assessed to determine the amount of expression of NT4, NT3, NGF and BDNF using the complete kit of RT-PCR.Results: Levels of T4 and T3 in the control group were 28 ug/dl and 1.59 ug/dl, respectively. In the low-dose intervention group, the amounts of the mentioned hormones were 8 ug/dl and 0.85 ug/dl, significantly, indicating a significant reduction in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group. Moreover, T4 and T3 were 6 ug/dl and 0.79 ug/dl in the high-dose group, respectively, conveying a significant decrease in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group (P<0.05).

MicroRNA-10a-5p suppresses cancer proliferation and division in human cervical cancer by targeting BDNF.

The aim of the present study was to investigate the effect and mechanism of microRNA (miR)-10a-5p in human cervical cancer. The expression level of miR-10-5p in cervical cancer lines was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In cervical cancer HeLa and SiHa cells, miR-10-5p was ectopically overexpressed by lentiviral transduction. Brain-derived neurotrophic factor (BDNF) was then overexpressed in HeLa and SiHa cells to evaluate its selective effect on miR-10-5p in cervical cancer modulation. The targeting of miR-10-5p on its downstream gene, BDNF, was evaluated using RT-qPCR and western blot analysis. Cervical cancer cell viability and cell cycle was evaluated using an MTT assay and flow cytometry, respectively. The results indicated that miR-10-5p expression was significantly lower in cervical cancer cell lines compared with normal cells (P<0.05). Ectopic overexpression of miR-10-5p significantly inhibited cancer cell viability and induced cell cycle arrest in HeLa and SiHa cells (both P<0.05). miR-10-5p overexpression significantly reduced BDNF gene expression (P<0.05) and also reduced BDNF protein levels in cervical cancer cells compared with the control. In conclusion, the current study indicated that miR-10-5p is a cervical cancer suppressor, which regulates BDNF expression in cervical cancer.

Growth hormone protects against kainate excitotoxicity and induces BDNF and NT3 expression in chicken neuroretinal cells

There is increasing evidence to suggest a beneficial neuroprotective effect of growth hormone (GH) in the nervous system. While our previous studies have largely focused on retinal ganglion cells (RGCs), we have also found conclusive evidence of a pro-survival effect of GH in cells of the inner nuclear layer (INL) as well as a protective effect on the dendritic trees of the inner plexiform layer (IPL) in the retina. The administration of GH in primary neuroretinal cell cultures protected and induced neural outgrowths. Our results, both in vitro (embryo) and in vivo (postnatal), showed neuroprotective actions of GH against kainic acid (KA)-induced excitotoxicity in the chicken neuroretina. Intravitreal injections of GH restored brain derived neurotrophic factor (BDNF) expression in retinas treated with KA. In addition, we demonstrated that GH over-expression and exogenous administration increased BDNF and neurotrophin-3 (NT3) gene expression in embryonic neuroretinal cells. Thus, GH neuroprotective actions in neural tissues may be mediated by a complex cascade of neurotrophins and growth factors which have been classically related to damage prevention and neuroretinal tissue repair.

P.1.h.018 - Memory impairments and changes of brain-derived neurotrophic factor gene expression in depressive-like state development

P.1.h.018 - Memory impairments and changes of brain-derived neurotrophic factor gene expression in depressive-like state development

The effect of childhood trauma on serum BDNF in bipolar depression is modulated by the serotonin promoter genotype.

In healthy humans, both childhood trauma and the short form of the serotonin promoter transporter genotype (5-HTTLPR) are associated with lower levels of brain-derived neurotrophic factor (BDNF). In subjects with bipolar disorder (BD), lower levels of BDNF and a higher degree of childhood trauma were observed compared with healthy controls. However, is still unknown if the functional 5-HTTLPR polymorphisms exerts an effect on both abnormalities. In 40 inpatients affected by a major depressive episode in the course of BD, we genotyped 5-HTTLPR, measured serum BDNF with ELISA, and assessed early adversities by the childhood trauma questionnaire (CTQ). Data were analyzed in the context of the general linear model correcting for age, sex, ongoing lithium treatment, severity of current depression, and CTQ minimization/denial scores to investigate the effect of 5-HTTLPR polymorphism and childhood trauma on BDNF levels. Early trauma were negatively associated with BDNF serum levels (higher CTQ scores, lower BDNF; p=0.0019). 5-HTTLPR l/l homozygotes showed significantly higher BDNF levels than 5-HTTLPR*s carriers (30.57±6.13 vs 26.82±6.41; p=0.0309). A separate-slopes analysis showed that 5-HTTLPR significantly influenced the relationship between early trauma and adult BDNF (interaction of 5-HTTLPR with CTQ scores: p=0.0023), due to a significant relationship between trauma and BDNF in 5-HTTLPR*s carriers, but not among l/l homozygotes. Putatively detrimental effects of childhood trauma exposure on adult BDNF serum levels are influenced by 5-HTTLPR genotype in patients affected by BD. Possible mechanisms include epigenetic modulation of BDNF gene expression, due to different reactivity to stressors in 5-HTTLPR genotype groups.

Minimal traumatic brain injury causes persistent changes in DNA methylation at BDNF gene promoters in rat amygdala: A possible role in anxiety-like behaviors

Minimal traumatic brain injury (MTBI) often transforms into chronic neuropsychiatric conditions including anxiety, the underlying mechanisms of which are largely unknown. In the present study, we employed the closed-head injury paradigm to induce MTBI in rats and examined whether DNA methylation can explain long-term changes in the expression of the brain-derived neurotrophic factor (BDNF) in the amygdala as well as trauma-induced anxiety-like behaviors. The MTBI caused anxiety-like behaviors and altered the expression of DNA methyltransferase (DNMT) isoforms (DNMT1, DNMT3a, and DNMT3b) and factors involved in DNA demethylation such as the growth arrest and DNA damage 45 (GADD45a and GADD45b). After 30days of MTBI, the over-expression of DNMT3a and DNMT3b corresponded to heightened DNMT activity, whereas the mRNA levels of GADD45a and GADD45b were declined. The methylated cytosine levels at the BDNF promoters (Ip, IVp and IXp) were increased in the amygdala of the trauma-induced animals; these coincided negatively with the mRNA levels of exon IV and IXa, but not of exon I. Interestingly, treatment with 5-azacytidine, a pan DNMT inhibitor, normalized the MTBI-induced DNMT activity and DNA hypermethylation at exon IVp and IXp. Furthermore, 5-azacytidine also corrected the deficits in the expression of exons IV and IXa and reduced the anxiety-like behaviors. These results suggest that the DNMT-mediated DNA methylation at the BDNF IVp and IXp might be involved in the regulation of BDNF gene expression in the amygdala. Further, it could also be related to MTBI-induced anxiety-like behaviors via the regulation of synaptic plasticity.

Protective Effects Induced by Microwave-Assisted Aqueous Harpagophytum Extract on Rat Cortex Synaptosomes Challenged with Amyloid β-Peptide.

Harpagophytum procumbens is a plant species that displays anti-inflammatory properties in multiple tissues. The iridoid glycosides arpagoside, harpagide, and procumbide appear to be the most therapeutically important constituents. In addition, harpagoside treatment exerted neuroprotective effects both in vitro and in vivo. Considering these findings, the aim of the present work is to explore the possible protective role of the previously described microwave-assisted aqueous extract of H.procumbens on rat hypothalamic (Hypo-E22) cells, and in rat cortex challenged with amyloid β-peptide (1-40). In this context, we assayed the protective effects induced by H.procumbens by measuring the levels of malondialdehyde, 3-hydroxykynurenine (3-HK), brain-derived neurotrophic factor, and tumor necrosis factor-α, 3-HK. Finally, we evaluated the effects of H.procumbens treatment on cortex levels of dopamine, norepinephrine, and serotonin. H.procumbens extract was well tolerated by Hypo-E22 cells and upregulated brain-derived neurotrophic factor gene expression but down-regulated tumor necrosis factor-α gene expression. In addition, the extract reduced amyloid β-peptide stimulation of malondialdehyde and 3-HK and blunted the decrease of dopamine, norepinephrine, and serotonin, in the cortex. In this context, our work supports further studies for the evaluation and confirmation of Harpagophytum in the management of the clinical symptoms related to Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain.

Spaceflight entails various stressful environmental factors including microgravity. The effects of gravity changes have been studied extensively on skeletal, muscular, cardiovascular, immune and vestibular systems, but those on the nervous system are not well studied. The alteration of gravity in ground-based animal experiments is one of the approaches taken to address this issue. Here we investigated the effects of centrifugation-induced gravity changes on gene expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors (5-HTRs) in the mouse brain. Exposure to 2g hypergravity for 14 days showed differential modulation of gene expression depending on regions of the brain. BDNF expression was decreased in the ventral hippocampus and hypothalamus, whereas increased in the cerebellum. 5-HT1BR expression was decreased in the cerebellum, whereas increased in the ventral hippocampus and caudate putamen. In contrast, hypergravity did not affect gene expression of 5-HT1AR, 5-HT2AR, 5-HT2CR, 5-HT4R and 5-HT7R. In addition to hypergravity, decelerating gravity change from 2g hypergravity to 1g normal gravity affected gene expression of BDNF, 5-HT1AR, 5-HT1BR, and 5-HT2AR in various regions of the brain. We also examined involvement of the vestibular organ in the effects of hypergravity. Surgical lesions of the inner ear’s vestibular organ removed the effects induced by hypergravity on gene expression, which suggests that the effects of hypergravity are mediated through the vestibular organ. In summary, we showed that gravity changes induced differential modulation of gene expression of BDNF and 5-HTRs (5-HT1AR, 5-HT1BR and 5-HT2AR) in some brain regions. The modulation of gene expression may constitute molecular bases that underlie behavioral alteration induced by gravity changes.

Placental and cord blood brain derived neurotrophic factor levels are decreased in nondiabetic macrosomia.

To measure levels of placental brain derived neurotrophic factor (BDNF) gene expression and umbilical cord blood BDNF in neonates with nondiabetic macrosomia and determine associations between these levels and macrosomia. This case-control study included 58 nondiabetic macrosomic and 59 normal birth weight mother-infant pairs. Data were collected from interviews and our hospital's database. BDNF gene expression was quantified in placental tissues using quantitative real-time polymerase chain reaction (n=117). Umbilical cord blood BDNF levels were measured by enzyme-linked immunosorbent assay (n=90). Multivariate logistic regression models were used to evaluate associations between BDNF levels and macrosomia. Placental BDNF gene expression (P=0.026) and cord blood BDNF (P=0.008) were lower in neonates with nondiabetic macrosomia than in normal birth weight controls. Cord blood BDNF was significantly lower in vaginally delivered macrosomic neonates than vaginally delivered controls (P=0.014), but cord BDNF did not differ between vaginal and cesarean section delivery modes in macrosomic neonates. Cord blood BDNF was positively associated with gestational age in control neonates (r=0.496, P<0.001), but not in macrosomic neonates. Cord blood BDNF was positively associated with placental BDNF relative expression (r s=0.245, P=0.02) in the total group. Higher cord blood BDNF levels were independently associated with protection against nondiabetic macrosomia (adjusted odds ratio 0.992; 95% confidence interval 0.986-0.998). Both placental BDNF gene expression and cord blood BDNF were downregulated in neonates with nondiabetic macrosomia compared with normal birth weight neonates. Cord BDNF may partly derive from BDNF secreted by the placenta. Higher cord plasma BDNF levels protected against nondiabetic macrosomia.

Lotus Root Extract Stimulates BDNF Gene Expression Through Potential Mechanism Depending on HO-1 Activity in C6 Glioma Cells

ABSTRACTPolyphenolic compounds have been suggested to be involved in the preservation of neural function via the production of neurotrophic factors in the brain. The nonedible joint part of lotus root (a rhizome of Nelumbo nucifera) has been reported to contain large amounts of polyphenolic compounds and, therefore, is expected to improve neural function by stimulating the production of brain-derived neurotrophic factor (BDNF) in glial cells. The effect of the aqueous extract prepared from the joint part of lotus root on BDNF gene expression was examined in C6 glioma cells as an in vitro model. This extract was shown to increase BDNF messenger ribonucleic acid (mRNA) levels to the elevation of HO-1 mRNA levels in the glioma cells, but failed to cause the elevation of BDNF mRNA levels in the cells pretreated with a HO-1 antisense oligodeoxynucleotide (ODN) or an HO-1 enzyme inhibitor zinc protoporphyrin (ZnPP). These findings strongly suggest that the aqueous extract prepared from the nonedible joint part of lotus root might be able to stimulate BDNF gene expression by enhancing HO-1 activity in the glioma cells, proposing the possibility that the joint part of lotus root might potentially improve neural function through the stimulation of BDNF production in glial cells.

DNA methylation mechanism of intracellular zinc deficiency-induced injury in primary hippocampal neurons in the rat brain

Objective: To explore Zn2+ deficiency-induced neuronal injury in relation to DNA methylation, providing valuable data and basic information for clarifying the mechanism of Zn2+ deficiency-induced neuronal injury.Methods: Cultured hippocampal neurons were exposed to the cell membrane-permeant Zn2+ chelator N,N,N',N'-Tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) (2 μM), and to TPEN (2 μM) plus ZnSO4 (5 μM) for 24 hours. We analyzed intracellular Zn2+ levels, neuronal viability, and protein/mRNA levels for DNA (cytosine-5) methyltransferase 1 (DNMT1), DNA (cytosine-5-) methyltransferase 3 alpha (DNMT3a), methyl CpG binding protein 2 (MeCP2), Brain-derived neurotrophic factor (BDNF), and growth arrest and DNA-damage-inducible, beta (GADD45b) in the treated neurons.Results: We found that exposure of hippocampal neurons to TPEN (2 μM) for 24 hours significantly reduced intracellular Zn2+ concentration and neuronal viability. Furthermore, DNMT3a, DNMT1, BDNF, and GADD45b protein levels in TPEN-treated neurons were significantly downregulated, whereas MeCP2 levels were, as expected, upregulated. In addition, DNMT3a and DNMT1 mRNA levels in TPEN-treated neurons were downregulated, while MeCP2, GADD45b, and BDNF mRNA were largely upregulated. Addition of ZnSO4 (5 μM) almost completely reversed the TPEN-induced alterations.Conclusion: Our data suggest that free Zn2+ deficiency-induced hippocampal neuronal injury correlates with free Zn2+ deficiency-induced changes in methylation-related protein gene expression including DNMT3a/DNMT1/MeCP2 and GADD45b, as well as BDNF gene expression.

The Combinatory Effects of Diet and Exercise on BDNF Gene Expression

Brain Derived Neurotrophic Factor (BDNF) plays a critical role in the synaptic activity and plasticity of mature neurons and regulates the formation and maintenance of memory. Furthermore, human and mouse BDNF levels were found to be altered in psychiatric diseases. Actually, BDNF signaling not only contributes to the pathophysiology of depression, but also is important for the therapeutic effects of antidepressants. On the other hand, exercise induces beneficial responses in the brain, many of which are mediated through induction of BDNF expression. Moreover, BDNF expression was shown to be enhanced under select dietary conditions. However the exact mechanisms for these inductions have been elusive. The aim of the present work was to explore the effect of combining different diets with exercise on BDNF expression in the brain.First, C57BL/6 mice were divided into 6 groups based on the diet they received (standard versus high protein versus high fat) and whether they were provided with a running wheel to exercise during 28 days or not. Results showed that high protein diets induced BDNF expression and that combining this diet with voluntary exercise had an additive effect on BDNF expression. In contrast, a high fat diet attenuated the positive effects of exercise on BDNF expression.In a second experiment, the effect of dietary leucine (1.5% or 3%) was tested in mice exposed to the same 28‐day voluntary exercise paradigm as the first experiment. Results showed that supplementation with 1.5% leucine significantly induced BDNF in the brain, and this effect was additive with exercise as well. Future work will investigate whether the effect found is restricted to leucine or may be extended to other branched chain amino acids such as isoleucine or valine.The present results enrich our understanding of how exercise and different diets coordinate to induce BDNF gene expression and may be used in identifying novel therapeutic targets for depression.

Schwann cells promote the capability of neural stem cells to differentiate into neurons and secret neurotrophic factors.

The present study investigated whether co-culturing Schwann cells (SCs) with neural stem cells (NSCs) improves viability, direction of differentiation and secretion of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in NSCs. The three groups assessed were as follows: SCs, NSCs, and a co-culture of SCs and NSCs. Cellular morphological changes were observed under an inverted phase contrast microscope and quantified. Cells were identified by immunofluorescence staining: S100 for SCs, Nestin for NSCs, microtubule associated protein (Map) 2 and NeuN for neurons and glial fibrillary acidic protein for astrocytes. Cell viability was evaluated by MTT assay. Secretion of BDNF and GDNF was quantified; mRNA expression was quantified by reverse transcription-quantitative polymerase chain reaction. The majority of NSCs in the co-cultured group differentiated into neurons. The cell survival rate of the co-culture group was significantly higher than the other groups on days 3, 5 and 10 (P<0.01). The secretion of BDNF in the co-culture group was significantly higher than NSCs on days 3, 5 and 7 (P<0.05), while the amount of GDNF in co-culture was significantly higher than both NSCs and SCs on day 1 (P<0.05). BDNF and GDNF gene expression in the co-culture group was significantly higher than SCs (P<0.01). Gene expression of Map2 in co-culture group was also significantly higher than both NSC and SC groups (P<0.01). Therefore, co-cultured SCs and NSCs promote differentiation of NSCs into neurons and secrete higher levels of neurotropic factors including BDNF and GDNF.

Prolonged maternal separation attenuates BDNF-ERK signaling correlated with spine formation in the hippocampus during early brain development.

Maternal separation (MS) is known to affect hippocampal function such as learning and memory, yet the molecular mechanism remains unknown. We hypothesized that these impairments are attributed to abnormities of neural circuit formation by MS, and focused on brain-derived neurotrophic factor (BDNF) as key factor because BDNF signaling has an essential role in synapse formation during early brain development. Using rat offspring exposed to MS for 6h/day during postnatal days (PD) 2-20, we estimated BDNF signaling in the hippocampus during brain development. Our results show that MS attenuated BDNF expression and activation of extracellular signal-regulated kinase (ERK) around PD 7. Moreover, plasticity-related immediate early genes, which are transcriptionally regulated by BDNF-ERK signaling, were also reduced by MS around PD 7. Interestingly, detailed analysis revealed that MS particularly reduced expression of BDNF gene and immediate early genes in the cornu ammonis 1 (CA1) of hippocampus at PD 7. Considering that BDNF-ERK signaling is involved in spine formation, we next evaluated spine formation in the hippocampus during the weaning period. Our results show that MS particularly reduced mature spine density in proximal apical dendrites of CA1 pyramidal neurons at PD 21. These results suggest that MS could attenuate BDNF-ERK signaling during primary synaptogenesis with a region-specific manner, which is likely to lead to decreased spine formation and maturation observed in the hippocampal CA1 region. It is speculated that this incomplete spine formation during early brain development has an influence on learning capabilities throughout adulthood.

Mind-body medicine epigenetic technique (MET), cognitive flexibility, and brain-derived neurotrophic factor (BDNF) gene expression.

172 Background: This is a pilot study update on the potential of MET to up-regulate BDNF gene expression with breast cancer patients assessed with high cognitive flexibility. MET is a technique developed to manage chronic stress and anxiety. BDNF gene expression is associated with learning and memory. Cognitively flexibility is defined as the ability to focus and sustain attention. It also implies vivid imagination and holistic thinking. Methods: The selection process for the study participants was nonrandom. The following was the eligibility criteria. 1. Inclusion Criteria: Breast Cancer, Stages II, III 2. Exclusion Criteria: Cognitively impaired, weak or ill. The study utilized two groups. Each group was assigned two research participants. Group One received one session of MET. Group Two received two sessions of MET. Each MET session was approximately 25-35 minutes in duration. Blood samples were taken at baseline and post-MET sessions to provide evidence in gene expression changes. For Group Two, the post-MET session blood draw was done 7 days after baseline. 1. Primary Endpoint: To determine whether MET can up-regulate BDNF gene expression. 2. Secondary Endpoint:To determine whether there is a correlation between up-regulated BDNF gene expression and cognitive flexibility. The blood samples were sent to genomics labs at the Children’s Hospital of Los Angeles and the University of Nevada Las Vegas for mRNA extraction and microarray analysis. The gene expression was measured by DNA microarray results using the “PrimeView gene chip” and “Partek Genomics Suite” statistical software. Results: One participant from Group 1 evidenced a biologically significant up-regulation of BDNF gene expression. This participant was assessed with high cognitive flexibility. One major limitation of these findings is the statistical insignificance of the results due to the small number of participants. Conclusions: This pilot study evidenced the up-regulation of BDNF gene expression potentially due to MET and provided evidence for the potential correlation of BDNF gene expression and cognitive flexibility. This study also provided a foundation for a larger study with more participants.

Effects of Lavandula angustifolia essential oil on Interleukin 23 and Brain-Derived neurotrophic factor gene expression in peripheral blood mononuclear cells of multiple sclerosis patients

Introduction: We aimed to determine the effect of lavandula angustifolia essential oil (LEO) on IL-23 and brain-derived neurotrophic factor (BDNF) gene expressions in peripheral blood mononuclear cells (PBMCs) of relapse-remitting MS (RRMS) patients. Methods : LEO was prepared using the hydrodistilation method on the plants aerial parts. 8 female RRMS patients and 8 healthy sex and age matched controls were entered into this study. PBMC cells were separated using Ficoll method and were treated with a concentration of 225 µg/ml LEO which and then the mRNAs were used for determining the effects of LEO on IL-23 and BDNF gene expressions using Quantitative Real Time PCR technique. Moreover in order to determine the anti-inflammatory effects of LEO, we measured the gene expression of IL-6 and IL-23 in stimulated healthy PBMC cells treated with LEO. Results: Results showed that there is no significant difference between PBMC of patients compared to healthy controls in case of IL-23 gene expression. Moreover, LEO has no significant effect on gene expression of IL-23 in PBMC of neither patients nor control. Also the results showed that BDNF gene expression is reduced to 41% compared to healthy controls and LEO can increase the BDNF gene expression by 81% in patients PBMCs. Moreover we observed that LEO can significantly reduce the LPS stimulated IL-6 gene expression in healthy PBMCs but had no significant effect on IL-23 gene expression. Conclusion : The present study demonstrated that L.angustifolia essential oil may have a protective effect against neuron damage via increasing the gene expression of BDNF in PBMCs from RRMS patients. However, further studies are necessary to confirm our results.

Dual and multi-drug delivery nanoparticles towards neuronal survival and synaptic repair.

Among the macromolecular drug targets in neurodegenerative disorders, the neurotrophin brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related kinase receptor (TrkB) present strong interest for nanomedicine development aiming at neuronal and synaptic repair. Currently, BDNF is regarded as the neurotrophic factor of highest therapeutic significance. However, BDNF has delivery problems as a protein drug. The enhanced activation of the transcription factor CREB (cAMP response element-binding protein) has been evidenced to increase the BDNF gene expression and hence the production of endogenous BDNF. We assume that BDNF delivery by nanocarriers and mitochondrial protection may provide high potential for therapeutic amelioration of the neuroregenerative strategies. Beneficial therapeutic outcomes may be expected for synergistic dual or multi-drug action aiming at (i) neurotrophic protein regulation in the central and peripheral nervous systems, and (ii) diminishment of the production of reactive oxygen species (ROS) and the oxidative damage in mitochondria. Our research strategy is based on a nanoarchitectonics approach for the design of nanomedicine assemblies by hierarchical self-assembly. We explore nanoarchitectonics concepts in soft-matter nanotechnology towards preparation of biodegradable self-assembled lipid nanostructures for safe neuro-therapeutic applications of multi-target nanomedicines.