Brain-derived Neurotropic Factor Expression Research Articles

Heat-Processed Soybean Germ Extract and Lactobacillus gasseri NK109 Supplementation Reduce LPS-Induced Cognitive Impairment and Colitis in Mice.

Soybean alleviates cognitive impairment. In our preparatory experiment, we found that dry-heat (90 °C for 30 min)-processed soybean embryo ethanol extract (hSE) most potently suppressed lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α expression in BV2 cells among dry-heat-, steaming-, and oil exclusion-processed soybean embryo ethanol extracts (SEs). Heat processing increased the absorbable soyasaponin Bb content of SE. Therefore, we investigated whether hSE and its supplement could mitigate LPS-impaired cognitive function in mice. Among dry-heat-, steaming-, and oil exclusion-processed SEs, hSE mitigated LPS-impaired cognitive function more than parental SE. hSE potently upregulated LPS-suppressed brain-derived neurotropic factor (BDNF) expression in the hippocampus, while LPS-induced TNF-α and IL-1β expression in the hippocampus and colon were downregulated. Lactobacillus gasseri NK109 additively increased the cognitive function-enhancing activity of hSE in mice with LPS-induced cognitive impairment as follows: the hSE and NK109 mix potently increased cognitive function and hippocampal BDNF expression and BDNF-positive neuron cell numbers and decreased TNF-α expression and NF-κB-positive cell numbers in the hippocampus and colon. These findings suggest that hSE and its supplement may decrease colitis and neuroinflammation by suppressing NF-κB activation and inducing BDNF expression, resulting in the attenuation of cognitive impairment.

Azadiradione up-regulates the expression of parvalbumin and BDNF via Ube3a

Azadiradione is a small bioactive limonoid found in the seed of Azadirachta Indica, an Indian medicinal plant commonly known as Neem. Recently, it has been shown to ameliorate the disease pathology in fly and mouse model of Huntington’s disease by restoring impaired proteostasis. Here we report that the azadiradione could be involved in modulating the synaptic function through increased expression of Ube3a, a dual function protein having ubiquitin ligase and co-activator functions and associated with Angelman syndrome and autism. Treatment of azadiradione to HT22 hippocampal cell line and in adult mice induced the expression of Ube3a as well as two important synaptic function and plasticity regulating proteins, parvalbumin and brain-derived neurotropic factor (BDNF). Interestingly, another synaptic plasticity modulating protein Arc (activity-regulated cytoskeletal associated protein) was down-regulated by azadiradione. Partial knockdown of Ube3a in HT22 cell abrogated azadiradione induced expression of parvalbumin and BDNF. Ube3a-maternal deficient mice also exhibited significantly decreased expression of parvalbumin and BDNF in their brain and treatment of azadiradione in these animals did not rescue the altered expression of either parvalbumin or BDNF. These results indicate that azadiradione-induced expression of parvalbumin and BDNF in the brain is mediated through Ube3a and suggest that azadiradione could be implicated in restoring synaptic dysfunction in many neuropsychiatric/neurodegenerative disorders.

Alleviation of Cognitive Impairment-like Behaviors, Neuroinflammation, Colitis, and Gut Dysbiosis in 5xFAD Transgenic and Aged Mice by Lactobacillus mucosae and Bifidobacterium longum.

Neuropsychiatric disorders including Alzheimer's disease (AD) may cause gut inflammation and dysbiosis. Gut inflammation-suppressing probiotics alleviate neuropsychiatric disorders. Herein, to understand whether anti-inflammatory probiotics Lactobacillus mucosae NK41 and Bifidobacterium longum NK46, which suppressed tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated macrophages, could alleviate cognitive impairment, we first examined their effects on cognitive function, gut inflammation, and gut microbiota composition in 5xFAD-transgenic mice. Oral administration of NK41 or NK46 decreased cognitive impairment-like behaviors, hippocampal amyloid-β (Aβ), TNF-α and interleukin (IL)-1β expression, hippocampal NF-κB+Iba1+ cell population, and Aβ accumulation, while hippocampal brain-derived neurotropic factor (BDNF) and IL-10 expression and BDNF+NeuN+ cell population increased. They also decreased TNF-α and IL-1β expression and NF-κB+CD11c+ cell population in the colon. They also reduced fecal and blood LPS levels and gut Proteobacteria and Verrucomicrobia populations (including Akkkermansiaceae), which are positively associated with hippocampal TNF-α and fecal LPS levels and negatively correlated with hippocampal BDNF level. However, they increased Odoribactericeae, which positively correlated with BDNF expression level and TNF-α to IL-10 expression ratio. The combination of NK41 and NK46 (4:1, NKc), which potently inhibited TNF-α expression in LPS-stimulated macrophages, additively alleviated cognitive impairment-like behaviors in 5xFAD-transgenic or aged mice. NKc increased hippocampal BDNF+NeuN+ cell population and BDNF expression in 5xFAD-transgenic or aged mice, while hippocampal TNF-α and IL-1β expression decreased. NKc also decreased TNF-α and IL-1β expression in the colon and LPS levels in the blood and feces. These findings suggest that gut bacteria and its product LPS may be closely connected with occurrence of cognitive impairment and neuroinflammation and the combination of NK41 and NK46 can additively alleviate cognitive impairment and neuroinflammation by inducing NF-κB-suppressed BDNF expression and suppressing LPS-producing gut bacteria.

Disinhibition of Mesolimbic Dopamine Circuit by the Lateral Hypothalamus Regulates Pain Sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.

BDNF expression in brain regions of Anorexia Nervosa mouse model, a biomarker of diagnostic and prognostic?

IntroductionAnorexia nervosa (AN) is a complex mental disorder mainly characterized by a voluntary food restriction and excessive physical activity resulting in dramatic weight loss. Changes in the brain-derived neurotropic factor (BDNF) have been reported in AN patients compared to controls. According to meta-analysis, functional variant rs6265 Val66Met of the BDNF gene has been found genetically associated to AN. We also reported an association of this functional variant and electrodermal response to images of thinness suggesting an association between rs6265 and a reward effect of weight loss in AN. In animal models, BDNF modulates negatively the central control of food intake and its injection in rodents induces weight loss and anorexia. Thus, besides its function on neuronal survival, synaptic plasticity and mood, BDNF was also reported to have a metabolic effect via both central nervous system and peripheral organs, which makes BDNF a good candidate for AN diagnosis biomarker.ObjectivesOur study investigates the levels of expression of Bdnf, gene and protein, taking advantage of the mouse AN-like model by measuring Bdnf levels in specific brain areas and blood in food-restricted and refeed animals.MethodsWe used a mouse AN-like model combining a phase of chronic food restriction (50%) during 15 days followed by an ad libitum refeeding period of one week. Female mice have or not access to a running with wheel to create a similar metabolic environment that those patients suffering from AN during restriction and recovery once hospitalised. The Bdnf mRNA and protein levels were measured in samples of blood and brain regions (prefrontal cortex, hippocampus, hypothalamus, dorsal striatum, nucleus Accumbens, ventral tegmental area and amygdala) using quantitative PCR and ELISA methods in the different groups of mice (ad libitum, ad libitum with wheel, food restriction and food restriction with wheel). Statistical analysis will compare the measures for different samples by one-way or two-way ANOVAs depending the group of animals or brain regions and blood.ResultsTo date, no difference of the level of transcription for Bdnf was observed between the different groups of mice (ad libitum, ad libitum with wheel, food restriction and food restriction with wheel) in the prefrontal cortex, hippocampus and hypothalamus. We expect significant differences of Bdnf expression in the other brain regions of interest for the food restricted animals with or without the wheel compared to ad libitum animals. We expect also differences in the level of expression of Bdnf in fasted animals compared to the refeed animals.ConclusionsThe BDNF could represent a potential biomarker of AN for the diagnostic and the prognosis in the evolution to the remission when weight recover and thus will allow a better understanding of the aetiology of AN. This study is supported by Fédération pour la Recherche sur le Cerveau.Disclosure of InterestNone Declared

Effects of a variable light intensity lighting program on the welfare and performance of commercial broiler chickens.

Our previous variable-light intensity lighting program studies indicate the light intensity preference behavior of broilers for their daily activity including eating and resting. To evaluate the effects of variable-light intensity lighting program on performance and welfare of broilers, four commercial trials were conducted for looking at behaviors, mortality, leg-health, performance, and brain welfare indicator genes including tryptophan hydroxylase 2 and tyrosine hydroxylase (TH), glucocorticoid receptor (GR), brain-derived neurotropic factor (BDNF), and melanopsin (Opn4) gene expression. One-day-old broilers were housed in four commercial broiler houses. Each quadrant (section) of the house was placed with 4,800 chicks. A total of four lighting programs began on day 7 with 5 lux (lx), 20 lx, natural light (NL, 480 lx), and variable light (2-5/40 lx) using LED lights on a 16L:8D photoperiod. In the variable-light house, the number of dustbathing holes was significantly higher than that in natural-light houses and 5-lx and 20-lx houses. Daily physical activities, footpad condition, fear response to novel objects, body weight, feed conversion ratio, and the number of leg-problem induced culled birds were affected by the variable-light intensity lighting program. Expression of tryptophan hydroxylase 2 in the DRN and VTA of variable-light treated birds was lower than that of 5-lx- and 20-lx-treated birds on day 42 (p < 0.05). Higher expression of VTA-TH in 5-lx-treated birds than that in 20-lx-, NL-, and variable-light-treated birds suggests the high stress-susceptibility of 5-lx treated birds. Lower VTA-GR expression in 20-lx- and variable-light-treated birds indicates lower stress than that in NL- and 5-lx-treated birds (p < 0.05). The VTA-BDNF expression of NL-treated birds was 2.5 fold higher than that of 5-lx-, 20-lx-, and variable-light-treated birds (p < 0.05), and variable-light-treated birds showed the lowest level of BDNF expression (p < 0.05), suggesting the chronic social defeat stress in NL-treated birds. The result of VTA-Opn4 expression on day 42 suggests the possible role of VTA-Opn4 in broiler welfare through central light perception. Taken together, the variable-light intensity lighting program increased volunteer natural behaviors and physical activity, which may improve footpad condition and leg health of birds, consequently. Performance data including the increased daily weight gain and the lowered feed conversion ratio and results of brain welfare indicator gene expression showed the beneficial effect of the variable-light intensity lighting program on the performance and welfare of commercial broilers.

Myricetin prevents sleep deprivation-induced cognitive impairment and neuroinflammation in rat brain via regulation of brain-derived neurotropic factor.

Memory formation in the hippocampus is formed and maintained by circadian clock genes during sleep. Sleep deprivation (SD) can lead to memory impairment and neuroinflammation, and there remains no effective pharmacological treatment for these effects. Myricetin (MYR) is a common natural flavonoid that has various pharmacological activities. In this study, we investigated the effects of MYR on memory impairment, neuroinflammation, and neurotrophic factors in sleep-deprived rats. We analyzed SD-induced cognitive and spatial memory, as well as pro-inflammatory cytokine levels during SD. SD model rats were intraperitoneally injected with 10 and 20 mg/kg/day MYR for 14 days. MYR administration significantly ameliorated SD-induced cognitive and spatial memory deficits; it also attenuated the SD-induced inflammatory response associated with nuclear factor kappa B activation in the hippocampus. In addition, MYR enhanced the mRNA expression of brain-derived neurotropic factor (BDNF) in the hippocampus. Our results showed that MYR improved memory impairment by means of anti-inflammatory activity and appropriate regulation of BDNF expression. Our findings suggest that MYR is a potential functional ingredient that protects cognitive function from SD.

Topical review- salivary biomarkers in chronic muscle pain.

Muscle related temporomandibular disorders (myogenous TMD), one of the most common orofacial pain conditions, is characterized by facial pain and often accompanied by jaw movement limitations. Although the underlying biological mechanisms are still unclear, a cluster of proteins and peptides is assumed tobe involved in the pathophysiology. These proteins andpeptides may be measured in a simple non-invasive saliva sample. This work investigated whether saliva can be used to sample algogenic substances that can serve asmolecular biomarkers for TMD myalgia. Saliva and blood samples were collected from healthy individuals (n=69) and patients diagnosed with TMD myalgia (n=39) according to the Diagnostic Criteria for TMD. Unstimulated and stimulated whole, parotid, and sublingual saliva were analysed. The protein profiles were investigated using two-dimensional gel electrophoresis followed by identification with liquid chromatography tandem mass spectrometry. Levels of nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), and brain derived neuro-tropic factor (BDNF) were determined using western blotting based technology and multiplex electro-chemiluminescence assay panel. Glutamate, serotonin, and substance p (SP) were determined using commercially available methods. Different saliva collection approaches resulted insignificant differences in the protein profile as well as inthe expression of NGF, BDNF, CGRP, SP, and glutamate. Stimulated whole saliva showed least variability in protein concentration (35%) and was correlated to plasma levels ofglutamate. Unlike SP and glutamate, NGF and BDNF expressed a rhythmic variation in salivary expression withhigher levels in the morning (p<0.05). Patients with a diagnosis of TMD myalgia had significantly higher levels of salivary glutamate but lower salivary NGF and BDNF compared to controls; in addition, the lower NGF and BDNF levels correlated to psychological dysfunction. Thequantitative proteomics data revealed 20 proteins that were significantly altered in patients compared to controls. The identified proteins are involved in metabolic processes, immune response, and stress response. Dissimilarities in protein profile and clinical variables were observed between TMD myalgia and myofascial pain. The work highlights the importance of consistency in saliva collection approaches, including thetiming of the collection. It displayed significant changes in pain specific mediators and protein profile in TMD myalgia and furthermore dissimilarities between subclasses indicating different pathophysiology. After extensive validation, potential salivary biomarkers can becombined with clinical features to better understand and diagnose TMD myalgia.

Daphne genkwa flower extract promotes the neuroprotective effects of microglia

BackgroundMicroglia are innate immune cells in the central nervous system that play a crucial role in neuroprotection by releasing neurotrophic factors, removing pathogens through phagocytosis, and regulating brain homeostasis. The constituents extracted from the roots and stems of the Daphne genkwa plant have shown neuroprotective effects in an animal model of Parkinson's disease. However, the effect of Daphne genkwa plant extract on microglia has yet to be demonstrated. PurposeTo study the anti-inflammatory and neuroprotective effects of Daphne genkwa flower extract (GFE) in microglia and explore the underlying mechanisms. MethodsIn-vitro mRNA expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase, Arginase1, and brain derived neurotropic factor (BDNF) were analyzed by reverse transcription polymerase chain reaction in microglia cells. Nitric oxide (NO) and TNF-α protein were respectively analyzed by Griess reagent and Enzyme Linked Immunosorbent Assay. Immunoreactivity of Iba-1, Neu-N, and BDNF in mouse brain were analyzed by immunofluorescence staining. Phagocytosis capacity of microglia was examined using fluorescent zymosan-red particles. ResultsGFE significantly inhibited lipopolysaccharide (LPS)-induced neuroinflammation and promoted neuroprotection both in vitro and in vivo. First, GFE inhibited the LPS-induced inflammatory factors NO, iNOS, and TNF-α in microglial cell lines and primary glial cells, thus demonstrating anti-inflammatory effects. Arginase1 and BDNF mRNA levels were increased in primary glial cells treated with GFE. Phagocytosis was also increased in microglia treated with GFE, suggesting a neuroprotective effect of GFE. In vivo, neuroprotective and anti-neuroinflammatory effects of GFE were also found in the mouse brain, as oral administration of GFE significantly inhibited LPS-induced neuronal loss and inflammatory activation of microglia. ConclusionGFE has anti-inflammatory effects and promotes microglial neuroprotective effects. GFE inhibited the pro-inflammatory mediators and enhanced neuroprotective microglia activity by increasing BDNF expression and phagocytosis. These novel findings of the GFE effect on microglia show an innovative approach that can potentially promote neuroprotection for the prevention of neurodegenerative diseases.

Influence of Nutritional Ketosis Achieved through Various Methods on Plasma Concentrations of Brain Derived Neurotropic Factor.

Brain-Derived Neurotropic Factor (BDNF) expression is decreased in conditions associated with cognitive decline as well as metabolic diseases. One potential strategy to improve metabolic health and elevate BDNF is by increasing circulating ketones. Beta-Hydroxybutyrate (BHB) stimulates BDNF expression, but the association of circulating BHB and plasma BDNF in humans has not been widely studied. Here, we present results from three studies that evaluated how various methods of inducing ketosis influenced plasma BDNF in humans. Study 1 determined BDNF responses to a single bout of high-intensity cycling after ingestion of a dose of ketone salts in a group of healthy adults who were habitually consuming either a mixed diet or a ketogenic diet. Study 2 compared how a ketogenic diet versus a mixed diet impacts BDNF levels during a 12-week resistance training program in healthy adults. Study 3 examined the effects of a controlled hypocaloric ketogenic diet, with and without daily use of a ketone-salt, on BDNF levels in overweight/obese adults. We found that (1) fasting plasma BDNF concentrations were lower in keto-adapted versus non keto-adapted individuals, (2) intense cycling exercise was a strong stimulus to rapidly increase plasma BDNF independent of ketosis, and (3) clinically significant weight loss was a strong stimulus to decrease fasting plasma BDNF independent of diet composition or level of ketosis. These results highlight the plasticity of plasma BDNF in response to lifestyle factors but does not support a strong association with temporally matched BHB concentrations.

Mechanisms of β-adrenergic receptors agonists in mediating pro and anti-apoptotic pathways in hyperglycemic Müller cells.

The current study aimed to investigate the stimulatory effect of beta-adrenergic receptors (β-ARs) on brain derived neurotropic factor (BDNF) and cAMP response element binding protein (CREB). Human Müller cells were cultured in low and high glucose conditions. Cells were treated with xamoterol (selective agonist for β1-AR), salmeterol (selective agonist for β2-AR), isoproterenol (β-ARs agonist) and propranolol (β-ARs antagonist), at 20µM concentration for 24h. Western Blotting assay was performed for the gene expression analysis. DNA damage was evaluated by TUNEL assay. DCFH-DA assay was used tocheck the level of reactive oxygen species (ROS). Cytochrome C release was measured by ELISA. Xamoterol, salmeterol and isoproterenol showed no effect on Caspase-8 but it reduced the apoptosis and increased the expression of BDNF in Müller cells. A significant change in the expression of caspase-3 was observed in cells treated with xamoterol and salmeterol as compared to isoproterenol. Xamoterol, salmeterol and isoproterenol significantly decreased the reactive oxygen species (ROS) when treated for 24 hours. Glucose-induced cytochrome c release was disrupted in Müller cells. β-ARs, stimulated by agonist play a protective role in hyperglycemic Müller cells, with the suppression of glucose-induced caspase-3 and cytochrome c release. B-Ars may directly mediate the gene expression of BDNF.

Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats.

Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.

DW2009 Elevates the Efficacy of Donepezil against Cognitive Impairment in Mice.

Lactobacillus plantarum C29 and DW2009 (C29-fermented soybean) alleviate cognitive impairment through the modulation of the microbiota-gut-brain axis. Therefore, we examined whether combining donepezil, a well-known acetylcholinesterase inhibitor, with C29 or DW2009 could synergistically alleviate cognitive impairment in mice. Oral administration of donepezil combined with or without C29 (DC) or DW2009 (DD) alleviated lipopolysaccharide (LPS)-induced cognitive impairment-like behaviors more strongly than treatment with each one alone. Their treatments significantly suppressed the NF-κB+/Iba1+ (activated microglia) population, NF-κB activation, and tumor necrosis factor-α and interleukin-1β expression in the hippocampus, while the brain-derived neurotropic factor (BDNF)+/NeuN+ cell population and BDNF expression increased. Their treatments strongly suppressed LPS-induced colitis. Moreover, they increased the Firmicutes population and decreased the Cyanobacteria population in gut microbiota. Of these, DD most strongly alleviated cognitive impairment, followed by DC. In conclusion, DW2009 may synergistically or additively increase the effect of donepezil against cognitive impairment and colitis by regulating NF-κB-mediated BDNF expression.

The Effect of Monosodium Glutamate on Neuronal Signaling Molecules in the Hippocampus and the Neuroprotective Effects of Omega-3 Fatty Acids.

Monosodium glutamate (MSG) is a flavoring substance added to many ready-to-eat foods and has known neurotoxic effects. This study was performed in order to examine the potential toxic effect of MSG on neurons in various regions of the hippocampus in prepubertal rats. It also investigated the protective effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on brain-derived neurotropic factor (BDNF), n-methyl-d-aspartate receptor (NMDA-R), and neuropeptide-Y (NPY) expression in the brain, using immunohistochemical and biochemical methods. Six female prepubertal Wistar albino rats were used in each group. Group 1, the control group, received 0.9% saline solution subcutaneously (sc) on days 1, 3, 5, 7, and 9. Group 2 received 4 mg/g MSG sc on days 1, 3, 5, 7, and 9. Group 3 received MSG + EPA (4 mg/g sc on days 1, 3, 5, 7, and 9. Oral 300 mg/kg for 9 d), while Group 4 received MSG + DHA (4 mg/g sc on days 1, 3, 5, 7, and 9 and 300 mg/kg orally for 9 d, respectively). At the end of the ninth day the hippocampal regions of the brain were removed and either fixed for immunohistochemical staining or stored at -80 °C for biochemical parameter investigation. BDNF, NMDA-R, and NPY expression results were evaluated using immunohistochemistry and an enzyme-linked immunosorbent assay. According to our findings, neurons in the control group hippocampal CA1 and DG regions exhibited strong BDNF, NPY, and NMDA-R reactions, while an expression in both regions decreased in the MSG group (p < 0.00). However, in the MSG-EPA and MSG-DHA groups, BDNF, NPY, and NMDA-R immunoreactions in neurons in the same region were similar to those of the control group (p = 0.00). No significant difference was observed in terms of expression in hippocampal neurons between the MSG-EPA and MSG-DHA groups (p > 0.00). In conclusion, since MSG caused a decrease in BDNF, NMDA-R, and NPY neural signaling molecules in the CA1 and DG regions of the hippocampus of prepubertal rats compared to the control group, care is required over the consumption of MSG, since it may affect memory-related neurons in these age groups. In addition, we concluded that the use of omega-3 fatty acids such as EPA and DHA in addition to MSG may protect against the neurotoxic effects of MSG.

Adverse Maternal Environment Alters MicroRNA-10b-5p Expression and Its Epigenetic Profile Concurrently with Impaired Hippocampal Neurogenesis in Male Mouse Hippocampus

An adverse maternal environment (AME) predisposes adult offspring toward cognitive impairment in humans and mice. However, the underlying mechanisms remain poorly understood. Epigenetic changes in response to environmental exposure may be critical drivers of this change. Epigenetic regulators, including microRNAs, have been shown to affect cognitive function by altering hippocampal neurogenesis which is regulated in part by brain-derived neurotropic factor (BDNF). We sought to investigate the effects of AME on miR profile and their epigenetic characteristics, as well as neurogenesis and BDNF expression in mouse hippocampus. Using our mouse model of AME which is composed of maternal Western diet and prenatal environmental stress, we found that AME significantly increased hippocampal miR-10b-5p levels. We also found that AME significantly decreased DNA methylation and increased accumulations of active histone marks H3 lysine (K) 4me3, H3K14ac, and ­H3K36me3 at miR-10b promoter. Furthermore, AME significantly decreased hippocampal neurogenesis by decreasing cell numbers of Ki67⁺ (proliferation marker), NeuroD1⁺ (neuronal differentiation marker), and NeuN⁺ (mature neuronal marker) in the dentate gyrus (DG) region concurrently with decreased hippocampal BDNF protein levels. We speculate that the changes in epigenetic profile at miR-10b promoter may contribute to upregulation of miR-10b-5p and subsequently lead to decreased BDNF levels in a model of impaired offspring hippocampal neurogenesis and cognition in mice.

Association of blood lead levels with neurobehavior and BDNF expression in school going children

BackgroundChildhood Lead (Pb) toxicity has been an ongoing concern for decades; however, its underlying pathogenesis remains unclear. Although its prevalence has come down in developed countries (USA, Europe); it is relatively high in low to middle-income countries of South-East Asia. The current study aimed to evaluate the association of blood lead levels (BLLs) with neurobehavioral alterations and changes in Brain-Derived Neurotropic Factor (BDNF) expression in Indian school children. MethodologySchool going children in age group of 9–15 years (N = 72) were included in the study. Neurobehavioral changes were assessed using Childhood Psychopathological Measurement Schedule (CPMS) and BLL were measured by Graphite Furnace Atomic Absorption Spectrophotometry (GFAAS). BDNF mRNA expression and serum BDNF levels were assessed by Real-Time PCR and ELISA, respectively. ResultsMedian BLL was 4.95 μg/dL (IQR = 4.47), very close to the recommended toxic cut off levels (<5 μg/dL). BLLs had a direct correlation with both CPMS scores and BDNF expression. Depression was found to be significantly higher in boys than in girls with high BLLs. BDNF mRNA expression and serum BDNF levels were higher among children with high BLL, although not to significant levels. ConclusionWe report a significant association of neurobehavioral changes with the prevalence of high Pb levels in Indian children. Additionally significant correlation of BDNF with BLL in these children suggests a causal role of BDNF in Pb induced neurological damage.

Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD?

Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world, their diagnosis still relies solely on the characterization of subjective symptoms (many of which are shared by multiple disorders) self-reported by patients. Thus, the need for objective measures that aid in the detection of and differentiation between psychiatric disorders becomes urgent. In this paper, we explore the potential of neurosteroids and neurotrophic proteins as biomarkers for MDD and PTSD. Circulating levels of the GABAergic neuroactive steroid, allopregnanolone, are diminished in MDD and PTSD patients, which corroborates the finding of depleted neurosteroid levels observed in animal models of these disorders. The neurotrophic protein, brain-derived neurotropic factor (BDNF), is also reduced in the periphery and in the brain of MDD patients and depressed-like animals that express lower neurosteroid levels. Although the role of BDNF in PTSD psychopathology seems less clear and merits more research, we propose a causal link between allopregnanolone levels and BDNF expression that could function as a biomarker axis for the diagnosis of both MDD and PTSD.

RETRACTED: Noopept; a nootropic dipeptide, modulates persistent inflammation by effecting spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression throughout apoptotic process

There are largely unknown associations between changes in pain behavior responses during persistent peripheral inflammation and spinal cell alteration such as apoptosis. Some evidence suggests that microglia and microglia related mediators play notable roles in induction and maintenance of central nervous system pathologies and inflammatory pain. By considering those relationships and microglia related nootrophic factors, such as the Brain Derived Neurotrophic Factor (BDNF) in CNS, we attempted to assess the relationship between microglia dependent BDNF and its precursor with pain behavior through spinal cell apoptosis as well as the effect of Noopept on this relationship. Persistent peripheral inflammation was induced by a single subcutaneous injection of Complete Freund's Adjuvant (CFA) on day 0. Thermal hyperalgesia, paw edema, microglial activity, microglia dependent BDNF, pro-BDNF expression, and apoptosis were assessed in different experimental groups by confirmed behavioral and molecular methods on days 0, 7, and 21 of the study. Our findings revealed hyperalgesia and spinal cell apoptosis significantly increased during the acute phase of CFA-induced inflammation but was then followed by a decrement in the chronic phase of the study. Aligned with these variations in spinal microglial activity, microglia dependent BDNF significantly increased during the acute phase of CFA-induced inflammation. Our results also indicated that daily administration of Noopept (during 21 days of the study) not only caused a significant decrease in hyperalgesia and microglia dependent BDNF expression but also changed the apoptosis process in relation to microglia activity alteration. It appears that the administration of Noopept can decrease spinal cell apoptosis and hyperalgesia during CFA-induced inflammation due to its direct effects on microglial activity and microglia dependent BDNF and pro-BDNF expression.

Brain-derived Neurotropic factor (BDNF) mediates the protective effect of Cucurbita pepo L. on salivary glands of rats exposed to chronic stress evident by structural, biochemical and molecular study.

Acute and chronic stresses affect the salivary glands, representing the source of plasma BDNF during stressful conditions. Pumpkin is a medicinal plant with an evident antioxidant, anti-inflammatory and potential antidepressant effects. Objective To assess the structural and biochemical effects induced by exposure to chronic unpredictable mild stress (CUMS) on salivary glands of albino rats, and to evaluate the role of pumpkin extract (Pump) in ameliorating this effect.Methodology Four groups (n=10 each) of male albino rats were included in this study: the control, CUMS, Fluoxetine-treated and Pump-treated. The corticosterone, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the oxidant/antioxidant profile were all assessed in the serum. The level of BDNF mRNA was measured in the salivary glands using qRT-PCR. Histopathological changes of the salivary glands were also assessed.Results The depressive-like status was confirmed behaviorally and biochemically. Exposure to CUMS significantly up-regulated (p<0.001) the level of serum corticosterone. CUMS induced degenerative changes in the secretory and ductal elements of the salivary glands evident by increased apoptosis. Both Fluoxetine and Pumpkin significantly up-regulated (p<0.001) BDNF expression in the salivary glands and ameliorated the CUMS-induced histopathological and biochemical alterations in the salivary glands. Pumpkin significantly (p<0.001) increased the serum levels of antioxidant enzymes SOD, GPX and CAT, and reduced the serum levels of the pro-inflammatory cytokines TNF-α, IL-6.Conclusion Pumpkin ameliorates the depressive-like status induced in rats following exposure to chronic stress through exerting a promising anti-inflammatory, antioxidant and anti-depressant-like effects. The pumpkin, subsequently, improved stress-induced structural changes in the salivary glands that might be due to up-regulation of BDNF expression in the glands.

Potential neuroprotective effects of heat-killed Lactococcus lactis KC24 using SH-SY5Y cells against oxidative stress induced by hydrogen peroxide.

The present study was an investigation of the neuroprotective effects of probiotic bacteria in SH-SY5Y neuroblastoma cells experiencing oxidative stress. The bacterial strains were: commercial Lactobacillus rhamnosus GG; two isolated bacterial strains (Lactobacillus delbrueckii KU200170 and Lactobacillus plantarum KU200661); and probiotic Lactococcus lactis KC24. To evaluate the neuroprotective effects of the bacteria, a conditioned medium (CM) was prepared using HT-29 cells cultured with the heat-killed probiotic strains. Of the bacterial strains tested, the oxidatively stressed SH-SY5Y cells were most viable when cultured with L. lactis KC24-CM. L. lactis KC24-CM promoted the expression of brain-derived neurotropic factor (BDNF) in the HT-29 cells. It also significantly increased BDNF expression and reduced the apoptosis-related Bax/Bcl-2 ratio in the oxidatively stressed SH-SY5Y cells. Therefore, L. lactis KC24 is a potential psychobiotic for use in the functional food industry.