Hippocampal Neurotrophic Factor Research Articles

Electroacupuncture Alleviates Memory Deficits in APP/PS1 Mice by Targeting Serotonergic Neurons in Dorsal Raphe Nucleus.

Alzheimer's disease (AD) has become a significant global concern, but effective drugs able to slow down AD progression is still lacked. Electroacupuncture (EA) has been demonstrated to ameliorate cognitive impairment in individuals with AD. However, the underlying mechanisms remains poorly understood. This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD. APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu (BL 23) and Baihui (GV 20). Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus (DRN). Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests. Golgi staining, western blot, and immunostaining were utilized to determine EA-induced neuroprotection. EA at Shenshu (BL 23) and Baihui (GV 20) effectively ameliorated learning and memory impairments in APP/PS1 mice. EA attenuated dendritic spine loss, increased the expression levels of PSD95, synaptophysin, and brain-derived neurotrophic factor in hippocampus. Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B. Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory. EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN. Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.

Solanum melongena extract supplementation protected skeletal muscle and brain damage by regulation of BDNF/PGC1α/irisin pathway via brain function-related myokines in high-fat diet induced obese mice

In this study, we investigated the protective effects of SM on skeletal muscle and brain damage by regulation of BDNF/PGC1α/irisin pathway via brain function related myokines in high-fat diet-induced OB mice. OB was induced by high-fat diet for 6 weeks. SM extract (SME) was administered with 200 mg/kg BW (LSM) and 500 mg/kg BW (HSM) by oral gavage every day for 12 weeks. Behavior tests such as grip strength, Y-maze, and passive avoidance test were conducted to analyze muscle and cognitive function. Histopathological changes in skeletal muscle and brain were examined by hematoxylin and eosin staining and the protein levels of biomarkers related to oxidative stress, inflammation, protein degradation, neuro-plasticity, and cell cycling were measured by western blot. SME regulated morphological changes (muscle cross-sectional area: 1.23%, 1.40%; density of neurons in hippocampus:1.74%, 1.73%) in T2DM mice. Importantly, SME supplementation significantly increased several muscle-derived myokines which might influence the expression of neuronal markers in OB mice (FGF21: 1.27%, 1.34%; PGC1α: 1.0%, 1.32%; IRISIN: 1.9%, 1.08%; BDNF: 1.35%, 1.23%). Accordingly, SME activated hippocampal neurotrophic factors including BDNF (1.0%, 1.2%) and its associated PGC1α/irisin pathway (PGC1α :1.1%, 1.1%; IRISIN:1.1%, 0.9%) significantly. This study demonstrated the possibliy that protective myokines increased by SME supplementation may contribute to neuro-protection in OB mice. Taken together, the current study suggests that SME can be used to prevent skeletal muscle and brain damage in OB by protecting against oxidative stress and inflammatin via modulation of the BDNF/PGC1α/irisin pathway in the therapeutic approach of obese patients.

Annona muricate Extract Supplementation Contributes to Improve Aberrant Multi-Organ Energy Metabolism via Muscle-Brain Connectivity in Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is related with the incidence of sarcopenia and cognitive impairment that reduces quality of life in the elderly. Recent evidence has demonstrated that sarcopenia is associated with cognitive dysfunction, and muscle-derived endocrine factors might contribute to cognitive function by the skeletal muscle-brain endocrine loop. This study investigated the beneficial effects of Annona muricata (AM, graviola) on multi-organ energy metabolism with muscle-brain connectivity via brain function-related myokines in mice. Body composition, fasting blood glucose level, insulin, HbA1c%, histopathological changes, and the protein levels of insulin-signaling, energy metabolism, neuroprotection, inflammation, and protein-degradation pathways were measured. AM extract (AME) treatment selectively enhanced insulin signaling in the skeletal muscle and hippocampus of T2DM mice. Furthermore, AME treatment effectively increased muscle-derived fibroblast growth factor 21 (FGF21), cathepsin-B (CTSB), irisin, brain-derived neurotrophic factor (BDNF), and liver-derived FGF21 that contribute to whole-body energy homeostasis. In particular, AME increased the levels of circulating myokines (FGF21, BDNF, irisin, and CTSB), and these were accordance with the hippocampal neurotrophic factors (BDNF and CTSB) in T2DM mice. In conclusion, we suggest that AME would be a potential nutraceutical for improving the energy metabolism associated with muscle-brain connectivity via brain function-related myokines in T2DM.

Antibiotics-induced depression in mice via the microbiota-gut-brain axis

BackgroundIntestinal dysbacteriosis is associated with depression. This study aimed to establish an antibiotics-induced depression mouse model and explore the mechanism of antibiotic-induced depression. MethodsC57BL/6 J mice were treated with antibiotics to prepare the antibiotic-induced depression mouse model. Behavioral tests and depression-related bio-markers were examined. To understand the abundance of different bacteria in intestinal flora and screen out the predominant bacterial species, metagenomic analysis of feces was carried out. Finally, we detected the expression of NF-κB-p65 and p-NF-κB-p65 in PFC and the hippocampus using Western blot. ResultsMixtures A and B caused depression-like behavior in mice. Norepinephrine, 5-hydroxytryptamine, and brain-derived neurotrophic factor in hippocampus and PFC of antibiotic-induced depression mice significantly decreased. The serum adrenocorticotropic hormone and corticosterone concentrations increased. The abundance values of Bacteroides thetaiotaomicron, Klebsiella oxytoca, and Klebsiella aerogenes in antibiotic-induced depression mice significantly increased, and the characteristic KO genes and metabolic pathways in antibiotic-induced depression mice were significantly different with in CUMS depression mice (the positive control) and normal mice. The relative levels of p-NF-κB-p65 in antibiotics-induced depression mice were significantly higher than in normal mice. LimitationsHow dysbacteriosis induces inflammation in the central nervous system is unclear. ConclusionsSpecific antibiotic mixture can cause depression-like behavior and changes of depression-related bio-markers in mice. The antibiotic-induced depression mice display changes in the species and metabolism of intestinal bacterial flora. The activation of NF-κB inflammatory signaling pathway in the central nervous system may act as one of the mechanisms in the development of antibiotic-induced depression.

Effect of Oral Administration of Lactiplantibacillus plantarum SNK12 on Temporary Stress in Adults: A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group Study.

Mouse studies have reported anti-stress effects of Lactiplantibacillus plantarum SNK12 (SNK). Specifically, oral SNK administration increased mRNA levels of hippocampal neurotrophic factor and gamma-aminobutyric acid receptor in mice with sub-chronic mild stress-induced social defeat; moreover, it improved depressive behavior. We aimed to evaluate the efficacy of SNK ingestion against stress in healthy adults. We used the Uchida–Kraepelin test for the stress load, with a low-dose (50 mg/day), high-dose (150 mg/day), and placebo groups (dextrin). The primary outcome was the psychological evaluation as measured by the Profile of Mood States 2nd Edition (POMS2) using total mood disturbance (TMD) scores. The secondary outcomes were the score of each POMS2 item, salivary cortisol as a stress marker, and autonomic balance with the low frequency (LF)/ high frequency (HF) ratio. Compared with the placebo group, the SNK ingestion group showed significantly lower TMD scores. Additionally, compared with the placebo group, the high-dose group showed significantly lower scores for Tension-Anxiety and Confusion-Bewilderment, while the low-dose group showed significantly lower Anger-Hostility scores, salivary cortisol levels, and LF/HF scores. Our findings suggest that SNK ingestion could relieve stress (negative feelings, anxiety, tension, embarrassment, confusion, anger, and hostility) resulting from the temporary load caused by work and study.

Differential effects of excess high-fructose corn syrup on the DNA methylation of hippocampal neurotrophic factor in childhood and adolescence.

Consumption of fructose-containing beverages such as high-fructose corn syrup (HFCS) is increasing, raising concerns about the negative effects of excessive fructose intake. A recent report indicated that excess HFCS intake impairs hippocampal function. In this study, we focused on neurotrophic factors (NFs) in the hippocampus from the viewpoint of epigenetics to clarify the adverse effects of fructose. We analyzed the effects of HFCS intake on hippocampal function in three age categories: childhood and adolescence (postnatal day (PD) 21–60), young adulthood (PD60-100), and late adulthood (PD100-140). For the experiments, male Sprague-Dawley rats were divided into three age categories, the control group was received distilled water and the HFCS group was received 20% HFCS solution for 40 days in each period. We analyzed mRNA and protein levels for qPCR and western blotting, respectively, of a hippocampal NF, brain-derived neurotrophic factor (Bdnf). HFCS consumption reduced hippocampal Bdnf mRNA and protein expressions in childhood and adolescence. Moreover, pyrosequencing assays revealed increased DNA methylation at the Bdnf promoter in childhood and adolescence. This Bdnf levels reduction may be due to hypermethylation of the promoter regions. It should be noted that this phenomenon was observed only in childhood and adolescence fructose consumption. Our results indicate that the sensitivity of the hippocampus to fructose may vary with age. This study provides insight into the adverse effects of excessive HFCS consumption on the hippocampus in children.

Dietary Supplement of Anoectochilus roxburghii (Wall.) Lindl. Polysaccharides Ameliorates Cognitive Dysfunction Induced by High Fat Diet via "Gut-Brain" Axis.

PurposeAnoectochilus roxburghii (Wall.) Lindl. polysaccharides (ARPs) have been reported to exhibit multiple pharmacological activities including anti-inflammatory and anti-hyperglycemia. This study aims to investigate the effect of ARPs on cognitive dysfunction induced by high fat diet (HFD).MethodsSix-week-old male mice were treated with ARPs by dietary supplementation for 14 weeks. The effect of ARPs on cognitive function was determined by assessing the changes in spatial learning and memory ability, neurotrophic factors in hippocampus, inflammatory parameters, intestinal barrier integrity, and gut microbiota.ResultsARPs supplementation can effectively ameliorate cognitive dysfunction, decrease the phosphorylation levels of Tau protein in hippocampus. Meanwhile, the increased body weight, plasma glucose, total cholesterol, inflammatory factors induced by HFD were abolished by ARPs treatment. Furthermore, ARPs treatment restored the intestinal epithelial barrier as evidenced by upregulation of intestinal tight junction proteins. Additionally, ARPs supplementation significantly decreased the relative abundance of several bacteria genus such as Parabacteroides, which may play regulatory roles in cognitive function.ConclusionThese results suggest that ARPs might be a promising strategy for the treatment of cognitive dysfunction induced by HFD. Mechanistically, alleviation of cognitive dysfunction by ARPs might be associated with the “gut-brain” axis.

Memory Improving Effects in Social-Isolated Aged Rats by Seaweed Glycoproteins

Social isolation and loneliness that could induce cognitive decline are serious public health problems in elderly. The trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is a critical process in long-term potentiation of synapses that is necessary for memory formation. We previously found that glycoproteins of an edible seaweed Capsosiphon fulvescens (C. fulvescens) prevent aging-induced cognitive impairment via regulation of brain-derived neurotrophic factor in hippocampus. This study was to investigate whether chronic administration of hydrophilic glycoproteins of C. fulvescens (Cf-hGP) prevent cognitive dysfunctions caused by social isolation in aged rats and this effect is regulated by post synaptic density protein 95 (PSD-95)-mediated AMPAR trafficking and the glycosylation of Cf-hGP. Social isolation for four weeks decreased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2), PSD-95 (Ser295) and AMPAR GluR1 (Ser845) and increased expression of metabotropic glutamate receptor 5 (mGluR5) in synaptosome of the dorsal hippocampus, which was attenuated by chronic Cf-hGP treatment (15 mg/kg/day, 4 weeks). Blockade of mGluR5 abolished decrease in ERK1/2-mediated phosphorylation of PSD-95 (Ser295) and GluR1 (Ser845) in the socially isolated rats. In particular, chronic Cf-hGP treatment enhanced binding of ERK1/2 to PSD-95 and upregulated the surface movement of AMPAR GluR1 in the dorsal hippocampus. In addition, Cf-hGP treatment prevented spatial memory impairment caused by the social isolation, which was attenuated by inhibition of ERK1/2 or deglycosylation of Cf-hGP. These findings suggest that Cf-hGP-induced clustering of ERK1/2-mediated PSD-95 in the dorsal hippocampus improves memory formation in socially isolated aged rats and protein glycosylation contributes to enhancing the Cf-hGP effect.

Effect of aerobic training on heat shock protein 27 and brain-derived neurotrophic factor in hippocampus and prefrontal cortex of type II diabetic rats

Background: According to the experimental studies, the levels of heat shock protein 27 (HSP27) and brain-derived neurotrophic factor (BDNF) are decreased in diabetes which is associated with impaired cognitive function in the brain. Therefore, the increased expression of these two proteins in some brain regions associated with learning and memory can be one of the positive effects of aerobic training on cognition improvement at diabetes. The aim of the present study was to evaluate the effects of aerobic treadmill exercise training (ATET) on HSP27 and BDNF proteins in the prefrontal cortex and hippocampus of streptozotocin (STZ)-induced diabetes in rats. Methods: Twenty healthy adult male Wistar rats approximately 3-month old, weighing 250 ± 25gr were used in this study. Experimental diabetes was induced by a high-fat diet (HFD) for 4 weeks and a low dose of STZ (35 mg/kg, intraperitoneally). Then diabetic animals were divided into two groups (n=10 per each group): control group (C) and aerobic training group (E). The exercise program was treadmill running at 13 m/min, 25 min/day, for 5 days/week at 0˚ slope for the first week, with a gradual increase to 27 m/min for 60 min/day in week 8. Un-paired t-test was used to compare two groups with the considered significant at p<0.05. Results: The results showed that ATET significantly increased protein expression of HSP27 and BDNF in the hippocampus and prefrontal cortex as compared to C group. Conclusion: Our findings showed that aerobic treadmill exercise program can increase the protein expression of HSP27 and BDNF associated with cognition and synaptic plas­ticity and thus counteract the neurodegenerative diseases of the nervous system.

The role of pre-pubertal training history on hippocampal neurotrophic factors and glucocorticoid receptor protein levels in adult male rats

Neurotrophic factors play an integral role in hippocampal plasticity, and interaction with HPA axis components, especially glucocorticoid receptors (GR), can mediate the structural and functional changes. In the present work, we investigated the long-term effects of combined exercise training (CET) and voluntary physical activity in an enriched environment (EE) in the pre-pubertal period on hippocampal neurotrophic factors and GR. For this purpose, a longitudinal study was designed. After three weeks, all rats were kept in the standard cages without any interventions until adulthood. Western blot analysis revealed a significant increase in hippocampal BDNF and VEGF protein levels in both EE and CET groups (P < 0.001), along with an increase in GR protein levels. In addition, EE decreased serum corticosterone levels compared to CET (P < 0.05). Serum insulin-like growth factor-1 (IGF-1) levels did not demonstrate remarkable changes between groups. Training interventions during sensitive developmental periods may produce profound and long-lasting effects on the hippocampus, at least in part by interactive effects of neurotrophic factors cascades and GR.

Neuroprotective Effects of Euonymus alatus Extract on Scopolamine-Induced Memory Deficits in Mice

Euonymus alatus is considered to elicit various beneficial effects against cancer, hyperglycemia, menstrual discomfort, diabetic complications, and detoxification. The young leaves of this plant are exploited as food and also utilized for traditional medicine in East Asian countries, including Korea and China. Our preliminary study demonstrated that ethanolic extract from the Euonymus alatus leaf (EAE) exhibited the strongest antioxidant enzyme-inducing activity among more than 100 kinds of edible tree leaf extracts. This study investigated whether EAE could attenuate the cognitive deficits caused by oxidative stress in mice. Oral intubation of EAE at 100 mg/kg bw or higher resulted in significant improvements to the memory and behavioral impairment induced via i.p. injection of scopolamine. Furthermore, EAE enhanced the expression levels of hippocampal neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor in mice, activated the Nrf2, and the downstream heme oxygenase-1 (HO-1) a quintessential antioxidant enzyme. As rutin (quercetin-3-O-rutinose) was abundantly present in EAE and free quercetin was able to induce defensive antioxidant enzymes in an Nrf2-dependent manner, our findings suggested that quercetin derived from rutin via the intestinal microflora played a significant role in the protection of the mouse hippocampus from scopolamine-induced damage through BDNF-mediated Nrf2 activation, thereby dampening cognitive decline.

Correlation between Depressive Behavior and Expressions of S100β and Brain-derived Neurotrophic Factor in Hippocampus and Frontal Cortex of Rats

Objective To investigate the association between chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in rats and expressions of brain-derived neurotrophic factor (BDNF) and S100β in the hippocampal and prefrontal cortex. Methods Rats were randomly assigned to three groups:saline control group,saline+CUMS group,and citalopram +CUMS group. CUMS was used for depression modeling in rats. Depressive-like behavior in rats were evaluated by open-field test,sucrose preference test,and novel object recognition test. S100β and BDNF expressions were tested by enzyme-linked immunosorbent assay. Results Rats in the saline+CUMS group had significantly lower score in sucrose preference [(52.48±13.14)%],basic motor tasks [(845.8±371.4)s],fine motor tasks [(565.6±211.9)s],and longer resting time [(282.6±11.8)s] compared to the control group [(84.30±6.15)% (t=7.49,P=0.000),(1239.1±281.6)s (t=2.83,P=0.008),(801.8±150.9)s (t=3.05,P=0.003),(268.2±12.8)s (t=2.72,P=0.001)]. Compared with the citalopram+CUMS group,rats from the saline+CUMS group also showed significantly lower results in sucrose preference [(80.55±11.31)%,t=5.39,P=0.000],basic motor tasks [(1156.4±314.7)s,t=2.13,P=0.031],and fine motor tasks [(736.1±150.0)s,t=2.21,P=0.008]. There were no significant differences in the expression of hippocampal and prefrontal BDNF between these two groups,but rats from the saline+CUMS group expressed significantly higher levels of S100β compared to rats from the citalopram+CUMS group [(13.22±2.23) ng/g vs. (10.55±2.72) ng/g,t=2.67,P=0.014]. Pearson correlation analysis revealed that the expression of S100β was positively correlated with the expression of BDNF in the prefrontal cortex and hippocampus (r=0.35,P=0.034;r=0.36,P=0.034).The novel object recognition index was positively correlated with the expression of BDNF in the hippocampus(r=0.38,P=0.021),and the duration of fine-motor activities was negatively correlated with S100β in the prefrontal cortex (r=-0.36,P=0.037). Conclusions Different types of depressive behaviors in rats induced by CUMS are associated with the selective expression of S100β and BDNF in two different brain cortex. S100β protein and BDNF may independently participate in the pathogenesis of depression.

Preliminary investigation of the effect of oral supplementation of Lactobacillus plantarum strain SNK12 on mRNA levels of neurotrophic factors and GABA receptors in the hippocampus of mice under stress-free and sub-chronic mild social defeat-stressing conditions

The effect of Lactobacillus plantarum SNK12 (CPLP) supplementation on mRNA levels of hippocampal neurotrophic factors and gamma aminobutyric acid receptors (GABAR) was tested. In Experiment 1, stress-free, unsupplemented and CPLP (4 × 108 cells/head)-supplemented male C57BL/6J (B6) mice were the experimental animals. In Experiment 2, intruder (male, B6) mice [negative control; unsupplemented, sub-chronic mild social defeat stress (sCSDS)-induced; and CPLP-supplemented, sCSDS-induced] were exposed to aggressor mice (adult male Slc:ICR). mRNA levels of neurotrophic factors and GABAR in hippocampal samples of these mice were analyzed. In CPLP-supplemented mice of both experiments, mRNA levels of bdnf, nt-3, and GABAR were upregulated. Moreover, a tendency toward the improvement of habituation ability (Experiment 1) and behavior (Experiment 2) was observed in mice, which may be associated with upregulated neurotrophic factors and GABAR. We demonstrated that oral supplementation of CPLP to stress-free and stress-induced mice upregulated mRNA levels of hippocampal neurotrophic factors and GABAR.

Jia-Wei-Kai-Xin-San, an Herbal Medicine Formula, Ameliorates Cognitive Deficits via Modulating Metabolism of Beta Amyloid Protein and Neurotrophic Factors in Hippocampus of Aβ1-42 Induced Cognitive Deficit Mice.

Jia-Wei-Kai-Xin-San (JWKXS) is a Chinese medicine formula applied for treating morbid forgetfulness in ancient China. Today, this formula is frequently applied for Alzheimer’s disease and vascular dementia (VD) in clinic. Here, we developed it as granules and aimed to evaluate its anti-AD effect on β amyloid protein 1–42 (Aβ1-42) induced cognitive deficit mice and reveal the possible molecular mechanisms. Firstly, daily intra-gastric administration of chemically standardized of JWKXS granules for 7 days significantly ameliorated the cognitive deficit symptoms and inhibited cell apoptosis in hippocampus on Aβ1-42 injection mice. JWKXS granules significantly decreased Aβ level, increased superoxide dismutase activity and decreased malondialdehyde level in hippocampus of model mice. It also restored acetylcholine amounts, inhibited acetylcholinesterase activities and increased choline acetyltransferase activities. In addition, JWKXS granules enabled the transformation of precursors of NGF and BDNF into mature forms. Furthermore, JWKXS granules could regulate gene expressions related to Aβ production, transportation, degradation and neurotrophic factor transformation, which led to down-regulation of Aβ and up-regulation of NGF and BDNF. These findings suggested that JWKXS granules ameliorated cognitive deficit via decreasing Aβ levels, protecting neuron from oxidation damages and nourishing neuron, which could serve as alternative medicine for patients suffering from AD.

Voluntary, involuntary and forced exercises almost equally reverse behavioral impairment by regulating hippocampal neurotrophic factors and oxidative stress in experimental Alzheimer's disease model.

The purpose of this study was to compare the neuroprotective effects of voluntary, involuntary, and forced exercise trainings on behavioral impairment as well as hippocampal Alzheimer's disease (AD) pathology and oxidative stress markers, and levels of neurotrophic factors in the rat model of AD. The rats were assigned to control, Alzheimer model, Alzheimer + voluntary exercise, Alzheimer + involuntary exercise, or Alzheimer + forced exercise group. The rat model of AD was established by D-(+)-Galactose (D-GAL) and AlCl3 administration for 90 days. Voluntary, involuntary (swimming) or forced exercise (load-swimming) trainings were performed for 90 days starting with the D-GAL and AlCl3 administration and then several behavioral tests were applied. Locomotor activity, exploratory behavior, and spatial memory were lower but anxiety levels were higher in the Alzheimer model group, than in the other groups (P < 0.05). The hippocampal levels of the amyloid beta 1-42, microtubule associated protein Tau, malondialdehyde, and protein carbonyl levels were higher, but brain-derived neurotrophic factor, nerve growth factor, glutathione and superoxide dismutase levels were lower in the Alzheimer model group, than in the other groups (P < 0.05). The results of the present study suggest that all exercise modalities almost equally attenuated non-cognitive and cognitive disturbances in a rat model of AD. Elevated neurotrophic factors, and improved oxidative stress could mediate these beneficial effects.

Antidepressant-Like Effects of Cistanche tubulosa Extract on Chronic Unpredictable Stress Rats Through Restoration of Gut Microbiota Homeostasis.

Growing evidence shows that neuropsychiatric disorders, such as depression, are linked with gut microbiome through the gut–brain axis. Cistanches Herba is well known for the treatment of “kidney-yang” deficiency in traditional Chinese medicine (TCM), and has been used for treatment of neurodegenerative diseases in recent years. In this study, chronic unpredictable stress (CUS)-induced depression model was established to explore the impact of Cistanche tubulosa extract (CTE) on behavioral tests, monoamine neurotransmitters and neurotrophic factors in hippocampus and colon, gut microbiota composition, and short-chain fatty acids (SCFAs) production. Moreover, correlation analysis was used to evaluate the functional relationship between altered gut microbiota, changed neurotransmitters and neurotrophins in hippocampus and colon, and disturbed concentration of SCFAs. CTE significantly improved depression-like behaviors in rats under CUS. Brain level of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) expression in CUS rats were restored by CTE. The relative abundance of gut microbiota and the concentrations of acetate and hexanoic acid could also be modulated by CTE treatment. We further showed that the application of CTE in CUS rats led to strong correlation among disrupted gut microbiota composition, hippocampus neurotransmitter levels, and production of neuroactive metabolite SCFAs. Altogether, these results identify CTE as a potential treatment for depressive symptoms by restoring homeostasis of gut microbiota for microbiota–gut–brain axis disorders, opening new avenues in the field of neuropsychopharmacology.

Rosmarinic acid reverses the deleterious effects of repetitive stress and tat protein

Human immunodeficiency virus type 1 (HIV) has infected more than 40 million people worldwide and is associated with central nervous system (CNS) disruption in at least 30% of these persons. The use of highly active antiretroviral therapy (HAART) has significantly reduced the systemic immunopathology associated with HIV, but the occurrence of neurological disorders continues to be reported in notable numbers. The present study evaluated the potential of rosmarinic acid to reverse the detrimental effects of an intracerebral injection of the viral protein tat. Control and tat-injected rats were also subjected to repetitive restrain stress (RRS) for 28 days, 6 h per day, to investigate whether subsequent stress exposure would worsen the effects of tat. 14 days after the initiation of RRS, animals were treated with rosmarinic acid (10 mg/kg given intraperitoneally) daily until the end of the stress exposure period. We assessed locomotor activity and anxiety-like behavioral changes. We also measured plasma corticosterone levels and quantified the expression of mineralocorticoid receptors (MR), glucocorticoid receptors (GR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Rosmarinic acid attenuated anxiety-like behavior induced by tat and stress, reduced plasma corticosterone levels and increased the expression of hippocampal GR, MR and BDNF when compared to controls. These results suggest that rosmarinic acid may reverse the anxiogenic effect of HIV-1 viral protein tat and related stress through modulation of the hypothalamic-pituitary-adrenal axis and hippocampal neurotrophic factor levels.

The effect of 3,4- methylenedioxymethamphetamine on expression of neurotrophic factors in hippocampus of male rats.

Background: 3,4- methylenedioxymethamphetamine (MDMA) is a chemical derivative of amphetamine that can induce learning and memory impairment. Due to the effect of neurotrophins on memory and learning, the impact of MDMA was evaluated on the brain - derived neurotrophic factor (BDNF), neurotrophin- 4 (NT-4), and tropomyosin- related kinase B (Trk- β) expression in the hippocampus. Methods: In this study, 20 adult male Wistar rats (200-250 g) received saline (1 mL) or 10 mg/kg of MDMA intraperitoneally as single or multiple injection for 2 consecutive days per week for 2 months. Expression of BDNF, Trk-β, and NT4 were assessed using Western blotting and RT PCR methods. Results: Our results revealed that the expression of BDNF, Trk- β, and NT4 proteins and genes significantly decreased in MDMA groups compared to the sham group (p<0.05). Furthermore, the acute group showed the lowest expression of these proteins. Conclusion: The results of the present study suggest that ecstasy administration may downregulate the expression of BDNF, Trk- β, and NT-4 in hippocampus, which is more extensive in case of acute treatment. It seems that in the chronic group, hippocampus was able to compensate the ecstasy- induced neurotoxicity.

Effect of Prenatal Exposure to Waterpipe Tobacco Smoke on Learning and Memory of Adult Offspring Rats.

Waterpipe tobacco smoking has increased in prevalence worldwide, including among pregnant women. In this study, we investigated the effect of prenatal maternal waterpipe tobacco smoke (WTS) exposure during different stages of pregnancy on learning and memory of adult offspring rats. Pregnant rats received either fresh air or mainstream WTS (2 hours daily) during early, mid, late, or whole gestational period. Male offspring rats were followed through 20 weeks. Outcomes included (1) spatial learning and memory using the radial arm water maze (RAWM), (2) levels of brain derived neurotrophic factor (BDNF) in the hippocampus, and (3) oxidative stress biomarkers (superoxide dismutase, catalase, glutathione peroxidase and thiobarbituric acid reactive substances). Relative to offspring whose mothers were exposed to fresh air, prenatal exposure to WTS at any stage of pregnancy resulted in short- and long-term memory impairment in adult offspring rats (p < .05). This impairment was associated with reduced levels of BDNF in hippocampus (p < .05). However, prenatal WTS did not affect the level of oxidative stress biomarkers in hippocampus. Prenatal WTS during late gestation increased the activity of catalase as compared to control. Prenatal maternal WTS exposure can impair the memory of adult male offspring. These results support development of interventions that target pregnant women who smoke waterpipe during pregnancy. We examined for the first time the effect of prenatal waterpipe tobacco smoke exposure on learning and memory of offspring. The results showed that in utero exposure to waterpipe tobacco smoke was associated with impaired memory and decreased brain derived neurotrophic factor in hippocampus of adult male offspring rats.

Effects of isolation rearing and early antipsychotic intervention on oxidative stress-induced apoptosis and brain-derived neurotrophic factor in hippocampus in a rat model of schizophrenia

Background: Oxidative stress-induced neuronal dysfunction has been considered an essential factor for the development of schizophrenia. However, a longitudinal and causal relation between the impacts of developmental stress and oxidative stress remains unsolved. The present study aimed to examine whether the oxidative stress-relevant dysfunctions of the apoptotic index can be induced in rats of isolation rearing (IR, a rodent model of schizophrenia) and to see if the intervention of antipsychotics can reverse these dysfunctions. Materials and Methods: Pharmacological manipulation (risperidone [RIS] [1 mg/kg/day], olanzapine [OLA] [2.5 mg/kg/day], or saline [SAL] vehicle) was introduced 4 weeks (adolescence) or 8 weeks (young adulthood) after IR (i.e., rats were 7- or 11-week-old). The regime of RIS, OLA, or SAL was continued for 9 weeks. Locomotor activity was employed to validate the IR effect. Rats' hippocampus immediately after sacrifice was removed to measure messenger RNA expression of Bax, Bcl-2, brain-derived neurotrophic factor (BDNF) and the plasma level of nitric oxide (NO). Results: The results showed: (i) IR rats were more hyperactive. (ii) RIS may exert anti-apoptotic effects on IR rats, particularly at their adolescent age (as indexed by increased Bcl-2 and decreased Bax/Bcl-2 ratio). (iii) The therapeutic potential of RIS can be also observed in the change of BDNF in an age-independent manner, in which RIS effectively increased the BDNF level in IR but not social (SOC) rats. (iv) Plasma NO was not altered. Conclusion: The study results support the utility of the IR paradigm in exploring mental disorders with neurodevelopmental origin in which early pharmacological intervention may provide a therapeutic benefit in the overloaded oxidative stress and the dysfunction of BDNF.