Hippocampal Brain-derived Neurotrophic Factor Research Articles

Fenofibrate ameliorates olanzapine's side effects without altering its central effect: emphasis on FGF-21-adiponectin axis.

The present work was designed to investigate whether fenofibrate could ameliorate olanzapine deleterious effect on insulin resistance via its effect on fibroblast growth factor-21 (FGF-21)-adiponectin axis without affecting olanzapine antipsychotic effect in postweaning socially isolated reared female rats. Treatment with olanzapine (6 mg/kg, intraperitoneally) or fenofibrate (100 mg/kg, orally) have been started 5 weeks after isolation, then behavioral tests, hippocampal content of neurotransmitters, and brain-derived neurotrophic factor (BDNF) were assessed. Moreover, insulin resistance, lipid profile, FGF-21, adiponectin, inflammatory, and oxidative stress markers of adipose tissue were assessed. Treatment of isolated-reared animals with olanzapine, or fenofibrate significantly ameliorated the behavioral and biochemical changes induced by postweaning social isolation. Co-treatment showed additive effects in improving hippocampal BDNF level. Besides, fenofibrate reduced the elevation in weight gain, adiposity index, insulin resistance, lipid profile, and FGF-21 level induced by olanzapine treatment. Also, fenofibrate increased adiponectin level which was reduced upon olanzapine treatment. Moreover, fenofibrate improved both adipose tissue oxidative stress and inflammatory markers elevation as a result of olanzapine treatment. Fenofibrate could ameliorate olanzapine-induced insulin resistance without affecting its central effect in isolated reared rats via its action on FGF-21-adiponectin axis.

Targeting Brain-Derived Neurotrophic Factor (BDNF) - An Important Strategy to Alzheimer's Disease

Many theories have been proposed to explain why candidate disease-modifying drugs (DMTs) for Alzheimer's disease (AD) failed. Late initiation of treatments during AD development, inappropriate drug dosages, incorrect selection of main therapeutic targets, and primarily inadequate understanding of the complex pathophysiology of AD are the most prominent ones. Reduced expression of Brain Derived Neurotrophic Factor (BDNF) is essential in the pathogenesis of Alzheimer's disease. BDNF plays important functions in cell survival and differentiation, neuronal outgrowth and plasticity. It can be a novel target for the treatment of the disease. In Alzheimer's disease, the hippocampus, parietal, entorhinal, and frontal cortex all have the most extreme BDNF deficits. Lower levels of BDNF can be linked to neuronal death, masking any gene-related effects. High BDNF levels have been attributed to a lower risk of dementia and Alzheimer's. Improvements in BDNF levels imparted by exercise, plant based drugs, trkB receptor agonist and BDNF enhancer drug have been proved to enhance cognitive performance. Plant-based products and nutraceuticals can boost BDNF levels. Polyphenols are essential plant compounds with a wide range of therapeutic potentials. Flavonoids like calycosin, genistein, isorhamnetin, and luteolin have been shown to affect the level of BDNF. Curcumin, a compound derived from spice turmeric (curcuma longa), has a variety of biological functions in the brain, including antidepressant properties which also increase BDNF level in the hippocampus. Riluzole is used to treat amyotrophic lateral sclerosis (ALS). In a depression model with chronic corticosteroid intake, riluzole also restores hippocampal BDNF levels. Evidence indicates that BDNF deficiency plays a role in the pathogenesis of Alzheimer's disease. Drugs used to treat Alzheimer's disease have the unintended property of modulating BDNF levels in brain regions specifically involved in the disease's pathophysiology. The discovery of molecules that precisely control BDNF in particular cellular phenotypes could increase the effectiveness of therapy against AD.

Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters.

Regular exercise training induces mitochondrial biogenesis in the brain via activation of peroxisome proliferator-activated receptor gamma-coactivator 1α (PGC-1α). However, it remains unclear whether a single bout of exercise would increase mitochondrial biogenesis in the brain. Therefore, we first investigated whether mitochondrial biogenesis in the hippocampus is affected by a single bout of exercise in mice. A single bout of high-intensity exercise, but not low- or moderate-intensity, increased hippocampal PGC-1α mRNA and mitochondrial DNA (mtDNA) copy number at 12 and 48h. These results depended on exercise intensity, and blood lactate levels observed immediately after exercise. As lactate induces mitochondrial biogenesis in the brain, we examined the effects of acute lactate administration on blood and hippocampal extracellular lactate concentration by in vivo microdialysis. Intraperitoneal (I.P.) lactate injection increased hippocampal extracellular lactate concentration to the same as blood lactate level, promoting PGC-1α mRNA expression in the hippocampus. However, this was suppressed by administering UK5099, a lactate transporter inhibitor, before lactate injection. I.P. UK5099 administration did not affect running performance and blood lactate concentration immediately after exercise but attenuated exercise-induced hippocampal PGC-1α mRNA and mtDNA copy number. In addition, hippocampal monocarboxylate transporters (MCT)1, MCT2, and brain-derived neurotrophic factor (BDNF) mRNA expression, except MCT4, also increased after high-intensity exercise, which was abolished by UK5099 administration. Further, injection of 1,4-dideoxy-1,4-imino-D-arabinitol (glycogen phosphorylase inhibitor) into the hippocampus before high-intensity exercise suppressed glycogen consumption during exercise, but hippocampal lactate, PGC-1α, MCT1, and MCT2 mRNA concentrations were not altered after exercise. These results indicate that the increased blood lactate released from skeletal muscle may induce hippocampal mitochondrial biogenesis and BDNF expression by inducing MCT expression in mice, especially during short-term high-intensity exercise. Thus, a single bout of exercise above the lactate threshold could provide an effective strategy for increasing mitochondrial biogenesis in the hippocampus.

Treadmill exercise sex-dependently alters susceptibility to depression-like behaviour, cytokines and BDNF in the hippocampus and prefrontal cortex of rats with sporadic Alzheimer-like disease

Alzheimer's disease (AD) is associated with increased depression-related behaviours. Previous studies have reported a greater risk of AD and depression in women. In recent years, we and others have provided evidence that exercise during life could be used as a therapeutic strategy for stress-related disorders such as depression. The main goal of the current study was to determine whether treadmill exercise during life can reduce depression-related behaviours in male and female Wistar rats with sporadic Alzheimer-like disease (ALD). Animals were subjected to treadmill exercise eight weeks before and four weeks after ALD induction by streptozocin (STZ). We measured body weight, food intake, and depression-related symptoms in rats using five behavioural tests. We measured brain-derived-neurotrophic factor (BDNF), tumour-necrosis factor (TNF)-α, and interleukin (IL)-10 levels in the hippocampus and prefrontal cortex of animals. Our findings showed that exercise but not ALD induction decreased body weight and food intake in male and female rats. ALD induction increased depression-related symptoms and hippocampal TNF-α in male and female rats. Besides, treadmill exercise alone decreased depression-related behaviours and increased hippocampal BDNF in females but not males. We also found that treadmill exercise decreased depression-related behaviours and TNF-α in the hippocampus and prefrontal cortex, and increased IL-10 in the prefrontal cortex and BDNF in the hippocampus of female ALD-induced rats. However, treadmill exercise only reduced anhedonia-like behaviour and hippocampal TNF-α in male ALD-induced rats. Overall, the evidence from this study suggests that treadmill exercise alters depression-related behaviours, brain BDNF and cytokines in a sex-dependant manner in rats with sporadic Alzheimer-like disease.

Maternal high-fat diet increases anhedonic behavior and modulates hippocampal Mash1 and BDNF expression in adult offspring

BackgroundThe consumption of a high-fat diet (HFD) during pregnancy and perinatal periods can lead to long-term effects in the offspring central nervous system, affecting pathways related to neurogenesis and behavior, and increasing predispositions to depressive and anxiety-like behaviors. Thus, this study aimed to investigate the effects of a maternal HFD on the hippocampi of adult offspring and behaviors related to anxiety and depression. MethodsThe protein and mRNA expression of the brain-derived neurotrophic factor (BDNF), Mash1, Notch1, Hes5, serotonin transporter (SERT), 5-HT1A serotonergic receptor (5-HT1A), tryptophan hydroxylase 2 (TPH2, key enzyme of serotonin synthesis), JNK and pJNK were analyzed in the hippocampi of male Swiss mice. Hippocampal serotonin levels were measured using ELISA. The lipid peroxidation, total oxidant status, total antioxidant status, and GSH/GSSG were evaluated as oxidative stress measures. For the behavioral analysis, the open field, elevated plus maze, and sucrose preference tests were used. ResultsMaternal HFD led to increased body weight in dams and their offspring, as well as altered body composition and LDL levels in the offspring. There were no alterations in oxidative stress or JNK phosphorylation. Hippocampal Mash1 and BDNF expression were altered in HFD offspring. The HFD offspring exhibited anhedonic behavior. ConclusionThese findings suggest that maternal HFD leads to long-term alterations in the offspring's neurotrophic systems, impairing their behavior.

Coping with Exercise Induced Spatial Memory Improvement in Morphine Dependent Rats by Inhibiting Brain Derived Neurotrophic Factor (BDNF)

Background: Addiction as a chronic disorder that requires long treatment. One way to treating this chronic disease is exercise. Chronic exposure to opiates impairs spatial learning and memory. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we investigated whether voluntary exercise would ameliorate the cognitive deficits that are induced by morphine dependence. If an effect of exercise was observed, we aimed to investigate the possible role of hippocampal brain-derived neurotropic factor (BDNF) in the exercise-induced enhancement of learning and memory in morphine-dependent rats. Methods: The rats were injected with bi-daily doses (10 mg/kg, at 12 hr. intervals) of morphine over a period of 10 days of voluntary exercise. Following these injections, a water maze task was performed twice a day for 5 consecutive days, followed by a probe trial 2 days later. A specific BDNF inhibitor (TrkB-IgG chimera) was used to block the hippocampal BDNF action during the 10 days of voluntary exercise. Results: The voluntary exercise diminished the severity of the rats’ dependency on morphine. A blockade of the BDNF action blunted the exercise-induced improvement of spatial memory, hippocampal neuron counting and BDNF protein levels in the dependent rats. Our results indicate that voluntary exercise could be increase the expression of LTP by lowering the induction threshold for LTP in the DG of morphine-dependent rats. Conclusion: Thus, voluntary exercise might be considered as a potential method to ameliorate some of the deleterious behavioral consequences of the abuse of morphine and other opiates.

Synergistic effects of combined therapy with transcranial photobiomodulation and enriched environment on depressive- and anxiety-like behaviors in a mice model of noise stress.

The development of anxiety and depression due to chronic exposure to noise stress has remained as an unsolved health problem so far. Despite the studies suggesting the neuroenhancement effects of transcranial photobiomodulation (tPBM) and housing in an enriched environment (EE), the combined effects of these treatments have not been elucidated yet. Also, there is no available data on the relationship between the application of tPBM and hippocampal brain-derived neurotrophic factor (BDNF) expression in animal models of stress. The present study aims to investigate the application of the tPBM and EE (alone or in combination) on depressive- and anxiety-like behaviors in a mice model of noise stress. Mice were divided into five groups: control, noise, noise + EE, noise + tPBM, and noise + EE + tPBM. Except for the control group, other groups were subjected to 110 dB SPL white noise for 4h/day for 14 consecutive days and received their respective treatments. Forced Swimming Test (FST) was used to evaluate depressive-like behaviors. Elevated Plus Maze (EPM) and Open Field Test (OFT) were used to evaluate anxiety-like behaviors. BDNF, tyrosine receptor kinase B (TrkB), and cAMP response element-binding (CREB) protein levels in the hippocampus were determined by the Western blot method, and also serum corticosterone levels were assessed using an ELISA kit. Exposure to noise stress significantly elevated serum corticosterone level; downregulated hippocampal BDNF, TrkB, and CREB protein expressions; and resulted in depressive- and anxiety-like behaviors. While, the application of tPBM (810 nm wavelength, 8J/cm2 fluence, 10Hz pulsed wave mode), housing in EE, and their combination lowered corticosterone levels, upregulated the BDNF/TrkB/CREB signaling pathway in the hippocampus, and improved behavioral outcomes in noise stress subjected mice. Our finding revealed the improving effects of tPBM and EE on depressive and anxiety-like behaviors induced by noise stress, possibly by augmenting the BDNF/TrkB/CREB signaling pathway.

Therapeutic Potential of Curcumin in Reversing the Depression and Associated Pseudodementia via Modulating Stress Hormone, Hippocampal Neurotransmitters, and BDNF Levels in Rats.

Depressive state adversely affects the memory functions, especially in the geriatric population. The initial stage of memory deficits associated with depression is particularly called as pseudodementia. It is the starting point of memory disturbance before dementia. The purpose of this research was to study depression and its consequent pseudodementia. For this purpose 24 male albino Wistar rats were divided into four groups. Depression was induced by 14 days of chronic restraint stress (CRS) daily for 4h. After developing a depression model, pattern separation test was conducted to monitor pseudodementia in rats. Morris water maze test (MWM) was also performed to observe spatial memory. It was observed that model animals displayed impaired pattern separation and spatial memory. Treatment was started after the development of pseudodementia in rats. Curcumin at a dose of 200mg/kg was given to model rats for one week along with the stress procedure. Following the treatment with curcumin, rats were again subjected to the aforementioned behavioral tests before decapitation. Corticosterone levels, brain derived neurotrophic factor (BDNF) and neurochemical analysis were conducted. Model rats showed depressogenic behavior and impaired memory performance. In addition to this, high corticosterone levels and decreased hippocampal BDNF, 5-HT, dopamine (DA), and acetylcholine (ACh) levels were also observed in depressed animals. These behavioral biochemical and neurochemical changes were effectively restored following treatment with curcumin. Hence, it is suggested from this study that pseudodementia can be reversed unlike true dementia by controlling the factors such as depression which induce memory impairment.

Paternal fenvalerate exposure transgenerationally impairs cognition and hippocampus in female offspring

The impairments of maternal fenvalerate exposure have been well documented in previous study, but little was known about the effects of paternal fenvalerate exposure. The current study aimed to assess the effects of paternal fenvalerate exposure on spatial cognition and hippocampus across generations. Adult male mice (F0) were orally administered with fenvalerate (0, 2 or 20 mg/kg) for 5 weeks. F0 males were mated with untreated-females to generate F1 generation. F1 males were mated with F1 control females to generate F2 generation. For F1 and F2 adult offspring, spatial learning and memory were detected by Morris water maze. Results showed that spatial learning and memory were impaired in F1 females but not F1 males derived from F0 males exposed to 20 mg/kg FEN. Furthermore, significant impairment of spatial learning and memory were found in F2 females but not F2 males derived from F0 males exposed to 20 mg/kg FEN. As expected, histopathology showed that neural density in hippocampal CA3 region was reduced in F1 and F2 females but not F1 and F2 males derived from F0 males exposed to 20 mg/kg FEN. Mechanistically, hippocampal thyroid hormone receptor alpha1 (TRα1) was down-regulated in F1 and F2 females derived from F0 males exposed to 20 mg/kg FEN. Correspondingly, hippocampal brain-derived neurotrophic factor, tropomyosin receptor kinase B and p75 neurotrophin receptor, three downstream genes of TR signaling, were down-regulated in F1 and F2 females. Taken together, the present study firstly found that paternal fenvalerate exposure transgenerationally impaired spatial cognition in a gender-dependent manner. Hippocampal TR signaling may, at least partially, contribute to the process of cognitive impairment induced by paternal fenvalerate exposure. Further exploration in the mode of action of fenvalerate is critically important to promote human health and environmental safety.

The Role of Perioperative Sleep Disturbance in Postoperative Neurocognitive Disorders.

Postoperative neurocognitive disorder (PND) increases the length of hospital stay, mortality, and risk of long-term cognitive impairment. Perioperative sleep disturbance is prevalent and commonly ignored and may increase the risk of PND. However, the role of perioperative sleep disturbances in PND remains unclear. Nocturnal sleep plays an indispensable role in learning, memory, and maintenance of cerebral microenvironmental homeostasis. Hospitalized sleep disturbances also increase the incidence of postoperative delirium and cognitive dysfunction. This review summarizes the role of perioperative sleep disturbances in PND and elucidates the potential mechanisms underlying sleep-deprivation-mediated PND. Activated neuroinflammation and oxidative stress; impaired function of the blood-brain barrier and glymphatic pathway; decreased hippocampal brain-derived neurotrophic factor, adult neurogenesis, and sirtuin1 expression; and accumulated amyloid-beta proteins are associated with PND in individuals with perioperative sleep disorders. These findings suggest that the improvement of perioperative sleep might reduce the incidence of postoperative delirium and postoperative cognitive dysfunction. Future studies should further investigate the role of perioperative sleep disturbance in PND.

Vitamin D Regulatory Effect on Restraint Stress-Induced Changes in Serum Corticosterone and Hippocampus BDNF Levels in the Male Rats

Background: Chronic stress exerts negative effects on cognitive functions through inducing changes in the hippocampus. Brain-derived neurotrophic factor (BDNF) is an essential factor in cognitive functions, which is considerably reduced under chronic stress. 1,25(OH)2 vitamin D plays neuroprotective roles partially by regulating the expression of various neurotrophic factors. Objectives: Since few studies have studied the impact of vitamin D on BDNF levels, we conducted this brief experiment to understand the role of vitamin D in maintaining hippocampal BDNF protein levels by using restraining as a model of chronic stress in rats. Methods: Rats underwent restraint stress 3 h/day for 28 days, during which they received vitamin D (5, 10 μg/kg) or its vehicle (IP, twice weekly). After the stress period, serum corticosterone (CORT) and hippocampus BDNF protein levels were measured. Results: Restraint stress increased serum CORT (P < 0.001) and reduced BDNF protein levels (P < 0.001) as compared to the non-stress group. Vitamin D markedly maintained BDNF levels close to normal (P < 0.001), but did not change CORT levels significantly. Conclusions: This study demonstrated that 3h/day of chronic restraint stress for 28 days boosted serum CORT and declined hippocampal BDNF levels, similar to stronger restraint stress models. Vitamin D maintained BDNF level close to normal in the hippocampus, but it did not affect CORT level significantly.

Resveratrol prevented spatial deficits and rescued disarrayed hippocampus asymmetric dimethylarginine and brain-derived neurotrophic factor levels in young rats with increased circulating asymmetric dimethylarginine.

Increased plasma levels of asymmetric dimethylarginine can be encountered in chronic inflammatory disease, liver damage, renal failure, and multiple organ failure. In addition, an association between circulating asymmetric dimethylarginine levels and all-cause mortality has been reported. Male Sprague-Dawley rats, postnatal day 17 ± 1, received continuous asymmetric dimethylarginine infusion via an intraperitoneal pump. Spatial performance and dorsal hippocampal asymmetric dimethylarginine and brain-derived neurotrophic factor (BDNF) levels were examined, and the effect of resveratrol was tested. A 4-week continuous asymmetric dimethylarginine infusion in young male rats caused spatial deficits, increased asymmetric dimethylarginine levels, and decreased BDNF expression in the dorsal hippocampus. Increased oxidative stress and altered molecules in the dorsal hippocampus linked to asymmetric dimethylarginine and BDNF functions were detected. Resveratrol protected against these effects, reversing spatial deficits, and reducing the changes in the dorsal hippocampal asymmetric dimethylarginine and BDNF levels.

Hesperetin ameliorates electroconvulsive therapy-induced memory impairment through regulation of hippocampal BDNF and oxidative stress in a rat model of depression

Depression is one of the most common mental health disorders and it is generally characterized by negative mood. Although electroconvulsive therapy (ECT) is an effective treatment for depression, however, it can cause cognitive deficit. Hesperetin, an active ingredient in citrus peels, has antioxidant and neuroprotective properties. In this study, we evaluated the effect of hesperetin on memory impairment induced by ECT in a reserpine-induced depression model in male rat. For this purpose, 105 male rats weighing 230−250 g were randomly divided into control and reserpine-treated groups. The reserpine-treated animals were subdivided into: Reserpine, Hesperetin (10 and 20 mg/kg), ECT and ECT+Hesperetin (10 and 20 mg/kg). After taking the drugs, the effect of hesperetin was evaluated through behavioral NORT, Y Maze, FST, SPT and also via assessment of hippocampal brain-derived neurotrophic factor (BDNF) and oxidative stress biomarkers i.e., MDA, SOD and GSH. As a result, our biochemical studies showed a significant decrease of MDA in groups treated with ECT+Hesperetin as compared to ECT and hesperetin groups (P < 0.001) and a marked increase in SOD, GSH and BDNF in ECT+Hesperetin 20 group as compared to other groups (p < 0.05). Also, the results of behavioral tests revealed that treatment with hesperetin can increase the novel object recognition index and alternation behaviors in Y maze test as compared to the groups treated with hesperetin or ECT (p < 0.05). These results suggest that co-administration of hesperetin with ECT is effective for improvement of cognitive function and can alleviate ECT-induced memory impairment in reserpine-treated rats.

Ventral tegmental area serotonin 5-HT1A receptors and corticolimbic cFos/BDNF/GFAP signaling pathways mediate dextromethorphan/morphine anti-allodynia

AimsThe present study examined the role of ventral tegmental area (VTA) serotonergic 5HT1A receptors in dextromethorphan/morphine-induced anti-allodynia and the possible changes of corticolimbic cFos, brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) following the treatments. Materials and methodsThe VTA cannulation and the chronic constriction of the sciatic nerve were performed in male Wistar rats. Flexion withdrawal thresholds to mechanical stimulation in the hind-limb were determined using von Frey hairs. The expressions of cFos, BDNF, and GFAP were evaluated using the Western blotting technique. Key findingsBDNF (in the hippocampus), and GFAP (in the targeted sites) levels were increased following neuropathic pain. Morphine administration induced an anti-allodynic effect with a decrease in the amygdala BDNF level. Dextromethorphan/morphine-induced anti-allodynia was accompanied by the decrease of hippocampus/amygdala/PFC GFAP and amygdala cFos expressions. The PFC BDNF expression level was increased in dextromethorphan/morphine-treated rats. Intra-VTA microinjection of (S)-WAY100135 (1 µg/rat), a selective 5-HT1A receptor antagonist, inhibited the anti-allodynic effect of dextromethorphan/morphine. This treatment increased the cFos level in the hippocampus and the amygdala while decreased the PFC level of cFos. The hippocampal BDNF expression was significantly increased, while the amygdala and the PFC expressions of BDNF were decreased under treatment. (S)-WAY100135 plus dextromethorphan/morphine increased the hippocampal/amygdala and PFC levels of GFAP. SignificanceThese findings indicate that dextromethorphan could potentiate the analgesic effect of morphine via the implication of the VTA serotonin 5-HT1A receptors. It seems that the changes in the corticolimbic cFos/BDNF/GFAP signaling pathway may be involved in the observed anti-allodynic effect.

The effect of electronic cigarettes exposure on learning and memory functions: behavioral and molecular analysis

Objective: Electronic cigarettes (ECIGs) are battery-powered devices that emit vaporized solutions for the user to inhale. ECIGs are marketed as a less harmful alternative to combustible cigarettes. The current study examined the effects of ECIG aerosol exposure on learning and memory, expression of brain derived neurotrophic factor (BDNF), and the activity of antioxidant enzymes in the hippocampus. Methods: Male Wistar rats were exposed to ECIG aerosol, by a whole-body exposure system, 1 h/day for 1 week, 4 weeks, and 12 weeks. Spatial learning and memory were tested using the Radial Arm Water Maze (RAWM). Hippocampal BDNF protein level, and oxidative stress biomarkers (GPx, SOD, GSH, GSSG, GSH/GSSG ratio) were also assessed. Results: ECIG aerosol exposure for 4 and 12 weeks impaired both short- and long- term memory and induced reductions in the hippocampus BDNF, SOD and GPx activities, and GSH/GSSG ratio (p < 0.05). No changes in any examined biomarkers were observed after 1-week exposure to ECIG aerosol (p > 0.05). Conclusions: ECIG aerosol exposure impaired functional memory and elicited changes in brain chemistry that are consistent with reduced function and oxidative stress.

Black Bamboo Rhizome Extract Improves Cognitive Dysfunction by Upregulating the Expression of Hippocampal BDNF and CREB in Rats with Cerebral Ischaemia-Reperfusion Injury.

IntroductionThe study aimed to explore the effects of treatment with black bamboo rhizome extracts on learning and memory and determine the underlying mechanisms in rats with cerebral ischaemia-reperfusion injury.MethodsSprague-Dawley rats were randomly divided into the following four groups: control, middle cerebral artery occlusion (MCAO), low-dose drug, and high-dose drug groups. Rats underwent MCAO using a suture method before drug treatment. Then, neurological impairment was assessed using the Longa scoring method, and triphenyl tetrazolium chloride staining was used to analyse the cerebral infarction area. The Elliott formula was used to calculate water content in the brain tissue. A Morris water maze (MWM) was used to assess changes in learning and memory abilities, and Western blotting was used to detect cyclic adenosine phosphate response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of MCAO rats.ResultsAfter treatment with black bamboo rhizome extracts, the neurological dysfunction score was lower in the drug groups than in the MCAO group, and a significant difference was observed between the high-dose drug and MCAO groups (P<0.05). Additionally, the cerebral infarction area was significantly smaller in the drug groups than in the MCAO group (P<0.01), and the effect was more obvious in the high-dose drug group than in the low-dose drug group. There was also a significant difference in water content between the high-dose drug and MCAO groups, and cerebral oedema was significantly reduced in the high-dose drug group (P<0.05). In the MWM, the incubation period was significantly reduced, the number of platform crossings was significantly increased, and the search time was prolonged in the drug groups compared with those in the MCAO group (P<0.05). Moreover, the expression of BDNF and CREB was significantly increased in the drug groups compared to that in the MCAO group, and the increase was more obvious in the high-dose group than in the low-dose group (P<0.05).DiscussionBlack bamboo rhizome extracts significantly improved cognitive dysfunction, reduced cerebral oedema, decreased the cerebral infarction area, and improved the neurological function score and learning and memory abilities in rats with cerebral ischaemia-reperfusion injury.

Therapeutic effects of saffron extract on different memory types, anxiety, and hippocampal BDNF and TNF-α gene expressions in sub-chronically stressed rats

ABSTRACT Objective: While stress reportedly impairs memory, saffron enhances it. This study investigated the therapeutic effects of saffron extract on different memory types, anxiety-like behavior, and expressions of BDNF and TNF-α genes in sub-chronically stressed rats. Methods: Rats were randomly assigned to control, restraint stress (6 h/day/7 days), two 7-days saffron treatments with 30 and 60 mg/kg, and two stress-saffron groups (30 and 60 mg/kg/7 post-stress days). Serum cortisol level and hippocampal BDNF and TNF-α gene expressions were measured. Open field, passive avoidance, novel object recognition, and object location tests were performed to assess anxiety-like behavior and avoidance as well as cognitive and spatial memories, respectively. Results: The low saffron dose in the sub-chronic stressed group led to a significant increase in passive avoidance latency from day 3 onward whereas this effect was observed after 7 days under the high-dose treatment that simultaneously led to a significant decline in serum cortisol level. While the low saffron dose led to a sharp drop in hippocampal TNF-α gene expression, the high dose significantly increased the hippocampal BDNF gene expression in the sub-chronic stress group. Finally, both saffron doses reduced anxiety in the stressed groups. Conclusion: Compared to the low saffron dose, the high dose had a latent but long-lasting impact. Cognitive and spatial memories remained unaffected by either stress or saffron treatment. In addition, only the high saffron dose reversed anxiety in the sub-chronically stressed group. These findings suggest that various doses of saffron act differently on different brain functions under sub-chronic stress conditions. Abbreviations: Brain derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), hypothalamic–pituitary–adrenal axis (HPA), novel object recognition task (NORT), novel object location task (NOLT), open field test (OFT), passive avoidance (PA).

Xanthoceraside administration produces significant antidepressant effects in mice through activation of the hippocampal BDNF signaling pathway

Current available antidepressants have various adverse reactions and slow pharmacodynamics, so it is necessary to find novel antidepressants for effective treatment. Xanthoceraside (XAN), a novel triterpenoid saponin extracted from the fruit husks of Xanthoceras sorbifolium Bunge, has anti-amnesic and neuroprotective properties. The purpose and significance of this study is to assess whether XAN has antidepressant effects in mice using the forced swim test (FST), tail suspension test (TST) and chronic unpredictable mild stress (CUMS) model of depression. The effects of XAN treatment on the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway and neurogenesis were examined. The antidepressant mechanism of XAN was explored using a BDNF inhibitor (K252a) and an anti-BDNF antibody. It was found that XAN administration significantly reversed the depressive-like behaviors of CUMS-treated mice. XAN treatment also significantly prevented the decreasing effects of CUMS on the hippocampal BDNF signaling and neurogenesis. The antidepressant effects of XAN in mice were blocked by both administration of K252a and anti-BDNF antibody. Collectively, these findings indicate that XAN possesses antidepressant effects in mice which are mediated by activation of hippocampal BDNF signaling pathway, thus providing the first evidence that XAN can be a potential antidepressant candidate.

Effects of enriched environment on depression and anxiety-like behavior induced by early life stress: A comparison between different periods

BackgroundBrain development is a prolonged process and it is sensitive to the environment during critical periods. Stress in early life is believed to increase vulnerability to depression, while enriched environment (EE) has beneficial effects on neural plasticity and depression. In this study, we compared the therapeutic effect of EE during different periods on early life stress-induced depression, and investigated the role of brain-derived neurotrophic factor (BDNF) and protein kinase B (AKT) on the effect of EE. Plasma corticosterone level was also detected to evaluate the reactivity of hypothalamic-pituitary-adrenal axis. MethodsC57BL/6 mice were subjected to a 4-h maternal separation (MS) procedure during postnatal days 2–21. After this separation, the mice were assigned to standard environment groups (SE), EE in the early period groups (3–8 weeks, EEE) and EE in the adult groups (8–13 weeks, EEA). Depression and anxiety behavior were evaluated at 14-weeks of age. The plasma corticosterone was quantified utilizing enzyme-linked immunosorbent assay. Hippocampus BDNF and AKT/p-AKT were detected using Western blotting. ResultsThe results showed that MS increased depression and anxiety level, while EE in both intervention periods alleviated the symptoms of depression and anxiety. The EEE group showed better effects in terms of anhedonia and anxiety than the EEA group. The difference in despair behavior between the EEE and EEA groups was not significant. MS increased plasma corticosterone level, while EE decreased corticosterone level in both intervention periods. EE increased BDNF and p-AKT expression in the hippocampus, with stronger effects in the EEE group. ConclusionEE during the early development period was more effective in alleviating depression and anxiety induced by early life stress. BDNF and AKT may play a significant role in the effect of EE, and further research is needed to explore the detailed neurobiological mechanisms.

Effect of Electroacupuncture at Siguan Acupoints on Expression of BDNF and TrkB Proteins in the Hippocampus of Post-Stroke Depression Rats.

To study the effect of electroacupuncture at the Siguan acupoints on the expression of hippocampal brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in post-stroke depression (PSD) rats, in order to explore its possible mechanism Fifty specific pathogen-free (SPF)-grade adult male Sprague-Dawley (SD) rats were randomly divided into a blank group, stroke group, PSD group, Siguan acupoint group and fluoxetine group according to the random number method. PSD rats were modeled with middle cerebral artery occlusion combined with chronic unpredictable mild stress. After successful modeling, electroacupuncture was applied to Siguan acupoints for a total of 21days at 30min/session/day. The rats in the fluoxetine group were fed intragastrically according to body weight, once a day, for a total of 21days. The rats in each group were bound and intragastrically administered distilled water every day. The depressive behavior of rats was measured according to the horizontal and vertical scores of the open field test and the sucrose water consumption, and the changes in the number of BDNF- and TrkB-positive cells in the hippocampus of rats were observed by immunohistochemistry. After modeling, the behavioral indicators and the numbers of BDNF- and TrkB-positive cells in each model group were significantly lower than those in the blank group (P < 0.01). After treatment, the behavioral indicators and the numbers of BDNF- and TrkB-positive cells in the Siguan acupoint group and fluoxetine group were significantly higher than that in the PSD group (P < 0.01). During the treatment, the horizontal and vertical scores of the Siguan acupoint group were significantly increased on the seventh day of treatment, and the difference was statistically significant when compared with the PSD group (P < 0.05). The sucrose water consumption was significantly increased on the 14th day of treatment, and the difference was significant when compared with the PSD group (P < 0.05), both of which were earlier than that in the fluoxetine group. During the treatment, there was no significant difference between the two groups (P > 0.05). Electroacupuncture at Siguan acupoints has the same antidepressant effect as fluoxetine, and is more effective than fluoxetine in relieving depression in PSD rats. Its mechanism may be related to the activation of the expression of BDNF and its receptor TrkB.