Brain-derived Neurotrophic Factor mRNA Levels Research Articles

Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with loss of memory and cognitive abilities. Previous evidence suggested that exercise ameliorates learning and memory deficits by increasing brain derived neurotrophic factor (BDNF) and activating downstream pathways in AD animal models. However, upstream pathways related to increase BDNF induced by exercise in AD animal models are not well known. We investigated the effects of moderate treadmill exercise on Aβ-induced learning and memory impairment as well as the upstream pathway responsible for increasing hippocampal BDNF in an animal model of AD. Animals were divided into five groups: Intact, Sham, Aβ1−42, Sham-exercise (Sham-exe) and Aβ1−42-exercise (Aβ-exe). Aβ was microinjected into the CA1 area of the hippocampus and then animals in the exercise groups were subjected to moderate treadmill exercise (for 4 weeks with 5 sessions per week) 7 days after microinjection. In the present study the Morris water maze (MWM) test was used to assess spatial learning and memory. Hippocampal mRNA levels of BDNF, peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), fibronectin type III domain-containing 5 (FNDC5) as well as protein levels of AMPK-activated protein kinase (AMPK), PGC-1α, BDNF, phosphorylation of AMPK were measured. Our results showed that intra-hippocampal injection of Aβ1−42 impaired spatial learning and memory which was accompanied by reduced AMPK activity (p-AMPK/total-AMPK ratio) and suppression of the PGC-1α/FNDC5/BDNF pathway in the hippocampus of rats. In contrast, moderate treadmill exercise ameliorated the Aβ1−42-induced spatial learning and memory deficit, which was accompanied by restored AMPK activity and PGC-1α/FNDC5/BDNF levels. Our results suggest that the increased AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway by exercise are likely involved in mediating the beneficial effects of exercise on Aβ-induced learning and memory impairment.

Exogenous brain-derived neurotrophic factor attenuates cognitive impairment induced by okadaic acid in a rat model of Alzheimer's disease.

Decreased expression of brain-derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of Alzheimer's disease, and a typical pathological change in Alzheimer's disease is neurofibrillary tangles caused by hyperphosphorylation of tau. An in vivo model of Alzheimer's disease was developed by injecting okadaic acid (2 μL) and exogenous BDNF (2 μL) into the hippocampi of adult male Wister rats. Spatial learning and memory abilities were assessed using the Morris water maze. The expression levels of protein phosphatase 2A (PP2A), PP2Ac-Yp307, p-tau (Thr231), and p-tau (Ser396/404) were detected by western blot assay. The expression levels of BDNF, TrkB, and synaptophysin mRNA were measured by quantitative real-time polymerase chain reaction. Our results indicated that BDNF expression was suppressed in the hippocampus of OA-treated rats, which resulted in learning and memory deficits. Intra-hippocampal injection of BDNF attenuated this OA-induced cognitive impairment. Finally, our findings indicated an involvement of the PI3K/GSK-3β/AKT pathway in the mechanism of BDNF in regulating cognitive function. These results indicate that BDNF has beneficial effect on Alzheimer's disease, and highlight the potential of BDNF as a drug target for treatment of Alzheimer's disease.

Gypenosides Attenuate Lipopolysaccharide‐Induced Neuroinflammation and Memory Impairment in Rats

Neuroinflammation is deliberated a major factor in various neurodegenerative diseases. Gypenosides (GPS) have pharmacological properties with multiple beneficial effects including anti-inflammatory, antioxidative, and protective properties. In the present study, whether GPS could improve cognitive dysfunction and chronic inflammation caused by injecting lipopolysaccharide (LPS) in the hippocampus was investigated. Effects of GPS on inflammatory factors in the hippocampus and the downstream mechanisms of these effects were also examined. Induction of LPS into the lateral ventricle caused inflammatory reactions and memory impairment on the rats. Every day treatment of GPS (25, 50, and 100 mg/kg) for 21 consecutive days attenuated spatial recognition, discrimination, and memory deficits. GPS treatment significantly decreased proinflammatory mediators such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and nuclear factor-kappaB (NF-κB) levels in the brain. Furthermore, GPS reduced LPS-induced elevated levels of inducible nitric oxide synthase (iNOS) and toll-like receptor 4 (TLR4) mRNA and inhibition of brain-derived neurotrophic factor (BDNF) mRNA level. Collectively, these results showed that GPS may improve cognitive function and provide a potential therapy for memory impairment caused by neuroinflammation. Based on these, GPS may be effective in inhibiting the progress of neurodegenerative diseases by improving memory functions due to its anti-inflammatory activities and appropriate modulation of NF-κB/iNOS/TLR4/BDNF.

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

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

Inhibition of Inwardly Rectifying Potassium (Kir) 4.1 Channels Facilitates Brain-Derived Neurotrophic Factor (BDNF) Expression in Astrocytes.

Inwardly rectifying potassium (Kir) 4.1 channels in astrocytes regulate neuronal excitability by mediating spatial potassium buffering. Although dysfunction of astrocytic Kir4.1 channels is implicated in the development of epileptic seizures, the functional mechanisms of Kir4.1 channels in modulating epileptogenesis remain unknown. We herein evaluated the effects of Kir4.1 inhibition (blockade and knockdown) on expression of brain-derived neurotrophic factor (BDNF), a key modulator of epileptogenesis, in the primary cultures of mouse astrocytes. For blockade of Kir4.1 channels, we tested several antidepressant agents which reportedly bound to and blocked Kir4.1 channels in a subunit-specific manner. Treatment of astrocytes with fluoxetine enhanced BDNF mRNA expression in a concentration-dependent manner and increased the BDNF protein level. Other antidepressants (e.g., sertraline and imipramine) also increased the expression of BDNF mRNA with relative potencies similar to those for inhibition of Kir4.1 channels. In addition, suppression of Kir4.1 expression by the transfection of small interfering RNA (siRNA) targeting Kir4.1 significantly increased the mRNA and protein levels of BDNF. The BDNF induction by Kir4.1 siRNA transfection was suppressed by the MEK1/2 inhibitor U0126, but not by the p38 MAPK inhibitor SB202190 or the JNK inhibitor SP600125. The present results demonstrated that inhibition of Kir4.1 channels facilitates BDNF expression in astrocytes primarily by activating the Ras/Raf/MEK/ERK pathway, which may be linked to the development of epilepsy and other neuropsychiatric disorders.

Neuronal expression of brain derived neurotrophic factor in the injured telencephalon of adult zebrafish.

The reparative ability of the central nervous system varies widely in the animal kingdom. In the mammalian brain, the regenerative mechanisms are very limited and newly formed neurons do not survive longer, probably due to a non-suitable local environment. On the opposite, fish can repair the brain after injury, with fast and complete recovery of damaged area. The brain of zebrafish, a teleost fish widely used as vertebrate model, also possesses high regenerative properties after injury. Taking advantage of this relevant model, the aim of the present study was to investigate the role of brain-derived neurotrophic factor (BDNF) in the regenerative ability of adult brain, after stab wound telencephalic injury. BDNF is involved in many brain functions and plays key roles in the repair process after traumatic brain lesions. It has been reported that BDNF strengthens the proliferative activity of neuronal precursor cells, facilitates the neuronal migration toward injured areas, and shows survival properties due to its anti-apoptotic effects. BDNF mRNA levels, assessed by quantitative PCR and in situ hybridization at 1, 4, 7, and 15 days after the lesion, were increased in the damaged telencephalon, mostly suddenly after the lesion. Double staining using in situ hybridization and immunocytochemistry revealed that BDNF mRNA was restricted to cells identified as mature neurons. BDNF mRNA expressing neurons mostly increased in the area around the lesion, showing a peak 1 day after the lesion. Taken together, these results highlight the role of BDNF in brain repair processes and reinforce the value of zebrafish for the study of regenerative neurogenesis.

Study of the Role of CREB, BDNF, and VGF Neuropeptide in Long Term Antidepressant Activity of Crocin in the Rat Cerebellum.

Antidepressant activity of crocin, saffron main component, has been established before. Based on previous study, it is suggested that elevation in the levels of BDNF (brain-derived neurotrophic factor), CREB (cAMP response element binding) and VGF neuropeptide could be considered as one probable molecular mechanisms involved in antidepressant activity of long term crocin administration in the rat hippocampus. In this study we further investigated whether the antidepressant activity of crocin in long term administration was associated with alteration in these factors in the rat cerebellum. Crocin (12.5, 25 and 50 mg/kg/day) and imipramine (10 mg/kg/day) were administered interaperitoneally for 21 days to rats. At the end of experiment, animals were sacrificed and cerebellums were dissected. BDNF, VGF, CREB, and phospho-CREB (P-CREB) protein and mRNA levels in the rat cerebellum were evaluated using Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In the current study significant increases in mRNA and protein levels of VGF, CREB and (BDNF) in long term crocin treatment were not observed in the rat cerebellum. Although a slight increase was observed in protein level of P-CREB compared to normal saline, but it was not significant. It is concluded that antidepressant activity of crocin might be partially mediated to CREB. Moreover, other factors rather than BDNF and VGF neuropeptides may alter following long term crocin treatment in the cerebellum. To understand the precise mechanism of crocin antidepressant effects in the cerebellum, longer duration of crocin treatment in further studies is recommended.

Reoxygenation with 100% Oxygen Following Hypoxia in Mice Causes Apoptosis.

After hypoxia, reoxygenation with air is the consensus treatment for full-term neonates; however, the effect of hyperoxic reoxygenation of adults is unknown. The present study was designed to investigate the effects of reoxygenation with 100% oxygen after hypoxia on inflammation and apoptosis in mice. Eight-week-old mice were either subjected to hypoxia in 8% oxygen for 30 min or air served as controls. Following hypoxia, mice underwent reoxygenation for 30 min with 21% or 100% oxygen. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), caspase-3 and brain derived neurotrophic factor (BDNF) mRNA study and histopathological study were performed. Reoxygenation with 100% oxygen significantly increased TNF-α (2.5 h after hypoxia), IL-1β (5 h after hypoxia), caspase-3 (8 h after hypoxia) mRNA levels in the whole brain compared with 21% oxygen, and significantly decreased erythropoietin mRNA expression compared with 21% oxygen 9 h after reoxygenation. However, reoxygenation with 100% oxygen and 21% oxygen significantly decreased BDNF mRNA levels compared with control air group. There were no clear abnormal findings showing neuronal death among the three groups. Reoxygenation with 100% oxygen after hypoxia induced inflammation and apoptosis in adult mice. Therefore, these results suggest that the reoxygenation with 100% oxygen after hypoxia has harmful effects on adult brain as well as on neonatal brain.

The combination of escitalopram and aripiprazole: Investigation of psychomotor effects in rats.

Pre-clinical and clinical evidence suggests that the antidepressant efficacy of the selective serotonin reuptake inhibitor escitalopram can be enhanced by the dopamine and serotonin partial agonist aripiprazole. Given the range of possible neurochemical interactions between these drugs, the current study investigated whether aripiprazole alters the hedonic and psychomotor effects of escitalopram. Male Sprague Dawley rats ( n=116) received 10 mg/kg/day escitalopram (subcutaneous), 2 mg/kg/day aripiprazole (subcutaneous), or combined aripiprazole + escitalopram, and were tested for consumption of incentive nutritional stimuli (high-fructose corn syrup and chow), stereotypy and locomotor activity. At the conclusion of behavioral testing, mRNAs of two genes involved in reward processes were quantified: hypothalamic pro-opiomelanocortin and hippocampal brain-derived neurotrophic factor. Escitalopram produced a selective, but temporary, decrease in high fructose corn syrup consumption that was not altered by aripiprazole co-administration. Escitalopram had no significant effect on locomotion, but aripiprazole co-administration produced a persistent increase in stereotypy. Both brain-derived neurotrophic factor and pro-opiomelanocortin mRNA levels were lower in the aripiprazole + escitalopram group relative to the escitalopram group. Taken together, these results suggest that aripiprazole may enhance the antidepressant efficacy of escitalopram through improvement of psychomotor functions.

Rotigotine, a dopamine receptor agonist, increased BDNF protein levels in the rat cortex and hippocampus.

Brain-derived neurotrophic factor (BDNF) critically controls the fate and function of the neuronal network and has received much attention as a target of many brain diseases. Dopaminergic system dysfunction has also been implicated in a variety of neuropsychiatric diseases. Rotigotine, a non-ergot dopamine receptor agonist, is used in the treatment of Parkinson's disease and restless legs syndrome. To investigate the effects of rotigotine on neuronal functions both in vivo and in vitro, rats and primary cortical neurons were administered rotigotine, and the mRNA and protein expression levels of BDNF, its receptor TrkB and downstream signaling molecules, and synaptic proteins were determined. We found that BDNF protein was increased in the cortex and hippocampus of rats after 7days of rotigotine treatment. In contrast, BDNF mRNAs were reduced 6h after rotigotine treatment in cultured neurons presumably through the transient suppression of neuronal activity. We identified differential expression of D1, D2, and D3 receptors in the rat brain and cultured neurons. The observed increase in the expression of BDNF protein in the cortex and hippocampus after subchronic administration of rotigotine suggests that it may exert its medical effect in part through improving BDNF function in the brain. In addition, our results highlight the complex relationships between rotigotine and BDNF expression, which depend on the brain region, time course, and dose of the drug.

Protective effects of notoginsenoside R1 on cerebral ischemia-reperfusion injury in rats.

The objective of this study was to investigate the protective effect of notoginsenoside R1 (NGR1) on cerebral ischemia-reperfusion injury (CIRI) in rats, and its molecular mechanism, to provide new insights into the diagnosis and treatment of CIRI. Sixty Sprague-Dawley rats were randomly divided into four groups including the sham-operation group (Sham), cerebral ischemia-reperfusion model group (CIR), NGR1 treatment group (NGR1), and nimodipine positive control group (NDC) with 15 rats each. Bilateral common carotid arteries occlusion was used to establish the rat CIRI model. The area of cerebral infarction at the end of reperfusion was calculated by triphenyl tetrazolium chloride staining. Apoptosis of hippocampal neurons in each group was detected by Annexin V/propidium iodide double staining. Hippocampal expression of brain-derived neurotrophic factor (BDNF) mRNA, and Bcl-2 and Bax protein at the end of reperfusion were measured by RT-qPCR and western blot analysis, respectively. Data were analyzed by SPSS software analysis to ensure statistical significance. At the end of reperfusion, the area of cerebral infarction in the NGR1 and NDC groups was significantly smaller than that of the CIR group. Apoptosis analysis showed that compared with the CIR group, the apoptosis rate of hippocampal neurons was significantly decreased in the NGR1 and NDC groups. RT-qPCR and western blot analysis showed that at the end of reperfusion, higher levels of BDNF mRNA and the anti-apoptotic factor, Bcl-2, and lower levels of the pro-apoptotic factor, Bax, in the hippocampus were found in the NGR1 and NDC groups compared with the CIR group. The protective effect of NGR1 on CIRI was significantly stronger than that of nimodipine. In conclusion, NGR1 can reduce the area of cerebral infarction, reduce apoptosis of hippocampal neurons, and protect rats from CIRI. Those effects were achieved by activating the expression of BDNF and Bcl-2, and by inhibiting the expression of Bax.

The mechanism of mesenchymal stem cells on neural function in rats with traumatic brain injury

Objective To investigate the effect of mesenchymal stem cells (MSCs) on the neurological function of rats with traumatic brain injury, and to investigate the mechanism of the effect of MSCs. Methods 60 SD rats models with brain injury established by the modified Feeney method were divided into model group, MSCs group and phosphate buffer (PBS) group by. Another 20 healthy SD rats were chosen as the control group. Rats of MSCs group were transplantated with Umbilical cord mesenchymal stem cells isolated and cultured in vitro. Neurological function of rats in each group were evaluated by improved neurological function score (mNSS) standard at 1, 3, 7, 14, 21, 28 d after transplantation. Neuronal nuclear antigen (NeuN) expression level in the brain tissue of rats was detected with immunohistochemical method. Brain-derived neurotrophic factor (BDNF) mRNA level of in the brain tissue of rats was detected with reverse transcriptase-polymerase chain reaction (RT-PCR) method. The apoptosis level of cerebral tissue cells in rats was detected by TdT-mediated dUTP nick end labeling (TUNEL) method. Results Compared with the control group, mNSS score of rats in model group, MSCs group and PBS group increased, NeuN expression decreased increased (P=0.000). Compared with the model group and PBS group, mNSS score of rats in MSCs group significantly decreased, NeuN expression significantly decreased(P=0.000). Compared with the control group BDNF mRNA level (0.31±0.12), BDNF mRNA level in model group, PBS group and MSCs Group (1.32±0.34, 1.23±0.30, 0.81±0.21) significantly increased (P=0.000). Compared with model group and PBS group, the levels of BDNF mRNA in MSCs group significantly reduced (P=0.014, P=0.019). Compared with the apoptosis level of brain tissue in control group (3.14±1.12), apoptosis level in model group, PBS group and MSCs group (27.84±4.32, 25.35±4.89, 10.33±3.32) significantly increased (P=0.000). Compared with model group and PBS group, the level of apoptosis in brain tissue of MSCs group significantly decreased (P=0.000). Conclusion Mesenchymal stem cells can decreased the apoptosis level of brain injury in rats through the mechanism of repairing damaged neurons and promoting the BDNF secretion. It can promote the repair effect on neural function of rats with traumatic brain injury. Key words: Brain injury; Mesenchymal stem cells; Nerve function

Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease

Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.

Effects of Crocin on Spatial Memory Impairment Induced by Hyoscine and Its Effects on BDNF, CREB, and p-CREB Protein and mRNA Levels in Rat Hippocampus

Background: Crocus sativus L., (Iridaceace), known as saffron, is used in traditional medicine for different purposes such asmemory improvment. Crocin is one of the pharmacologically active constituents responsible for many medicinal properties of saffron. Objectives: In this study, the effects of crocin, an active saffron constituent, on hyoscine inducedmemory impairment and its effect onprotein andmRNAtranscript levels of CREB (cAMP response element binding protein), BDNF(brain-derived neurotrophic factor), and phospho-CREB (p-CREB) were investigated in rat hippocampus. Methods: Rats were intraperitoneally treated with crocin (10, 20, and 40 mg/kg), normal saline (1 mL/kg), and rivastigmine (1.5 mg/kg) 30 minutes prior to hyoscine (1 mg/kg) for five days. The effects were studied on spacial learning and memory using Morris water maze. Protein and transcript levels of CREB and BDNF were analyzed using western blotting and qRT PCR methods, respectively. Results: Five days treatment with crocin (20 and 40 mg/kg) and rivastigmine significantly increased the presence of animals in target quadrant in probe trial on the 8th day compared to hyoscine. Crocin (20 mg/Kg) increased significantly BDNF and CREB protein and transcript levels compared to hyoscine. Conclusions: Crocin improved memory impairment induced by hyoscine through reduction of the latency to find the platform in the probe trial in Morris water maze test. Crocin improved memory probably due to the increase of BDNF and CREB protein and transcript levels. © 2017, Jundishapur Journal of Natural Pharmaceutical Products.

Fluoxetine coupled with zinc in a chronic mild stress model of depression: Providing a reservoir for optimum zinc signaling and neuronal remodeling

BackgroundRecently, depression has been envisioned as more than an alteration in neurotransmitters centered around receptor signaling pathways. Consequently, the precise mechanisms of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs such as fluoxetine are being revisited. Zinc is a trace element that has been long implicated in the psychopathology and therapy of depression. Zinc has been found to be sequestered and dispensed during stress and inflammation through a family of proteins called metallothioneins (MTs). In addition, MTs are well known for their antioxidant and therefore cytoprotective action. Changes in MTs, their upstream regulators and downstream effectors in response to fluoxetine have not been yet studied. The aim of the present study is to examine whether depression-induced changes in protein levels and mRNA levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), MTs, antioxidant defensive enzyme heme oxygenase (HO-1), zinc-specific receptor GPR39 and brain derived neurotrophic factor (BDNF) in the hippocampus can be reversed by fluoxetine treatment, zinc supplementation or a combination of the two. Material and methodsThe present study investigated the effect of chronic (4weeks) combined treatment with zinc hydroaspartate (15mg/kg) and fluoxetine (10mg/kg) on a chronic mild stress model (CMS) in male Sprague–Dawley rats. ResultsHippocampal mRNA and protein levels of Nrf2, HO-1, MTs, GPR39 (protein level only) and BDNF were significantly higher in response to a combined therapy of fluoxetine and zinc than to either monotherapy. Additionally, HO-1 and MTs gene expression was correlated with that of Nrf2 in the FLX-only group. ConclusionFluoxetine therapy activated the expression of MTs and HO-1 through an Nrf2-dependent pathway. When FLX was escorted by zinc, activated MTs had a positive impact on BDNF through the zinc signaling receptor GPR39, resulting in general improvement in neuronal plasticity as well as reduction of neuronal atrophy and neuronal cell loss.

Contribution of BDNF/TrkB signalling in the rACC to the development of pain-related aversion via activation of ERK in rats with spared nerve injury

The rostral anterior cingulate cortex (rACC) is a key structure in mediating the negative affective component of chronic pain. Brain-derived neurotrophic factor (BDNF) is known to play a critical role in activity-dependent synaptic plasticity, learning and memory. It has been shown that BDNF signalling in the rACC might be involved in spontaneous pain-related aversion, but its underlying mechanism is still largely unknown. To address this question, we measured the mRNA and protein levels of BDNF in the rACC after nerve injury and found that BDNF expression was markedly higher in nerve-injured rats than in controls. Moreover, we found that conditioned place avoidance (CPA), a behavioural phenotype reflecting pain-related aversion, was acquired in rats with partial sciatic nerve transection. However, a local injection of a BDNF-tropomyosin receptor kinase B (TrkB) antagonist into the rACC completely suppressed this process. Importantly, we found that administration of exogenous BDNF into the rACC of intact rats was sufficient to produce CPA, while selectively blocking phosphorylated extracellular signal regulated kinase (p-ERK) with a mitogen-activated protein kinase (MAPK) inhibitor U0126 completely abolished the acquisition of BDNF-induced CPA. In conclusion, we demonstrate, for the first time, that ERK is an important downstream effector of the BDNF/TrkB-mediated signalling pathway in the rACC that contributes to the development of neuropathic pain-related aversion.

Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice.

Epigallocatechin-3-gallate (EGCG), a polyphenol in green tea, is an effective antioxidant and possesses neuroprotective effects. Brain-derived neurotrophic factor (BDNF) and cyclic AMP response element-binding protein (CREB) are crucial for neurogenesis and synaptic plasticity. In this study, we aimed to assess the protective effects of EGCG against sevoflurane-induced neurotoxicity in neonatal mice. Distinct groups of C57BL/6 mice were given EGCG (25, 50, or 75 mg/kg body weight) from postnatal day 3 (P3) to P21 and were subjected to sevoflurane (3%; 6 h) exposure on P7. EGCG significantly inhibited sevoflurane-induced neuroapoptosis as determined by Fluoro-Jade B staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Increased levels of cleaved caspase-3, downregulated Bad and Bax, and significantly enhanced Bcl-2, Bcl-xL, xIAP, c-IAP-1, and survivin expression were observed. EGCG induced activation of the PI3K/Akt pathway as evidenced by increased Akt, phospho-Akt, GSK-3β, phospho-GSK-3β, and mTORc1 levels. Sevoflurane-mediated downregulation of cAMP/CREB and BDNF/TrkB signalling was inhibited by EGCG. Reverse transcription PCR analysis revealed enhanced BDNF and TrkB mRNA levels upon EGCG administration. Improved performance of mice in Morris water maze tests suggested enhanced learning and memory. The study indicates that EGCG was able to effectively inhibit sevoflurane-induced neurodegeneration and improve learning and memory retention of mice via activation of CREB/BDNF/TrkB-PI3K/Akt signalling.

Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice

We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function.

CRHR1 exacerbates the glial inflammatory response and alters BDNF/TrkB/pCREB signaling in a rat model of global cerebral ischemia: implications for neuroprotection and cognitive recovery

This study examined the impact of corticotropin-releasing hormone type 1 receptor (CRHR1) blockade using Antalarmin (ANT) on the expression of markers of neuroplasticity and inflammation, as well as neuroprotection and behavioral recovery following global cerebral ischemia. Male Wistar rats (N=50) were treated with ANT (2μg/2μl; icv) or a vehicle solution prior to a sham or four vessel (4VO) occlusion. Seven days post ischemia, anxiety was assessed in the Elevated Plus Maze and Open Field tests, and fear and spatial learning in a Y-Maze Passive Avoidance Task and the Barnes Maze. Thirty days post ischemia, brain derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptor expression, hippocampal neuronal death and inflammation were determined by analyzing immunoreactivity (ir) of neuron-specific nuclear protein (NeuN), microglia (IBA1, ionized calcium binding adaptor molecule 1), astrocytes (GFAP, glial fibrillary acidic protein) and TNFα (tumor necrosis factor alpha) a pro-inflammatory cytokine. Our findings revealed that ANT improved behavioral impairments, while conferring neuroprotection and blunting neuroinflammation in all hippocampal sub-regions post ischemia. We also observed reduced BDNF and TrkB mRNA and protein levels at the hippocampus, and increased expression at the hypothalamus and amygdala post ischemia, site-specific alterations which were regularized by pre-ischemic CRHR1 blockade. These findings support that CRHR1 actively contributes to altered brain plasticity, neuronal inflammation and injury and recovery of function following ischemic brain insults.

Resolving the contributions of anaesthesia, surgery, and nerve injury on brain derived neurotrophic factor expression in the medial prefrontal cortex of male rats in the CCI model of neuropathic pain.

The medial prefrontal cortex (mPFC) is critical for selecting and shaping complex behavioral responses. In rodent models of neuropathic pain there is evidence for both structural and functional changes in the mPFC. Brain derived neurotrophic factor (BDNF) plays a critical role in the normal functioning of the mPFC. It has been suggested that the disruption of complex behaviors and mood seen in some neuropathic pain patients is mediated in part by alterations of BDNF in this cortical region. In Sprague-Dawley rats, mPFC levels of BDNF and TrkB mRNA and protein, were quantified and compared to controls (n = 24) 6 days after either: (a) halothane (1.5%) anaesthesia (n = 12), (b) sham surgery under halothane (n = 12), (c) sciatic nerve chronic constriction injury under halothane (n = 48). The social behaviors of the rats were quantified daily during the experimental period. Halothane anaesthesia increased BDNF and TrkB mRNA bilaterally. These increases were reversed in rats that underwent sham surgical and nerve injury procedures. Further, halothane anaesthesia, surgical procedures, and nerve injury each decreased BDNF protein levels. These results reveal a marked and distinct BDNF expression profile in the mPFC of rats that have undergone each stage of the procedure to produce neuropathic pain by chronic constriction injury of the sciatic nerve. The highly sensitive nature of neurotrophic signalling to general anaesthesia in the mature neuronal circuit of the adult rat brain highlights the importance of careful evaluation and interpretation of data evaluating the effects of experimental procedures on neural substrates.