Upregulation Of Brain-derived Neurotrophic Factor Expression Research Articles

Dexmedetomidine Stereotaxic Injection Alleviates Neuronal Loss Following Bilateral Common Carotid Artery Occlusion via Up-Regulation of BDNF Expression.

Neurogenesis is an important process in the recovery from neurological damage caused by ischemic lesions. Endogenous neurogenesis is insufficient to restore neuronal damage following cerebral ischemia. Dexmedetomidine (DEX) exerts neuroprotective effects against cerebral ischemia and ischemia/reperfusion injury. DEX promotes neurogenesis, including neuronal proliferation and maturation in the hippocampus. In a previous study, we showed that early neurogenesis increased 3 days after bilateral common carotid artery occlusion (BCCAO). In this study, we investigated the effect of DEX on neurogenesis 3 days after BCCAO. Male Sprague-Dawley (SD) rats (7-8 weeks old) were used as a BCCAO model. Right and left common carotid arteries of the rats were occluded using 4-0 silk sutures. Two hours after surgery, an intracranial DEX injection was administered to rats that underwent surgery using a stereotaxic injector. Brains were obtained from control and BCCAO rats 3 days after surgery. Immunohistochemistry was performed on the cortex and dentate gyrus of the hippocampus using a NeuN antibody. Western blot was performed with HIF1α and brain-derived neurotrophic factor (BDNF) antibodies. The number of mature neurons decreased 3 days after BCCAO, but DEX treatment alleviated neural loss in the parietal cortex and hippocampus. Up-regulation of BDNF was also observed after dexmedetomidine treatment. Stereotaxic injection of dexmedetomidine alleviates neural loss following BCCAO by up-regulating BDNF expression.

Neuroprotective effect of isovaleraldehyde accompanied with upregulation of BDNF and CREB phosphorylation via the PKA pathway.

Recently, the number of patients diagnosed with dementia has increased. The World Health Organization (WHO) estimates that 50 million patients suffer from dementia. Although several therapeutic strategies have been proposed, currently, there is no curative approach for treating dementia. Neurodegeneration is an irreversible process. As this disease gradually progresses over 15-20years, a low-cost and sustainable method for preventing these diseases is desired. Cacao nib is consumed in many countries, and a recent clinical study indicated that cocoa intake upregulates brain-derived neurotrophic factor (BDNF), which plays a significant role in memory formation and neuronal cell survival. In the present study, neural cells were treated with cacao nib extract or the 17 characteristic components of cacao nib. Treatment with Cacao nib extract upregulates BDNF mRNA expression. In addition, cacao nib extract elicits the phosphorylation of cAMP-response-element-binding protein (CREB), which regulates the transcription of BDNF. Among the 17 species screened, isovaleraldehyde (IVA), also known as an aroma component of cacao nibs extract, improved BDNF mRNA expression without SH-SY5Y cell toxicity. IVA also promoted CREB phosphorylation through a cAMP-dependent protein kinase (PKA)-dependent mechanism. In conclusion, IVA could be responsible for the BDNF upregulation effect of cacao nib, and IVA upregulated BDNF expression via the PKA-CREB axis.

Aerobic exercise improves cognitive impairment in mice with type 2 diabetes by regulating the MALAT1/miR-382-3p/BDNF signaling pathway in serum-exosomes

BackgroundIt has been documented that aerobic exercise (AE) has a positive effect on improving cognitive function in type 2 diabetes (T2DM) patients. Here, we tried to explore how AE regulates the expression of long non-coding RNA in serum-exosomes (Exos), thereby affecting cognitive impairment in T2DM mice as well as its potential molecular mechanism.MethodsT2DM mouse models were constructed, and serum-Exos were isolated for whole transcriptome sequencing to screen differentially expressed lncRNA and mRNA, followed by prediction of downstream target genes. The binding ability of miR-382-3p with a long non-coding RNA MALAT1 and brain-derived neurotrophic factor (BDNF) was explored. Then, primary mouse hippocampal neurons were collected for in vitro mechanism verification, as evidenced by the detection of hippocampal neurons' vitality, proliferation, and apoptosis capabilities, and insulin resistance. Finally, in vivo mechanism verification was performed to assess the effect of AE on insulin resistance and cognitive disorder.ResultsTranscriptome sequencing analysis showed that MALAT1 was lowly expressed and miR-382-3p was highly expressed in serum-Exos samples of T2DM mice. There were targeted binding sites between MALAT1 and miR-382-3p and between miR-382-3p and BDNF. In vitro experiments showed that MALAT1 upregulated BDNF expression by inhibiting miR-382-3p. Silencing MALAT1 or overexpressing miR-382-3p could reduce the expression of INSR, IRS-1, IRS-2, PI3K/AKT, and Ras/MAPK, inhibit neuronal proliferation, and promote apoptosis. In vivo experiments further confirmed that AE could increase the expression of MALAT1 in serum-Exos to competitively inhibit miR-382-3p and upregulate BDNF expression, thereby improving cognitive impairment in T2DM mice.ConclusionAE may upregulate the expression of MALAT1 in serum-Exos to competitively inhibit miR-382-3p and upregulate BDNF expression, thus improving cognitive impairment in T2DM mice.

Lacticaseibacillus rhamnosus TF318 prevents depressive behavior in rats by inhibiting HPA-axis hyperactivity and upregulating BDNF expression

Growing evidence suggests that probiotics can ameliorate depression by regulating the microbiota-gut-brain axis. However, the mechanism of action of probiotics in depressive disorders remains incompletely understood. This study aimed to investigate the effect of Lacticaseibacillus rhamnosus TF318 in a corticosterone (CORT)-induced rat model of depression. The sucrose preference test (SPT) and Morris water maze (MWM) test showed that oral administration of L. rhamnosus TF318 for 21 d significantly prevented depressive behaviors. Administration of L. rhamnosus TF318 resulted in lower hippocampal levels of adrenocorticotropic hormone and corticotropin-releasing factor and serum levels of CORT and restoration of hippocampal levels of 5-hydroxytryptamine, dopamine, and norepinephrine. A marked increase was observed in the hippocampal concentration of brain-derived neurotrophic factor (BDNF), a change that may have involved the cyclic adenosine monophosphate (cAMP)/cAMP response element-binding (CREB)/BDNF signaling pathway. Treatment with L. rhamnosus TF318 corrected CORT-induced abnormalities in the gut microbiota, significantly increasing the relative abundance of Firmicutes. In conclusion, supplementation with L. rhamnosus TF318 prevented CORT-induced depressive behaviors by upregulating BDNF expression and modulating gut microbiota, suggesting that this strain has the potential as a novel probiotic with antidepressant effects.

Hypoxic Preconditioning Modulates BDNF and Its Signaling through DNA Methylation to Promote Learning and Memory in Mice.

Hypoxic preconditioning (HPC) as an endogenous mechanism can resist hypoxia/ischemia injury and exhibit protective effects on neurological function including learning and memory. Although underlying molecular mechanisms remain unclear, HPC probably regulates the expression of protective molecules by modulating DNA methylation. Brain-derived neurotrophic factor (BDNF) activates its signaling upon binding to the tropomyosin-related kinase B (TrkB) receptor, which is involved in neuronal growth, differentiation, and synaptic plasticity. Therefore, this study focused on the mechanism by which HPC regulates BDNF and BDNF/TrkB signaling through DNA methylation to influence learning and memory. Initially, the HPC model was established by hypoxia stimulations on ICR mice. We found that HPC downregulated the expression of DNA methyltransferase (DNMT) 3A and DNMT3B. Then, the upregulation of BDNF expression in HPC mice was generated from a decrease in DNA methylation of the BDNF gene promoter detected by pyrophosphate sequencing. Subsequently, upregulation of BDNF activated BDNF/TrkB signaling and ultimately improved learning and spatial memory in HPC mice. Moreover, after mice were intracerebroventricularly injected with the DNMT inhibitor, the restraint of DNA methylation accompanied by an increase of BDNF and BDNF/TrkB signaling was also discovered. Finally, we observed that the inhibitor of BDNF/TrkB signaling prevented HPC from ameliorating learning and memory in mice. However, the DNMT inhibitor promoted spatial cognition in mice. Thus, we suggest that HPC may upregulate BDNF by inhibiting DNMTs and decreasing DNA methylation of the BDNF gene and then activate BDNF/TrkB signaling to improve learning and memory in mice. This may provide theoretical guidance for the clinical treatment of cognitive dysfunction caused by ischemia/hypoxia disease.

Effect of electroacupuncture on the expression of Iba-1 in spinal dorsal horn and hippocampus of chronic pain rats with knee osteoarthritis

To observe the effect of electroacupuncture(EA) on pain-ralated behaviors, morphology of hippocampus, concentrations of inflammatory cytokines and expression of ionized calcium binding adapter molecule 1(Iba-1) in dorsal horn of the spinal cord and the hippocampus, and brain-derived neurotrophic factor (BDNF) in hippocampus of rats with knee osteoarthritis (KOA), so as to explore the mechanism of EA in improving chronic pain of KOA. Forty SD rats were randomly divided into blank group, saline group, model group and EA group, with 10 rats in each group. Monosodium iodoacetate(MIA, 80 mg/mL, 50 μL) was injected into the left knee joint cavity of rats in the model group and EA group to establish the chronic pain model of KOA, while the same volume of normal saline was injected into the left knee joint cavity of rats in the saline group. Rats in the EA group received EA stimulation(2 Hz/100 Hz, 1-2 mA) at left "Yanglingquan"(GB34) and "Neixiyan"(EX-LE4) for 15 min, 14 d after MIA injection. The treatment was given once daily, 5 d as 1 session and 2 sessions of treatment were required. Methanical withdrawl threshold(MWT) and weight-bearing capacity tests on left hind limbs were carried out 1 d before, 7 d，14 d, 20 d and 26 d after MIA injection. At the 27th day, rats were sacrificed and HE staining was used to observe the morphology of hippocampal CA1 area. Concentrations of interleukin(IL)-1β and tumor necrosis factor(TNF)-α in the left L3-L5 spinal dorsal horn and hippocampal CA1 area were detected by ELISA, the expressions of Iba-1 in the spinal dorsal horn and hippo-campal CA1 area were detected by immunofluorescence, and the expression of BDNF in left hippocampal CA1 area was detected by Western blot. The HE staining results of the hippocampal CA1 area showed reduced number of neurons, unclear cell contour and boundary between nucleus and cytoplasm, and nuclear pyknosis in the model group, which was relatively milder in the EA group. Compared with the blank group, MWT and weight-bearing capacity of rats' left hind limbs, and expression of BDNF protein in hippocampal CA1 area were significantly decreased (P<0.01), while the contents of IL-1β and TNF-α, the expression of Iba-1 in spinal dorsal horn and hippocampal CA1 area were significantly increased (P<0.01) in the model group. In comparison with the model group, MWT and weight-bearing capacity of rats' left hind limbs, and protein expression of BDNF in hippocampal CA1 area were significantly increased (P<0.01), while the contents of IL-1β and TNF-α, and the expression of Iba-1 protein in spinal dorsal horn and hippocampal CA1 area were significantly decreased after EA intervention(P<0.01). EA at GB34 and EX-LE4 can alleviate the pain-related behaviors of KOA rats. The mechanism might be related to the inhibition of inflammatory reaction mediated by microglia in spinal dorsal horn and hippocampus, and the up-regulation of BDNF expression in hippocampus.

High-intensity interval training improves cognitive impairment of vascular dementia rats by up-regulating expression of brain-derived neurotrophic factor in the hippocampus.

The present study aims to investigate the effect and its potential mechanism of high-intensity intermittent training (HIIT) on cognitive function in vascular dementia (VD) rats. The VD rats with the cognitive impairment were induced by bilateral common carotid artery occlusion (BCCAO), and the ones in the moderate-intensity continuous training (MICT) group and HIIT group received MICT or HIIT for 5 consecutive weeks, respectively. The swimming speed, endurance, and grip strength of rats were all measured after training. The effect and mechanisms of HIIT on ameliorating the cognitive dysfunction were further evaluated by the Morris water maze test, histomorphological analysis, and Western blot analysis. As a result, no significant difference in motor function between VD rats and sham rats was observed. After 5-week HIIT, the motor function of VD rats was significantly enhanced. The results of the Morris water maze test revealed that HIIT significantly reduced escape latency as well as distance to find the platform compared with the sedentary control group (SED group), indicating the improvement in cognitive function. In addition, the hippocampal tissue damage of VD rats measured by H&E staining was markedly ameliorated after 5-week HIIT. Moreover, brain-derived neurotrophic factor (BDNF) expression level in the cerebral cortex and hippocampus tissue detected by Western blot were significantly up-regulated in HIIT group compared to SED group and MICT group. In conclusion, HIIT can improve BCCAO-induced cognitive impairment via up-regulating BDNF expression in VD rats.

A 5-HT6R agonist alleviates cognitive dysfunction after traumatic brain injury in rats by increasing BDNF expression

Effective treatment for cognitive dysfunction after traumatic brain injury (TBI) is lacking in clinical practice. Increased brain-derived neurotrophic factor (BDNF) expression in cognitive circuits can significantly alleviate cognitive dysfunction in animal models of TBI. Selective 5-hydroxytryptamine receptor 6 (5-HT6R) agonists significantly increase BDNF expression and improve cognitive function. Therefore, we evaluated the protective effect of a highly selective 5-HT6R agonist, WAY-181187, on cognitive dysfunction after TBI. We established a controlled cortical impact model of moderate TBI in rats and performed drug intervention for five consecutive days. Rats had spatial reference memory impairment in the Morris water maze one and four weeks after TBI. BDNF expression in the medial prefrontal cortex (mPFC) and hippocampus decreased two and five weeks after TBI. Additionally, five weeks after TBI, decreases in neuronal dendritic spine density and the proportion of thin, mushroom-shaped dendritic spines and an increased proportion of stubby-type dendritic spines were observed. WAY-181187 administration (3 mg/kg) for five consecutive days after TBI significantly alleviated cognitive dysfunction at one and four weeks (P < 0.001 and P < 0.01), upregulated BDNF expression in the mPFC and hippocampus at two (P < 0.01 and P < 0.05) and five (P < 0.01 and P < 0.001) weeks and increased the dendritic spine density and the proportions of thin, mushroom-shaped dendrites in the mPFC (P < 0.05, P < 0.001 and P < 0.01) and hippocampus (P < 0.05, P < 0.001 and P < 0.05) at five weeks after TBI. Our results confirm that WAY-181187 administration (3 mg/kg) in the acute phase alleviated cognitive dysfunction after TBI, possibly by upregulating BDNF expression in the mPFC and hippocampus, enhancing neuroplasticity.

Brain polar phenol content, behavioural and neurochemical effects of Corinthian currant in a rotenone rat model of Parkinson’s disease

ABSTRACT Objective Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of nigral dopaminergic neurons, leading to reduced motor control. A contributing factor for the nigrostriatal degeneration is known to be oxidative stress, while antioxidant/anti-inflammatory properties of natural polyphenols have been suggested to show beneficial effects. The present study questioned the potential neuroprotective effects of supplementary diet with Corinthian currant, using a rat rotenone PD model. Methods The alterations in motor activity, brain Corinthian currant polar phenols’ accumulation, expression patterns of tyrosine hydroxylase (TH), dopamine transporter (DAT) and brain-derived neurotrophic factor (BDNF) in the nigrostriatal dopaminergic system were determined in rotenone-treated, currant-diet rats and matching controls. Results Rotenone treatment resulted in motor deficits and TH expression decreases in the nigrostriatal pathway, exhibiting PD-like behavioural motor and neurochemical phenotypes. Interestingly, 38 days Corinthian currant consumption resulted in differential accumulation of polar phenols in mesencephalon and striatum and had a significant effect on attenuating motor deficits and dopaminergic cell loss in substantia nigra pars compacta. In addition, it induced up-regulation of BDNF expression in the nigrostriatal dopaminergic system. Discussion Taken all together, evidence is provided for the potential neuroprotective influences of Corinthian currant consumption, involving the neurotrophic factor BDNF, in rescuing aspects of PD-like phenotype.

The BDNF-TrkB signaling pathway in the rostral anterior cingulate cortex is involved in the development of pain aversion in rats with bone cancer via NR2B and ERK-CREB signaling

Patients with bone cancer pain (BCP) are more prone to aversion. which not only causes mental distress but also aggravates BCP. However, the mechanism of BCP-related aversion is still unclear. Previous studies have demonstrated that the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway of the rostral anterior cingulate cortex (rACC) plays an important role in the regulation of emotions related to chronic pain, such as neuropathic pain or inflammatory pain; however, few studies have investigated the role of this pathway in cancer pain. This study explored the role of BDNF in cancer pain-related aversion in the rACC and to determine whether N-methyl D-aspartate receptor subtype 2B (NR2B) and extracellular signal-regulated kinase (ERK)-cAMP response element-binding (CREB) signaling are involved in cancer pain-related aversion. A Sprague-Dawley rat model of BCP (one of the classic BCP models) was established, and the changes in pain aversion were detected by mechanical stimulation-induced conditioned place avoidance. Our findings confirmed that rats with BCP exhibited intense pain aversion accompanied by the up-regulated BDNF expression in the rACC. Additionally, the pain aversion of BCP rats was reduced while blocking the BDNF-TrkB. Furthermore, the expression of NR2B and phosphorylated ERK (pERK)/phosphorylated CREB (pCREB) were up-regulated with the development of pain aversion, whereas the use of NR2B blocker Ro25–6981, or ERK inhibitor U0126 could reduce the pain aversion. The expression of NR2B and pERK/pCREB were up-regulated after exogenous BDNF was injected into the rACC, whereas the expression levels of NR2B and pERK/pCREB were down-regulated after blocking the BDNF-TrkB signaling. In conclusion, the BDNF-TrkB signaling in the rACC mediates the generation of aversion in rats with BCP, which requires the involvement of NR2B and the ERK-CREB signaling pathway.

Protective Effects of Dexmedetomidine on Hippocampal Neurons in Rats Anesthetized with Sevoflurane

To explore effects of dexmedetomidine (Dex) on cognitive function and hippocampal neuronal apoptosis in rats anesthetized with sevoflurane (Sevo), and regulation of brain-derived neurotrophic factor (BDNF) and its downstream signaling. 30 Sprague-Dawley (SD) rats were randomly divided into control group inhaled 29% concentration oxygen), Sevo group (2 L/min oxygen flow +1.5% Sevo), Dex+Sevo group (after injection of 20 μg/kg Dex, treated with 2L/min oxygen flow+1.5% Sevo). Haematoxylin and eosin (HE) staining and Nissl’s staining were adopted to detect morphological and functional changes in hippocampus of rats. Apoptosis was detected by immunofluorescence, BDNF expression was detected by immunohistochemistry. Reverse transcription PCR (RT-PCR) was conducted to detect mRNA expression of key proteins in downstream signaling of BDNF. The results showed that Sevo induced apoptosis of hippocampus neurons, while Dex improved Sevo induced apoptosis. In contrast to the control, the positive expression of BDNF in hippocampus of Sevo group was notably decreased (P &lt; 0.05), and that of Dex+Sevo group was notably higher in contrast to Sevo group (P &lt; 0.05). Signaling pathways of MAPK, PI3K-Akt, and Ras were predicted by String software as the downstream pathways of BDNF. RT-PCR results showed that these 3 signaling pathways were involved in Dex improving Sevo-induced cognitive impairment and hippocampal neuron apoptosis. In conclusion, Dex could improve cognitive dysfunction and hippocampal neuron apoptosis in rats induced by Sevo, and the mechanism was related to upregulation of BDNF expression and activation of pathways of MAPK, PI3K-Akt, and Ras.

Low-Intensity Pulsed Ultrasound Prompts Both Functional and Histologic Improvements While Upregulating the Brain-Derived Neurotrophic Factor Expression after Sciatic Crush Injury in Rats

The aim of this study was to determine that low-intensity pulsed ultrasound (LIPUS) at an intensity of 140 mW/cm2 promotes functional and histologic improvements in sciatic nerve crush injury in a rat model and to investigate changes over time in relevant growth factors and receptors, exploring the mechanism of LIPUS in the recovery process after injury. Toe angle in the toe-off phase, regenerative axonal length, myelinated nerve fiber density, diameter of myelinated nerve fiber, axon diameter and myelin sheath thickness were significantly higher in the LIPUS group than in the sham group. Gene and protein expression of brain-derived neurotrophic factor (BDNF) was upregulated in the LIPUS group. In conclusion, LIPUS contributed to rapid functional and histologic improvement and upregulated BDNF expression after sciatic nerve crush injury in rats.

Enriched environment enhances NK cell maturation through hypothalamic BDNF in male mice.

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous preclinical studies have shown that the enriched environment (EE) confers anti-obesity and anti-cancer phenotypes that are associated with enhanced adaptive immunity and are mediated by brain-derived neurotrophic factor (BDNF). Natural killer (NK) cells have anti-cancer and anti-viral properties, and their absence or depletion is associated with inferior clinical outcomes. In this study, we investigated the effects of EE on NK cell maturation following their depletion. Mice living in EE displayed a higher proportion of NK cells in the spleen, bone marrow, and blood, compared to those living in the standard environment (SE). EE enhanced NK cell maturation in the spleen and was associated with upregulation of BDNF expression in the hypothalamus. Hypothalamic BDNF overexpression reproduced the EE effects on NK cell maturation in secondary lymphoid tissues. Conversely, hypothalamic BDNF knockdown blocked the EE modulation on NK cell maturation. Our results demonstrate that a bio-behavior intervention enhanced NK cell maturation and was mediated at least in part by hypothalamic BDNF.

Differential Expression of BDNF and BIM in Streptozotocin-induced Diabetic Rat Retina After Fluoxetine Injection

Chronic diabetic retinopathy (DR) is a diabetic complication that causes blindness. Brain-derived neurotrophic factor (BDNF) expression is induced by fluoxetine. We observed the effects of fluoxetine on a streptozotocin (STZ)-induced diabetic rat model in this study. Rats were divided into three groups: Control, diabetic (65 mg/kg STZ injection), and diabetic with fluoxetine injection (20 mg/kg/week, six times). Western blotting was performed using anti-BDNF and anti-hexaribonucleotide-binding protein-3. Expression of BCL2 apoptosis regulator-like protein 11 (BIM) was analysed using a reverse transcription-polymerase chain reaction. BDNF levels were significantly higher in the diabetic group treated with fluoxetine than in the untreated diabetic group. BIM expression was higher in the diabetic group than in the control group. BIM gene expression was lower in fluoxetine-treated diabetic group than in the untreated diabetic group. Fluoxetine had an anti-apoptotic effect with upregulation of BDNF expression in retina of rats with STZ-induced diabetes.

Design and Development of a Behaviorally Active Recombinant Neurotrophic Factor.

IntroductionCarbamoylated erythropoietin (CEPO) is a chemically engineered, nonhematopoietic derivative of erythropoietin (EPO) that retains its antidepressant and pro-cognitive effects, which are attributed to the increased expression of neurotrophic factors like brain derived neurotrophic factor (BDNF), in the central nervous system. However, the chemical modification process which produces CEPO from erythropoietin (EPO) requires pure EPO as raw material, is challenging to scale-up and can also cause batch-to-batch variability. To address these key limitations while retaining its behavioral effects, we designed, expressed and analyzed a triple, glutamine, substitution recombinant mimetic of CEPO, named QPO.Methods and MaterialsWe employ a combination of computational structural biology, molecular, cellular and behavioral assays to design, produce, purify and test QPO.ResultsQPO was shown to be a nonhematopoietic polypeptide with significant antidepressant-like and pro-cognitive behavioral effects in rodent assays while significantly upregulating BDNF expression in-vitro and in-vivo. The in-silico binding affinity analysis of QPO bound to the EPOR/EPOR homodimer receptor shows significantly decreased binding to Active Site 2, but not Active Site 1, of EPOR.DiscussionThe results of the behavioral and gene expression analysis imply that QPO is a successful CEPO mimetic protein and potentially acts via a similar neurotrophic mechanism, making it a drug development target for psychiatric disorders. The decreased binding to Active Site 2 could imply that this active site is not involved in neuroactive signaling and could allow the development of a functional innate repair receptor (IRR) model. Substituting the three glutamine substitution residues with arginine (RPO) resulted in the loss of behavioral activity, indicating the importance of glutamine residues at those positions.

Amitriptyline Protects Against Lidocaine-induced Neurotoxicity in SH-SY5Y Cells via Inhibition of BDNF-mediated Autophagy.

Amitriptyline (AMI) is a traditional tricyclic antidepressant that has been proven to exhibit neuroprotective effects in various neurological disorders. However, the underlying mechanism by which AMI attenuates lidocaine-induced neurotoxicity remains poorly understood. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin to neuronal development and survival in the brain, and recent studies have suggested that BDNF plays an important role in mediating lidocaine-induced neurotoxicity. The present study was performed to evaluate the protective effect of AMI against the neurotoxicity induced by lidocaine and to explore the role of BDNF-dependent autophagy in this process. The data showed that AMI pretreatment alleviated lidocaine-induced neurotoxicity, as evidenced by the restoration of cell viability, normalization of cell morphology, and reduction in the cell apoptosis index. In addition, autophagy inhibitor 3-methyladenine (3-MA) had a protective effect similar to that of AMI, but autophagy activator rapamycin eliminated the protective effect of AMI by suppressing mTOR activation. Moreover, at the molecular level, we found that AMI-mediated autophagy was involved in the expression of BDNF. The overexpression of BDNF or application of exogenous recombinant BDNF significantly suppressed autophagy and protected SH-SY5Y cells from apoptosis induced by Lido, whereas the neuroprotection of AMI was abolished by either knockdown of BDNF or use of a tropomyosin-related kinase B (TrkB) inhibitor ANA-12 in SH-SY5Y cells. Overall, our findings demonstrated that the protective effect of AMI against lidocaine-induced neurotoxicity correlated with inhibition of autophagy activity through upregulation of BDNF expression.

Muscle BDNF: a potential therapeutic target for Kennedy's disease.

Muscle BDNF: a potential therapeutic target for Kennedy's disease.

Altered BDNF Methylation in Patients with Chronic Musculoskeletal Pain and High Biopsychosocial Complexity.

PurposeThe INTERMED instrument, which was developed to measure patient’s biopsychosocial (BPS) complexity, represents a powerful diagnostic and therapeutic tool. Epigenetic changes are the interface between signals from the environment and genetic modifications, affecting gene expression, in particular, by DNA methylation of CpG dinucleotides in promotor regions of the corresponding genes. The brain-derived neurotrophic factor (BDNF) gene plays a crucial role in the central sensitization (CS) of pain. In this study, we hypothesized that chronic pain modifies the methylation levels of the BDNF gene in a manner that is interconnected with the BPS status.Patients and MethodsFifty-eight chronic musculoskeletal pain patients (CMSP) were enrolled in the study. DNA was extracted from blood samples, the methylation levels of 13 CpG sites in the BDNF promoter were measured by pyrosequencing, and association studies with various patient parameters and the INTERMED scores were performed.ResultsInterestingly, a negative correlation (−0.40) was found between the total INTERMED scores and the average CpG methylation values of the BDNF gene, but no correlation was observed with the severity of pain, degree of anxiety, depression, or kinesiophobia and catastrophism. Moreover, the association was independent of age, sex and level of comorbidities.ConclusionThis result shows that CMSP, in association with its biopsychosocial context, epigenetically decreases the degree of methylation of the BDNF promoter and should therefore increase the level of BDNF transcription. It also suggests a role of the INTERMED tool to detect a relationship between the BPS complexity and the epigenetic control of a target gene. The possible upregulation of BDNF expression might be, at least in part, the signal for chronic pain-induced central sensitization (CS). This could partly explain why patients with a higher level of complexity feel more pain than those with lower complexity.

Effect of 9 - PAHSA on cognitive dysfunction in diabetic mice and its possible mechanism

Diabetes mellitus (DM) is currently a major global health problem, which is associated with the development of cognitive dysfunction. However, although numerous clinical drugs for hyperglycemia have been used at present, safer and more effective therapeutic intervention strategies for diabetic cognitive impairments are still a huge challenge. Recently, several studies have indicated that a novel class of branched palmitic acid esters of hydroxyl stearic acids (PAHSAs) may have anti-diabetes and anti-inflammatory effects in insulin-resistant mice. Herein, whether the 9-PAHSA that one of the PAHSAs can attenuates DM-associated cognitive impairment in a mouse model of type 2 diabetes has been investigated. Our results showed that 9-PAHSA mildly prevented deficits of spatial working memory in Y-maze test while reversed the preference bias toward novel mice in Social choice test. Furthermore, the effect of REST on cognitive impairment of diabetes was explored for the first time. It was found that the expression of REST in diabetic mice increased, and the expression of target protein BDNF (Brain-derived neurotrophic factor) was decreased. After administration of 9-PAHSA, the situation was reversed. In summary, we conclude that exogenous supplement of 9-PAHSA can improve DM-related cognitive impairment to some extent, and the protective effect may be associated with decreased REST/NRSF (repressor element-1 silencing transcription factor/neuron-restrictive silence factor) and upregulated BDNF expression in frontal cortex.

A TrkB agonist and ampakine rescue synaptic plasticity and multiple forms of memory in a mouse model of intellectual disability

Fragile X syndrome (FXS) is associated with deficits in various types of learning, including those that require the hippocampus. Relatedly, hippocampal long-term potentiation (LTP) is impaired in the Fmr1 knockout (KO) mouse model of FXS. Prior research found that infusion of brain-derived neurotrophic factor (BDNF) rescues LTP in the KOs. Here, we tested if, in Fmr1 KO mice, up-regulating BDNF production or treatment with an agonist for BDNF's TrkB receptor restores synaptic plasticity and improves learning. In hippocampal slices, bath infusion of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) completely restored otherwise impaired hippocampal field CA1 LTP of Fmr1 KOs without effect in wild types (WTs). Similarly, acute, semi-chronic, or chronic treatments with 7,8-DHF rescued a simple hippocampus-dependent form of spatial learning (object location memory: OLM) in Fmr1 KOs without effect in WTs. The agonist also restored object recognition memory, which depends on cortical regions. Semi-chronic, but not acute, treatment with the ampakine CX929, which up-regulates BDNF expression, lowered the training threshold for OLM in WT mice and rescued learning in the KOs. Positive results were also obtained in a test for social recognition. An mGluR5 antagonist did not improve learning. Quantification of synaptic immunolabeling demonstrated that 7,8-DHF and CX929 increase levels of activated TrkB at excitatory synapses. Moreover, CX929 induced a robust synaptic activation of the TrkB effector ERK1/2. These results suggest that enhanced synaptic BDNF signaling constitutes a plausible strategy for treating certain aspects of the cognitive disabilities associated with FXS.