Release Of Brain-derived Neurotrophic Factor Research Articles

Exposure to dibutyl phthalate adsorbed to multi-walled carbon nanotubes causes neurotoxicity in mice by inducing the release of BDNF

Multi-walled carbon nanotubes (MWCNTs) and dibutyl phthalate (DBP) exist extensively in the environment, and they are easy to form compound pollution through π-π interactions in the environment. We investigate whether DBP, an environmental hormone disruptor, mediated by CNTs can more easily cross the blood-brain barrier, and whether DBP entering the brain has neurotoxic effects on the cells in the brain. Experimental subjects were 40 male Kunming (KM) mice randomly divided into 4 groups: the control group; the MWCNTs group; the DBP group; and the MWCNTs+DBP group. The mice were exposed via tail intravenous injection once every 3 days for 21 days, following which toxicology studies were carried out. The results of behavioral experiments showed that the mice in the combined exposure group (MWCNTs+DBP) exhibited spatial learning and memory impairment, and anxiety-like behavior. Staining of hippocampal sections of mouse brain tissue showed that, in the CA1, CA2, and DG areas, the number of neurons decreased, the nucleus was pyknotic, the cell body was atrophied, and levels of the microglia marker Iba-1 increased. By proteomic KEGG analysis, we found that the DEPs were mainly those related to neurodegenerative diseases. Immunohistochemistry in the hippocampus indicated that the level of brain-derived neurotrophic factor (BDNF) in the DG region was significantly increased. RT-PCR results revealed that the expression levels of P53, caspase3, and Bax genes related to apoptosis were up-regulated. The experimental results demonstrated that the mechanism of the combined-exposure injury to neurons in the hippocampus of mice may be that MWCNTs with adsorbed DBP can induce the release of BDNF, accelerate the apoptosis of neurons, and reduce the number of nerve cells, which activates microglia, causing neuroinflammation and nervous system toxicity.

Effect of multicomponent exercise in cognitive impairment: a systematic review and meta-analysis

BackgroundMulticomponent physical exercise is the most recommended type of physical intervention in older adults. Experimental data suggest the relevance of the muscle-brain axis and the relationship between muscle contraction and release of brain-derived neurotrophic factor, however, the impact of this relationship on cognition remains unclear, especially in people with diagnosis of cognitive impairment. This study assesses the effect of multicomponent physical exercise on global cognition in people with mild cognitive impairment or dementia.MethodsRandomized controlled trials published until January 2021 were searched across three electronic databases (PubMed, Scopus, and Cochrane Database). Data about exercises included in the multicomponent intervention (endurance, strength, balance, or flexibility), the inclusion of aerobic exercise, and the change in global cognition were extracted. The effect size was represented as a standardized mean difference. Risk of bias was assessed by the RoB2 tool.ResultsA total of 8 studies were included. The overall effect size suggested an effect of multicomponent exercise on global cognition. However, the subgroup analysis showed an effect only when aerobic exercise was included in the intervention. No effect when mild cognitive impairment and dementia were assessed separately was found.ConclusionThis study suggests that multicomponent physical exercise could have an effect on global cognition in people with mild cognitive impairment or dementia only when aerobic exercise is included in the intervention. Our results support the inclusion of structured physical exercise programs in the management of people with cognitive impairment.

Histamine H3R antagonist counteracts the impaired hippocampal neurogenesis in Lipopolysaccharide-induced neuroinflammation

Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with numerous neurodegenerative diseases such as aging and Alzheimer's disease (AD). Overactivation of microglia induced neuroinflammation is well acknowledged to contribute to the impaired neurogenesis in pathologies of these diseases and then leading to cognitive dysfunction. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia to modulate inflammatory response. However, whether inhibition of H3R is responsible for the neurogenesis and cognition in chronic neuroinflammation induced injury and the mechanism remains unclear. In this study, we found that inhibition of H3R by thioperamide reduced the microglia activity and promoted a phenotypical switch from pro-inflammatory M1 to anti-inflammatory M2 in microglia, and ultimately attenuated lipopolysaccharide (LPS) induced neuroinflammation in mice. Additionally, thioperamide rescued the neuroinflammation induced impairments of neurogenesis and cognitive function. Mechanically, the neuroprotection of thioperamide was involved in histamine dependent H2 receptor (H2R) activation, because cimetidine, an H2R antagonist but not pyrilamine, an H1R antagonist reversed the above effects of thioperamide. Moreover, thioperamide activated the H2R downstream phosphorylated protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) pathway but inhibited nuclear factor kappa-B (NF-κB) signaling. Activation of CREB by thioperamide promoted interaction of CREB-CREB Binding Protein (CBP) to increase anti-inflammatory cytokines (Interleukin-4 and Interleukin-10) and brain-derived neurotrophic factor (BDNF) release but inhibited NF-κB-CBP interaction to decrease pro-inflammatory cytokines (Interleukin-1β, Interleukin-6 and Tumor necrosis factor α) release. H89, an inhibitor of PKA/CREB signaling, abolished effects of thioperamide on neuroinflammation and neurogenesis. Taken together, these results suggested under LPS induced neuroinflammation, the H3R antagonist thioperamide inhibited microglia activity and inflammatory response, and ameliorated impairment of neurogenesis and cognitive dysfunction via enhancing histamine release. Histamine activated H2R and reinforced CREB-CBP interaction but weakened NF-κB-CBP interaction to exert anti-inflammatory effects. This study uncovered a novel histamine dependent mechanism behind the therapeutic effect of thioperamide on neuroinflammation.

A Common Human Brain-Derived Neurotrophic Factor Polymorphism Leads to Prolonged Depression of Excitatory Synaptic Transmission by Isoflurane in Hippocampal Cultures.

Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis by isoflurane was acutely irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met; rs6265) compared to neurons from wild-type mice. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism in persistent changes of synaptic function following isoflurane exposure. These short-term persistent alterations in excitatory synaptic transmission indicate a role for human genetic variation in anesthetic effects on synaptic plasticity and neurocognitive function.

MDMA-Assisted Therapy for Treatment-Resistant Posttraumatic Stress Disorder (PTSD) – One step further toward a patient-centered treatment pathway

IntroductionPTSD is a chronic, debilitating condition with limited treatment efficacy. Accessing traumatic memories often leads to overwhelming distress, impacting treatment process. Current approved pharmacological treatments have exhibited small to moderate effects when compared with placebo. Evidence suggests 3,4,-methylene-dioxymethamphetamine(MDMA)-assisted psychotherapy as a viable option for refractory PTSD.ObjectivesComprehensive review of early clinical research, proposed mechanisms, safety and emerging therapeutic models.MethodsEligible studies will be identified through strategic search of MEDLINE.ResultsPre-clinical and imaging studies suggest memory reconsolidation and fear extinction as candidate psychological and neurological mechanisms, involving MDMA’s combined effects of increasing serotonergic activity, as well the release of oxytocin and brain-derived neurotrophic factor in key memory and emotional circuits. Resulting reduction in amygdala and insula activation and increasing connectivity between the amygdala and hippocampus may create a “tolerance window” of neuroplasticity for emotional engagement and reprocessing of traumatic memories during psychotherapy. Early clinical trials report impressive and durable reduction in PTSD symptoms, with a safety profile comparable to that of SSRIs. A recently completed randomized, double-blind, placebo-controlled phase 3 trial reported full remission of PTSD symptoms in 67% of patients at 2 months, with no increase in suicidality, cardiovascular events or abuse behavior. Emerging treatment models underline the importance of unmedicated therapeutic sessions for preparation for the experience and subsequent integration as essential for full benefit and safety of the clinical context.ConclusionsThe psychological impact associated with the COVID-19 pandemic is an reminder of the emotional and economic burden associated with PTSD. MDMA-assisted therapy may be a breakthrough approach meriting further multidisciplinary investment and clinical research.DisclosureNo significant relationships.

Transgenerational Abnormalities Induced by Paternal Preconceptual Alcohol Drinking: Findings from Humans and Animal Models.

Alcohol consumption during pregnancy and lactation is a widespread preventable cause of neurodevelopmental impairment in newborns. While the harmful effects of gestational alcohol use have been well documented, only recently, the role of paternal preconceptual alcohol consumption (PPAC) prior to copulating has drawn specific epigenetic considerations. Data from human and animal models have demonstrated that PPAC may affect sperm function, eliciting oxidative stress. In newborns, PPAC may induce changes in behavior, cognitive functions, and emotional responses. Furthermore, PPAC may elicit neurobiological disruptions, visuospatial impairments, hyperactivity disorders, motor skill disruptions, hearing loss, endocrine, and immune alterations, reduced physical growth, placental disruptions, and metabolic alterations. Neurobiological studies on PPAC have also disclosed changes in brain function and structure by disrupting the growth factors pathways. In particular, as shown in animal model studies, PPAC alters brain nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) synthesis and release. This review shows that the crucial topic of lifelong disabilities induced by PPAC and/or gestational alcohol drinking is quite challenging at the individual, societal, and familial levels. Since a nontoxic drinking behavior before pregnancy (for both men and women), during pregnancy, and lactation cannot be established, the only suggestion for couples planning pregnancies is to completely avoid the consumption of alcoholic beverages.

IGF-1 release in the medial prefrontal cortex mediates the rapid and sustained antidepressant-like actions of ketamine

Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts rapid and sustained antidepressant actions. Preclinical studies demonstrated that the release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor in the medial prefrontal cortex (mPFC) is essential for the antidepressant-like effects of ketamine. However, the role of other neurotrophic factors in the antidepressant-like effects of ketamine has not been fully investigated. Since the intra-mPFC infusion of insulin-like growth factor 1 (IGF-1) reportedly produced antidepressant-like effects, the present study examined the role of endogenous intra-mPFC IGF-1 signaling in the antidepressant-like actions of ketamine. In vivo microdialysis showed that ketamine (10 and 30 mg/kg) significantly increased extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 h. Infusion of an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 min before or 2 h after ketamine injection blocked the antidepressant-like effects of ketamine in three different behavioral paradigms (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively). The ketamine-like antidepressant-like actions of the intra-mPFC infusion of BDNF (100 ng/side) and IGF-1 (50 ng/side) respectively were not blocked by co-infused IGF-1 nAb and BDNF nAb (200 ng/side). Moreover, intra-mPFC infusion of IGF-1 nAb 2 h post-ketamine blocked the antidepressant-like effects of ketamine in a murine lipopolysaccharide (LPS)-induced depression model. Intra-mPFC IGF-1 infusion also produced antidepressant-like effects in the LPS-challenged mice via mechanistic target of rapamycin complex 1 activation. These results suggest that persistent release of IGF-1, independently of BDNF, in the mPFC is essential for the antidepressant-like actions of ketamine.

Polydopamine-coated polycaprolactone/carbon nanotube fibrous scaffolds loaded with brain-derived neurotrophic factor for peripheral nerve regeneration

Carbon nanotubes (CNTs) have attracted increasing attention in the field of peripheral nerve tissue engineering due to their unique structural and physical characteristics. In this study, a novel type of aligned conductive scaffolds composed of polycaprolactone (PCL) and CNTs were fabricated via electrospinning. Utilizing mussel-inspired polydopamine (PDA) surface modification, brain-derived neurotrophic factor (BDNF) was loaded onto PCL/CNT fibrous scaffolds to obtain PCL/CNT-PDA-BDNF fibrous scaffolds capable of the sustained release of BDNF over 28 d. Schwann cells were cultured on these scaffolds, and the effect of the scaffolds on peripheral nerve regeneration in vitro was assessed by studying cell proliferation, morphology and the expressions of myelination-related genes S100, P0 and myelin basic protein. Furthermore, the effect of these scaffolds on peripheral nerve regeneration in vivo was investigated using a 10 mm rat sciatic nerve defect model. Both the in vitro and in vivo results indicate that PCL/CNT-PDA-BDNF fibrous scaffolds effectively promote sciatic nerve regeneration and functional recovery. Therefore, PCL/CNT-PDA-BDNF fibrous scaffolds have great potential for peripheral nerve restoration.

The Importance of Endoplasmic Reticulum Stress as a Novel Antidepressant Drug Target and Its Potential Impact on CNS Disorders.

Many central nervous system (CNS) diseases, including major depressive disorder (MDD), are underpinned by the unfolded protein response (UPR) activated under endoplasmic reticulum (ER) stress. New, more efficient, therapeutic options for MDD are needed to avoid adverse effects and drug resistance. Therefore, the aim of the work was to determine whether UPR signalling pathway activation in astrocytes may serve as a novel target for antidepressant drugs. Among the tested antidepressants (escitalopram, amitriptyline, S-ketamine and R-ketamine), only S-ketamine, and to a lesser extent R-ketamine, induced the expression of most ER stress-responsive genes in astrocytes. Furthermore, cell viability and apoptosis measuring assays showed that (R-)S-ketamine did not affect cell survival under ER stress. Under normal conditions, S-ketamine played the key role in increasing the release of brain-derived neurotrophic factor (BDNF), indicating that the drug has a complex mechanism of action in astrocytes, which may contribute to its therapeutic effects. Our findings are the first to shed light on the relationship between old astrocyte specifically induced substance (OASIS) stabilized by ER stress and (R-)S-ketamine; however, the possible involvement of OASIS in the mechanism of therapeutic ketamine action requires further study.

Acute Administration of Metformin Protects Against Neuronal Apoptosis Induced by Cerebral Ischemia-Reperfusion Injury via Regulation of the AMPK/CREB/BDNF Pathway.

Metformin is a first-line anti-diabetic agent with a powerful hypoglycemic effect. Several studies have reported that metformin can improve the prognosis of stroke patients and that this effect is independent of its hypoglycemic effect; however, the specific mechanism remains unclear. In this research, we explored the effect and specific mechanism of metformin in cerebral ischemia-reperfusion (I/R) injury by constructing a transient middle cerebral artery occlusion model in vivo and a glucose and oxygen deprivation/reoxygenation (OGD/R) model in vitro. The results of the in vivo experiments showed that acute treatment with low-dose metformin (10 mg/kg) ameliorated cerebral edema, reduced the cerebral infarction volume, improved the neurological deficit score, and ameliorated neuronal apoptosis in the ischemic penumbra. Moreover, metformin up-regulated the brain-derived neurotrophic factor (BDNF) expression and increased phosphorylation levels of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB) in the ischemia penumbra. Nevertheless, the above-mentioned effects of metformin were reversed by Compound C. The results of the in vitro experiments showed that low metformin concentrations (20 μM) could reduce apoptosis of human umbilical vein endothelial cells (HUVECs) under OGD/R conditions and promote cell proliferation. Moreover, metformin could further promote BDNF expression and release in HUVECs under OGD/R conditions via the AMPK/CREB pathway. The Transwell chamber assay showed that HUVECs treated with metformin could reduce apoptosis of SH-SY5Y cells under OGD/R conditions and this effect could be partially reversed by transfection of BDNF siRNA in HUVECs. In summary, our results suggest that metformin upregulates the level of BDNF in the cerebral ischemic penumbra via the AMPK/CREB pathway, thereby playing a protective effect in cerebral I/R injury.

Localized delivery of brain-derived neurotrophic factor from PLGA microspheres promotes peripheral nerve regeneration in rats

BackgroundRepair of peripheral nerve defect presents a considerable challenge for reconstructive surgeons. The aim of this study is to develop a brain-derived neurotrophic factor (BDNF) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres for the treatment of the peripheral nerve defect.MethodBDNF microspheres were prepared by using an oil-in-water emulsification-solvent evaporation method. The morphology, particle size, encapsulation efficiency, drug loading and sustained release performance of microspheres was observed and calculated. Adipose mesenchymal stem cells (ADSCs) were isolated and expanded. ADSCs were divided into four groups: control, BDNF, blank microsphere and BDNF microsphere groups. Cell count kit-8 (CCK-8) assays were used to assess cell proliferation. Cell migration was determined by Transwell assays. Twenty-eight male Sprague–Dawley rats underwent transection damage model on the right sciatic nerve. The wet weight ratio of the gastrocnemius muscle was calculated by comparing the weight of the gastrocnemius muscle from the operated side to that of the normal side. Neuroelectrophysiological testing was performed to assess nerve function recovery. Nerve regeneration was evaluated by histological analysis and immunohistochemical staining.ResultsThe microspheres were spherical and had uniform size (46.38 ± 1.00 μm), high encapsulation efficiency and high loading capacity. In vitro release studies showed that BDNF-loaded microspheres had good sustained release characteristics. The duration of BDNF release was extended to more than 50 days. BDNF or BDNF microsphere promote the proliferation and migration of ADSCs than control group (P < 0.05). Compared with control group, BDNF significantly decreased the nerve conduction velocity (NCV) and compound amplitude (AMP) (P < 0.05). The nerve fibers in the BDNF microsphere group were closely arranged and uniformly distributed than control group.ConclusionBDNF/PLGA sustained-release microsphere could promote the migration of ADSCs and promoted neural differentiation of ADSCs. Moreover, BDNF/PLGA sustained-release microsphere ameliorated nerve conduction velocity and prevented neuralgic amyotrophy.

Behavioral phenotyping of a rat model of the BDNF Val66Met polymorphism reveals selective impairment of fear memory

The common brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release and increased risk for anxiety disorders and PTSD. Here we behaviorally phenotyped a novel Val66Met rat model with an equivalent valine to methionine substitution in the rat Bdnf gene (Val68Met). In a three-day fear conditioning protocol of fear learning and extinction, adult rats with the Met/Met genotype demonstrated impaired fear memory compared to Val/Met rats and Val/Val controls, with no genotype differences in fear learning or extinction. This deficit in fear memory occurred irrespective of the sex of the animals and was not seen in adolescence (4 weeks of age). There were no changes in open-field locomotor activity or anxiety measured in the elevated plus maze (EPM) nor in other types of memory measured using the novel-object recognition test or Y-maze. BDNF exon VI expression in the dorsal hippocampus was higher and BDNF protein level in the ventral hippocampus was lower in female Val/Met rats than female Val/Val rats, with no other genotype differences, including in total BDNF, BDNF long, or BDNF IV mRNA. These data suggest a specific role for the BDNF Met/Met genotype in fear memory in rats. Further studies are required to investigate gene–environment interactions in this novel animal model.

Antillatoxin-Stimulated Neurite Outgrowth Involves the Brain-Derived Neurotrophic Factor (BDNF) - Tropomyosin Related Kinase B (TrkB) Signaling Pathway.

Voltage-gated sodium channel (VGSC) activators promote neurite outgrowth by augmenting intracellular Na+ concentration ([Na+]i) and upregulating N-methyl-d-aspartate receptor (NMDAR) function. NMDAR activation stimulates calcium (Ca2+) influx and increases brain-derived neurotrophic factor (BDNF) release and activation of tropomyosin receptor kinase B (TrkB) signaling. The BDNF-TrkB pathway has been implicated in activity-dependent neuronal development. We have previously shown that antillatoxin (ATX), a novel lipopeptide isolated from the cyanobacterium Moorea producens, is a VGSC activator that produces an elevation of [Na+]i. Here we address the effect of ATX on the synthesis and release of BDNF and determine the signaling mechanisms by which ATX enhances neurite outgrowth in immature cerebrocortical neurons. ATX treatment produced a concentration-dependent release of BDNF. Acute treatment with ATX also resulted in increased synthesis of BDNF. ATX stimulation of neurite outgrowth was prevented by pretreatment with a TrkB inhibitor or transfection with a dominant-negative Trk-B. The ATX activation of TrkB and Akt was blocked by both a NMDAR antagonist (MK-801) and a VGSC blocker (tetrodotoxin). These results suggest that VGSC activators such as the structurally novel ATX may represent a new pharmacological strategy to promote neuronal plasticity through a NMDAR-BDNF-TrkB-dependent mechanism.

Abstract TP234: Delayed Administration Of A Repurposed Drug With Sigma 1 Receptor Activity Improves Stroke Outcomes In Male Rats

Sigma-1 receptor ligands including agonists and antagonists have been shown to improve outcomes from experimental stroke when administered at delayed time points. However, clinical trials for one such agonist, cutamesine, failed to demonstrate benefit. In the present study, we sought to identify approved drugs that could be repurposed for Sigma-1 activity and the delayed treatment of stroke. High-throughput screening was used to identify Sigma-1 receptor selective binding and stimulation of brain-derived neurotrophic factor (BDNF) release for several potential ligands that are already approved for other indications. Two lead compounds, promethazine (an antihistamine) and oxeladin (a cough suppressant), were advance to in vivo studies. Both compounds displayed favorable oral absorption into the brain and high dose tolerance in rats. Neither compound significantly altered thrombosis in an in vitro blood coagulation assay. Daily oral administration of oxeladin (3 doses) or vehicle was started 48 hours after 90-minute transient middle cerebral artery occlusion in adult male Sprague-Dawley rats (n=12/group) and continued for 10 days in a treatment-blind manner. Rats receiving the two highest doses showed significant (P&lt;0.05, 2-way ANOVA and Dunnett’s test) improvements in Bederson scores (0.4±0.1 vs 1.5±0.2), an 11 point Neurological assessment (1.2±0.1 vs 3.9±0.2) , and the elevated body swing test (60% vs 90% bias) 1, 4, and 10 days after dosing compared to vehicle controls. A subset of rats was administered BrdU (50 mg/kg ip) every other day. However, there were no significant differences among groups in BrdU incorporation observed in the subventricular zone at 14 days after stroke. Additional studies are being performed to assess the mechanisms of neuroprotection. These data suggest that repurposing of approved/safe drugs with Sigma-1 receptor activity is a promising avenue for the treatment of chronic stroke.

Involvement of the BDNF-TrkB-KCC2 pathway in neuropathic pain after brachial plexus avulsion.

IntroductionBrachial plexus avulsion significantly increased brain‐derived neurotrophic factor (BDNF) release in the spinal cord. Here we investigated the involvement of the BDNF–TrkB–KCC2 pathway in neuropathic pain caused by BPA injury. We hypothesized that activation of BDNF–TrkB may inhibit neuronal excitability by downregulating KCC2 to maintain a high intracellular Cl‐concentration. We established a neuropathic pain rat model by avulsion of the lower trunk brachial plexus, and investigated the effects of the TrkB‐specific antibody K‐252a on the expression of BDNF, TrkB, and KCC2.MethodsWe randomly divided 40 male SD rats into four groups. In the brachial plexus avulsion group, C8‐T1 roots were avulsed from the spinal cord at the lower trunk level. In the K252a group, 5uL K252a was applied intrathecally daily for three days after avulsion. In the sham surgery group, expose only and without damage. The control group did not undergo any treatment. Mechanical hyperalgesia and cold allodynia were analyzed by electronic pain measuring instrument and acetone spray method at different time points on days 1, 3, 7, 10, 14, and 21 after surgery. At 21 days after surgery, the expression of BDNF and TrkB in dorsal horn neurons and GFAP in astrocytes were detected by immunohistochemistry at the C5‐T1 segment of the spinal cord. The expression levels of BDNF, TrkB, and KCC2 in the C5‐T1 spinal cord were measured by Western Blot at 7 and 21 days.ResultsMechanical hyperalgesia and cold allodynia were significantly reduced in the K252a group compared with the brachial plexus avulsion group. Compared with the BPA group, BDNF, TrkB and GFAP were significantly decreased in the K252a group at 21 days after treatment by immunohistochemical test. In the WB test, the expressions of BDNF and TrkB in the K252a group were quantitatively detected to be decreased, while the expression of KCC2 was increased, which was obvious at 7 and 21 days.ConclusionBDNF‐TrkB‐KCC2 pathway can significantly relieve neuropathic pain after BPA, and is a potential target for the treatment of neuropathic pain.

Serum and plasma brain-derived neurotrophic factor concentration are elevated by systemic but not local passive heating.

Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal adaptations. While previous studies suggest that whole-body heating can elevate circulating BDNF concentration, this is not known for local heating protocols. This study investigated the acute effects of whole-body versus local passive heating on serum and plasma BDNF concentration. Using a water-perfused suit, ten recreationally active males underwent three 90 min experimental protocols: heating of the legs with upper-body cooling (LBH), whole-body heating (WBH) and a control condition (CON). Blood samples were collected before, immediately after and 1 h post-heating for the determination of serum and plasma BDNF concentration, platelet count as well as the BDNF release per platelet. Rectal temperature, cardiac output and femoral artery shear rate were assessed at regular intervals. Serum and plasma BDNF concentration were elevated after WBH (serum: 19.1±5.0 to 25.9±11.3 ng/ml, plasma: 2.74±0.9 to 4.58±2.0; p<0.044), but not LBH (serum: 19.1±4.7 to 22.3±4.8 ng/ml, plasma: 3.25±1.13 to 3.39±0.90 ng/ml; p>0.126), when compared with CON (serum: 18.6±6.4 to 16.8±3.4 ng/ml, plasma: 2.49±0.69 to 2.82±0.89 ng/ml); accompanied by an increase in platelet count (p<0.001). However, there was no change in BDNF content per platelet after either condition (p = 0.392). All physiological measures were elevated to a larger extent after WBH compared with LBH (p<0.001), while shear rate and rectal temperature were higher during LBH than CON (p<0.038). In conclusion, WBH but not LBH acutely elevates circulating BDNF concentration. While these findings further support the use of passive heating to elevate BDNF concentration, a larger increase in shear rate, sympathetic activity and/or rectal temperature than found after LBH appears needed to induce an acute BDNF response by passive heating.

Glibenclamide Ameliorates the Expression of Neurotrophic Factors in Sevoflurane Anaesthesia-induced Oxidative Stress and Cognitive Impairment in Hippocampal Neurons of Old Rats.

IntroductionSeveral antidiabetic medications have been proposed as prospective treatments for cognitive impairments in type 2 diabetes patients, glibenclamide (GBC) among them. Our research aimed to evaluate the impact of GBC on hippocampal learning memory and inflammation due to enhanced neurotrophic signals induced by inhalation of sevoflurane.Material and MethodsRats (Sprague Dawley, both sexes) were assigned to four groups: a control (vehicle, p.o.), GBC (10 mg/kg b.w.; p.o.), low-dose sevoflurane and low-dose sevoflurane + GBC (10 mg/kg b.w.; p.o.) for 23 days. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining was performed to analyse the count of apoptotic cells and ELISA was conducted to assess the protein signals. A Western blot, a Y-maze test, and a Morris maze test were performed, and the results analysed. Blood and tissues were collected, and isolation of RNA was performed with qRT-PCR.ResultsThe Morris maze test results revealed an improvement in the length of the escape latency on days 1 (P < 0.05), 2 (P < 0.01), 3, and 4 in the low-dose Sevo group. Time spent in the quadrant and crossing axis and the percentage of spontaneous alterations showed a substantial decrease in the low-dose Sevo group which received GBC at 10 mg/kg b.w. Significant increases were shown in IL-6 and TNF-α levels in the low-dose Sevo group, whereas a decrease was evident in the GBC group.ConclusionOur results indicate that glibenclamide may be a novel drug to prevent sevoflurane inhalation-induced impaired learning and reduce brain-derived neurotrophic factor release, which may be a vital target for the development of potential therapies for cognitive deficits and neurodegeneration.

Esterase-Mediated Sustained Release of Peptide-Based Therapeutics from a Self-Assembled Injectable Hydrogel.

A synthetic strategy for conjugating small molecules and peptide-based therapeutics, via a cleavable ester bond, to a lipidated β3-tripeptide is presented. The drug-loaded β3-peptide was successfully co-assembled with a functionally inert lipidated β3-tripeptide to form a hydrogel. Quantitative release of lactose from the hydrogel, by the action of serum esterases, is demonstrated over 28 days. The esterase-mediated sustained release of the bioactive brain-derived neurotrophic factor (BDNF) peptide mimics from the hydrogel resulted in increased neuronal survival and normal neuronal function of peripheral neurons. These studies define a versatile strategy for the facile synthesis and co-assembly of self-assembling β3-peptide-based hydrogels with the ability to control drug release using endogenous esterases with potential in vivo applications for sustained localized drug delivery.

Toll-like receptor 4-mediated enteric glia loss is critical for the development of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants, whose pathogenesis remains incompletely understood, although activation of the Gram-negative bacterial receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium plays a critical role. Patients with NEC typically display gastrointestinal dysmotility before systemic disease is manifest, suggesting that dysmotility could drive NEC development. Both intestinal motility and inflammation are governed by the enteric nervous system, a network of enteric neurons and glia. We hypothesized here that enteric glia loss in the premature intestine could lead to dysmotility, exaggerated TLR4 signaling, and NEC development. We found that intestinal motility is reduced early in NEC in mice, preceding the onset of intestinal inflammation, whereas pharmacologic restoration of intestinal motility reduced NEC severity. Ileal samples from mouse, piglet, and human NEC revealed enteric glia depletion, and glia-deficient mice (Plp1ΔDTR, Sox10ΔDTR, and BdnfΔDTR) showed increased NEC severity compared with wild-type mice. Mice lacking TLR4 on enteric glia (Sox10-Tlr4ko) did not show NEC-induced enteric glia depletion and were protected from NEC. Mechanistically, brain-derived neurotrophic factor (BDNF) from enteric glia restrained TLR4 signaling on the intestine to prevent NEC. BDNF was reduced in mouse and human NEC, and BDNF administration reduced both TLR4 signaling and NEC severity in enteric glia–deficient mice. Last, we identified an agent (J11) that enhanced enteric glial BDNF release, inhibited intestinal TLR4, restored motility, and prevented NEC in mice. Thus, enteric glia loss might contribute to NEC through intestinal dysmotility and increased TLR4 activation, suggesting enteric glia therapies for this disorder.

A honokiol-enriched Magnolia officinalis Rehder & E.H. Wilson. bark extract possesses anxiolytic-like activity with neuroprotective effect through the modulation of CB1 receptor.

The exposure of neurons to an excessive excitatory stimulation induces the alteration of the normal neuronal function. Mood disorders are among the first signs of alterations in the central nervous system function. Magnolia officinalis bark extract has been extensively used in the traditional medicine systems of several countries, showing several pharmacological activities. Honokiol, the main constituent of M. officinalis, is a GABA modulator and a CB1 agonist, which is deeply investigated for its role in modulating mood disorders. Thus, we evaluated the possible neuroprotective effect of a standardized M. officinalis bark extract (MOE), enriched in honokiol, and its effect on animal mood behavioural tests and in an in vitro model of excitotoxicity. MOE showed neuroprotective effect using SH-SY5Y cells, by normalizing brain-derived neurotrophic factor release. Then, we tested the effect of MOE in different behavioural tests evaluating anxiety and depression and we observed a selective anxiolytic-like effect. Finally, we confirmed the involvement of CB1 in the final effect of MOE by the co-administration of the CB1 antagonist, AM251. These results suggest that MOE could be considered an effective and safe anxiolytic candidate with neuroprotective activity.