Astrocyte TrkB promotes brain injury and edema formation in ischemic stroke.

Following ischemic stroke astrocytes undergo rapid molecular and functional changes that may accentuate tissue damage. In this study we identified the neurotrophin receptor TrkB in astrocytes as a key promoter of acute CNS injury in ischemic stroke. In fact, TrkB protein was strongly upregulated in astrocytes after human and experimental stroke, and transgenic mice lacking astrocyte TrkB displayed significantly smaller lesion volume, lower brain atrophy and better motor performance than control animals after transient middle cerebral artery occlusion. Neuropathological studies evidenced that edema directly correlated with astrogliosis and was limited in transgenic mice. Importantly, adaptive levels of the water channel AQP4 was astrocyte TrkB-dependent as AQP4 upregulation after stroke did not occur in mice lacking astrocyte TrkB. In vitro experiments with wild-type and/or TrkB-deficient astrocytes highlighted TrkB-dependent upregulation of AQP4 via activation of HIF1-alpha under hypoxia. Collectively, our observations indicate that TrkB signaling in astrocytes contributes to the development of edema and worsens cerebral ischemia.

Psychedelic LSD activates neurotrophic signal but fails to stimulate neural stem cells.

Accumulating evidence has shown that some hallucinogens, such as LSD, have fast and persistent effects on anxiety and depression. According to a proposed mechanism, LSD activates the TrkB and HTR2A signaling pathways, which enhance the density of neuronal dendritic spines and synaptic function, and thus promote brain function. Moreover, TrkB signaling is also known to be crucial for neural stem cell (NSC)-mediated neuroregeneration to repair dysfunctional neurons. However, the impact of LSD on neural stem cells remains to be elucidated. In this study, we observed that LSD and BDNF activated the TrkB pathway in human NSCs similarly to neurons. However, unlike BDNF, LSD did not promote NSC proliferation. These results suggest that LSD may activate an alternative mechanism to counteract the effects of BDNF-TrkB signaling on NSCs. Our findings shed light on the previously unrecognized cell type-specificity of LSD. This could be crucial for deepening our understanding of the mechanisms underlying the effects of LSD.

BDNF sensitizes bone and joint afferent neurons at different stages of MIA-induced osteoarthritis.

There is emerging evidence that Brain Derived Neurotrophic Factor (BDNF), and one of its receptors TrkB, play important roles in the pathogenesis of osteoarthritis (OA) pain. Whilst these studies clearly highlight the potential for targeting BDNF/TrkB signaling to treat OA pain, the mechanism for how BDNF/TrkB signaling contributes to OA pain remains unclear. In this study, we used an animal model of mono-iodoacetate (MIA)-induced OA, in combination with electrophysiology, behavioral testing, Western blot analysis, and retrograde tracing and immunohistochemistry, to identify roles for BDNF/TrkB signaling in the pathogenesis of OA pain. We found that: 1) TrkB is expressed in myelinated medium diameter neurons that innervate the knee joint and bone in naïve animals; 2) peripheral application of BDNF increases the sensitivity of Aδ, but not C knee joint and bone afferent neurons, in response to mechanical stimulation, in naïve animals; 3) BDNF expression increases in synovial tissue in early MIA-induced OA, when pathology is confined to the joint, and in the subchondral bone in late MIA-induced OA, when there is additional damage to the surrounding bone; and 4) TrkB inhibition reverses MIA-induced changes in the sensitivity of Aδ but not C knee joint afferent neurons early in MIA-induced OA, and Aδ but not C bone afferent neurons late in MIA-induced OA. Our findings suggest that BDNF/TrkB signaling may have a role to play in the pathogenesis of OA pain, through effects on knee joint afferent neurons when there is inflammation confined to the joint, and bone afferent neurons late in disease when there is involvement of damage to subchondral bone. Targeted manipulation of BDNF/TrkB signaling may provide therapeutic benefit for the management of OA pain.

[Effects of electroacupuncture on learning-memory function and synaptic plasticity in rats with cerebral ischemia-reperfusion injury based on the BDNF/TrkB pathway].

OBJECTIVE: To observe the effects of electroacupuncture (EA) at "Baihui" (GV 20) and "Sishencong" (EX-HN 1) on the expression of brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway, synaptophysin (SYN), and the levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in the hippocampus of the ischemic side in rats with cerebral ischemia-reperfusion injury (CIRI), and to explore the effects and action mechanism of EA on post-CIRI learning-memory function. METHODS: Forty-eight SPF-grade male SD rats were randomly divided into a sham operation group, a model group, an EA group, and a non-acupoint group, with 12 rats in each group. The CIRI model was established in the model group, the EA group, and the non-acupoint group using the modified ZeaLonga suture method. The rats in the EA group were treated with EA at "Sishencong" (EX-HN 1) and "Baihui" (GV 20), with disperse-dense wave at frequency of 2 Hz/10 Hz and intensity of 1 mA. The rats in the non-acupoint group were treated with EA at non-meridian and non-acupoint points under the ribs bilaterally with the same parameters as the EA group. EA were conducted for 30 min each session, once daily, for 7 days. During the intervention, body weight was measured daily at a fixed time, and neurological deficits were assessed on the 1st, 3rd, and 7th days into intervention. Brain infarct volume was measured using small animal magnetic resonance imaging before and after the intervention. After the intervention, learning-memory function were evaluated using the Morris water maze. Hippocampal morphology was observed with HE staining. The positive expression of SYN in the hippocampus of the ischemic side was detected by immunohistochemistry. BDNF, TrkB, and SYN protein expressions in the hippocampus of the ischemic side were detected by Western blot. IL-1ß and IL-18 levels in the hippocampus of the ischemic side were measured by ELISA. RESULTS: From the 2nd to the 7th day into intervention, compared with the sham operation group, the body weight of rats in the model group was decreased (P<0.01); compared with the model group and the non-acupoint group, the body weight of rats in the EA group was increased (P<0.01). On the 1st day into intervention, compared with the sham operation group, neurological function scores of rats in the model group, the EA group, and the non-acupoint group were increased (P<0.01); on the 3rd and 7th days into intervention, neurological function scores of rats in the model group were higher than those in the sham operation group (P<0.01); on the 7th day, neurological function scores of rats in the EA group were lower than those in the model group and the non-acupoint group (P<0.05). Compared with the sham operation group, escape latency was prolonged (P<0.05), and the number of platform crossings was decreased (P<0.01) in the model group; compared with the model group and the non-acupoint group, escape latency was shortened (P<0.05), and the number of platform crossings was increased (P<0.01) in the EA group. Before intervention, the high signal infarcts were observed in the left ventricles of rats in the model group, the EA group, and the non-acupoint group; after intervention compared with the model group and the non-acupoint group, infarct volume in the EA group was decreased (P<0.01). Neuronal cells in the model group and the non-acupoint group were sparsely and disorderedly arranged, with deep-stained cytoplasm and shrunken nuclei; the number and arrangement of neuronal cells in the EA group were similar to the sham operation group, with less deep-stained cytoplasm and shrunken nuclei compared to the model group. Compared with the sham operation group, the positive expression of SYN, and BDNF TrkB, and SYN protein expressions in the hippocampus of the ischemic side were decreased (P<0.01, P<0.05), while levels of IL-1ß and IL-18 were increased (P<0.01) in the model group; compared with the model group and the non-acupoint group, the positive expression of SYN, and BDNF, TrkB and SYN protein expressions in the hippocampus of the ischemic side were increased (P<0.01, P<0.05), while levels of IL-1ß and IL-18 were decreased (P<0.01) in the EA group. CONCLUSION: EA at "Baihui" (GV 20) and "Sishencong" (EX-HN 1) may improve learning-memory function in rats with CIRI by activating the BDNF/TrkB signaling pathway, reducing neuroinflammatory response, and promoting the recovery of synaptic plasticity.

Neuron and astrocyte specific 5mC and 5hmC signatures of BDNF's receptor, TrkB.

Brain derived neurotrophic factor (BDNF) is the most studied trophic factor in the central nervous system (CNS), and its role in the maturation of neurons, including synapse development and maintenance has been investigated intensely for over three decades. The primary receptor for BDNF is the tropomyosin receptor kinase B (TrkB), which is broadly expressed as two primary isoforms in the brain; the full length TrkB (TrkB.FL) receptor, expressed mainly in neurons and the truncated TrkB (TrkB.T1) receptor. We recently demonstrated that TrkB.T1 is predominately expressed in astrocytes, and appears critical for astrocyte morphological maturation. Given the critical role of BDNF/TrkB pathway in healthy brain development and mature CNS function, we aimed to identify molecular underpinnings of cell-type specific expression of each TrkB isoform. Using Nanopore sequencing which enables direct, long read sequencing of native DNA, we profiled DNA methylation patterns of the entire TrkB gene, Ntrk2, in both neurons and astrocytes. Here, we identified robust differences in cell-type specific isoform expression associated with significantly different methylation patterns of the Ntrk2 gene in each cell type. Notably, astrocytes demonstrated lower 5mC methylation, and higher 5hmC across the entire gene when compared to neurons, including differentially methylated sites (DMSs) found in regions flanking the unique TrkB.T1 protein coding sequence (CDS). These data suggest DNA methylation patterns may provide instruction for isoform specific TrkB expression across unique CNS cell types.

Developing a novel neutralizing monoclonal antibody against TrkB.

The TrkB receptor, which is highly expressed in various human cancers and considered a pro-oncogene, was targeted to develop neutralizing monoclonal antibodies against its immunoglobulin-like (Ig-like) domains. Recombinant TrkB-IgL peptide, including the Ig-like C2 type 1 (Ig-C2-type 1) and Ig-like C2 type 2 (Ig-C2-type 2) domains, was expressed and purified from E. coli. Mice were immunized with this peptide, and hybridoma clones producing anti-TrkB-IgL antibodies were generated. Among 23 ELISA-positive TrkB-IgL hybridoma clones, four (TrkB-IgL 5.11, 4.11, 4.6, 4.3) showed anti-proliferative effects compared to the control on human breast cancer (MCF-7) and human colon cancer (HCT116) cells, as assessed using the xCELLigence system. Western blot analysis revealed that TrkB-IgL 5.11 and 4.11 significantly suppressed TrkB-mediated signaling pathways compared to the control. Purified TrkB-IgL monoclonal antibodies (mAbs) exhibited anti-proliferative effects compared to both positive and negative controls using the xCELLigence system. The TrkB-IgL 5.11 mAb notably suppressed phosphorylation of TrkB, Akt, and ERK and induced Caspase-3 and Caspase-9 activities in a dose-dependent manner, as determined by Western blotting. Additionally, immunostaining confirmed the localization of these mAbs on the SH-SY5Y cell membrane, which is known for high TrkB expression. In conclusion, the TrkB-IgL 5.11 antibody effectively inhibits cancer cell proliferation and induces apoptosis by suppressing key signaling pathways. These findings demonstrate the potential of this antibody as a therapeutic agent for cancers that overexpress TrkB. Additionally, it is considered a promising candidate for humanization, which would facilitate its application in cancer treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04063-x.

A Combined Computational and Experimental Approach to Studying Tropomyosin Kinase Receptor B Binders for Potential Treatment of Neurodegenerative Diseases.

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores.

A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease.

In Alzheimer's disease (AD), amyloid ß (Aß)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aß in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.

The Antidepressant Action of Fluoxetine Involves the Inhibition of Dlx5/6 in Cortical GABAergic Neurons through a TrkB-Dependent Pathway.

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients' response to antidepressant treatment.

Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories.

Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.

Sprint Interval Training Improves Brain-Derived Neurotropic Factor-Induced Benefits in Brain Health-A Possible Molecular Signaling Intervention.

Physical exercise can significantly impact our bodies, affecting our functional capacity, structure establishment, and molecular makeup. The magnitude of these changes depends on the specific exercise protocols used. For instance, low-to-moderate-intensity exercise can activate important molecular targets in the short term, such as BDNF-mediated signaling, while high-intensity exercise can maintain these signaling molecules in the active state for a longer term. This makes it challenging to recommend specific exercises for obtaining BDNF-induced benefits. Additionally, exercise-induced molecular signaling targets can have positive and negative effects, with some exercises blunting these targets and others activating them. For example, increasing BDNF concentration through exercise can be beneficial for brain health, but it may also have a negative impact on conditions such as bipolar disorder. Therefore, a deeper understanding of a specific exercise-mediated mechanistic approach is required. This review will delve into how the sprint exercise-mediated activation of BDNF could help maintain brain health and explore potential molecular interventions.

Ablation of TrkB from Enkephalinergic Precursor-Derived Cerebellar Granule Cells Generates Ataxia.

In ataxia disorders, motor incoordination (ataxia) is primarily linked to the dysfunction and degeneration of cerebellar Purkinje cells (PCs). In spinocerebellar ataxia 6 (SCA6), for example, decreased BDNF-TrkB signalling appears to contribute to PC dysfunction and ataxia. However, abnormal BDNF-TrkB signalling in granule cells (GCs) may contribute to PC dysfunction and incoordination in ataxia disorders, as TrkB receptors are also present in GCs that provide extensive input to PCs. This study investigated whether dysfunctional BDNF-TrkB signalling restricted to a specific subset of cerebellar GCs can generate ataxia in mice. To address this question, our research focused on TrkbPenk-KO mice, in which the TrkB receptor was removed from enkephalinergic precursor-derived cerebellar GCs. We found that deleting Ntrk2, encoding the TrkB receptor, eventually interfered with PC function, leading to ataxia symptoms in the TrkbPenk-KO mice without affecting their cerebellar morphology or levels of selected synaptic markers. These findings suggest that dysfunctional BDNF-TrkB signalling in a subset of cerebellar GCs alone is sufficient to trigger ataxia symptoms and may contribute to motor incoordination in disorders like SCA6.

Phenylpropanoid-rich maize root extract serves as a natural antidepressant.

BACKGROUND: Depression is a serious and complex mental disease that has attracted worldwide attention because of its high incidence rate, high disability rate and high mortality. Excitotoxicity is one of the most important mechanisms involved in the pathophysiological process of depression. In our previous studies, n-butanol extract from maize roots was found to have good neuroprotective effects due to its antioxidative activity. However, the antidepressive effective constituents, efficacy in vivo and mechanism of action of maize root extracts have not been determined. PURPOSE: This study aimed to determine the main active neuroprotective compound in maize root extract and investigate its antidepressant effects and possible underlying mechanism in vitro and in vivo. METHODS: Sixteen extracts were isolated and purified from maize roots. The active components of the most active extracts of maize roots (hereafter referred to as EM 2) were identified using UF-HPLC-QTOF/MS. In vitro cell models of NMDA-induced excitotoxicity in SH-SY5Y cells were used to analyze the anti-excitatory activity of the extracts. The MTT assay and Annexin V-FITC/PI Apoptosis Detection were used to evaluate cell viability. Several network pharmacological strategies have been employed to investigate the potential mechanism of action of EM 2. The effects of EM 2 on depressive-like behaviors were evaluated in CUMS mice. Changes in the levels of related proteins were detected via western blotting. RESULTS: Among the 16 extracts extracted by n-butanol, EM 2 was determined to be the most active extract against NMDA-induced excitotoxicity by n-butanol extraction. Meanwhile, seventeen compounds were further identified as the main active components of EM 2. Mechanistically, EM 2 inhibited NMDA-induced excitatory injury in SH-SY5Y cells and alleviated the depressive-like behaviors of CUMS mice by suppressing NR2B and subsequently mediating the downstream CREB/TRKB/BDNF, PI3K/Akt and MAPK pathways, as well as the Nrf2/HO-1 antioxidant signaling pathway. CONCLUSION: The study indicated that EM 2 could potentially be developed as a potential therapeutic candidate to cure depression in NMDA-induced excitatory damage.

Peganum harmala L. seed extract attenuates anxiety and depression in rats by reducing neuroinflammation and restoring the BDNF/TrkB signaling pathway and monoamines after exposure to chronic unpredictable mild stress.

Depression is a mental disorder characterised by persistent low mood, anhedonia and cognitive impairment that affects an estimated 3.8% of the world's population, including 5% of adults. Peganum harmala L. (P. harmala) is a medicinal plant and has been reported to be effective against Alzheimer's disease, Parkinson's disease and depression. The present study was aimed to evaluate the behavioral and pharmacological effects of P. harmala seed extract in rats exposed to chronic unpredictable mild stress (CUMS) in vivo and to investigate the mechanism of action. CUMS-exposed rats were treated with P. harmala extract (75 and 150 mg/kg, i.p.) for 2 weeks. HPLC analysis was used to determine the concentration of harmaline and harmine alkaloids in the extract. Heavy metal analysis in seeds was performed by ICP-MS. Our results showed that P. harmala at the dose of 150 mg/kg significantly reduced the depressive-like behaviors in CUMS-exposed rats, as evidenced by increased sucrose consumption in the sucrose preference test (SPT), decreased immobility time in the forced swim test (FST) and plasma corticosterone levels, increased the time spent in open arms in the elevated plus maze (EPM), and improved memory and learning in the passive avoidance test (PAT). In addition, P. harmala decreased monoamine oxidase-A (MAO-A) levels, and increased serotonin (5-HT), dopamine (DA), and noradrenaline (NA) levels in the brains of rats exposed to CUMS. P. harmala decreased the expression of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB), and increased the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) in rat brain. Furthermore, P. harmala improved brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) protein expression in rat brain. In conclusion, P. harmala at a dose of 150 mg/kg is more effective in preventing depressive-like behavior in CUMS-exposed rats by improving neurotransmitter levels, reducing oxidative stress, suppressing neuroinflammation and activating the BDNF/TrkB pathway, all of which are important in the pathogenesis of depression.

Molecular Adaptations of BDNF/NT-4 Neurotrophic and Muscarinic Pathways in Ageing Neuromuscular Synapses.

Age-related conditions, such as sarcopenia, cause physical disabilities for an increasing section of society. At the neuromuscular junction, the postsynaptic-derived neurotrophic factors brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) have neuroprotective functions and contribute to the correct regulation of the exocytotic machinery. Similarly, presynaptic muscarinic signalling plays a fundamental modulatory function in this synapse. However, whether or not these signalling pathways are compromised in ageing neuromuscular system has not yet been analysed. The present study analyses, through Western blotting, the differences in expression and activation of the main key proteins of the BDNF/NT-4 and muscarinic pathways related to neurotransmission in young versus ageing Extensor digitorum longus (EDL) rat muscles. The main results show an imbalance in several sections of these pathways: (i) a change in the stoichiometry of BDNF/NT-4, (ii) an imbalance of Tropomyosin-related kinase B receptor (TrkB)-FL/TrkB-T1 and neurotrophic receptor p 75 (p75NTR), (iii) no changes in the cytosol/membrane distribution of phosphorylated downstream protein kinase C (PKC)ßI and PKCε, (iv) a reduction in the M2-subtype muscarinic receptor and P/Q-subtype voltage-gated calcium channel, (v) an imbalance of phosphorylated mammalian uncoordinated-18-1 (Munc18-1) (S313) and synaptosomal-associated protein 25 (SNAP-25) (S187), and (vi) normal levels of molecules related to the management of acetylcholine (Ach). Based on this descriptive analysis, we hypothesise that these pathways can be adjusted to ensure neurotransmission rather than undergoing negative alterations caused by ageing. However, further studies are needed to assess this hypothetical suggestion. Our results contribute to the understanding of some previously described neuromuscular functional age-related impairments. Strategies to promote these signalling pathways could improve the neuromuscular physiology and quality of life of older people.

Neurotrophins and Their Receptors: BDNF's Role in GABAergic Neurodevelopment and Disease.

Neurotrophins and their receptors are distinctly expressed during brain development and play crucial roles in the formation, survival, and function of neurons in the nervous system. Among these molecules, brain-derived neurotrophic factor (BDNF) has garnered significant attention due to its involvement in regulating GABAergic system development and function. In this review, we summarize and compare the expression patterns and roles of neurotrophins and their receptors in both the developing and adult brains of rodents, macaques, and humans. Then, we focus on the implications of BDNF in the development and function of GABAergic neurons from the cortex and the striatum, as both the presence of BDNF single nucleotide polymorphisms and disruptions in BDNF levels alter the excitatory/inhibitory balance in the brain. This imbalance has different implications in the pathogenesis of neurodevelopmental diseases like autism spectrum disorder (ASD), Rett syndrome (RTT), and schizophrenia (SCZ). Altogether, evidence shows that neurotrophins, especially BDNF, are essential for the development, maintenance, and function of the brain, and disruptions in their expression or signaling are common mechanisms in the pathophysiology of brain diseases.

BDNF-Regulated Modulation of Striatal Circuits and Implications for Parkinson's Disease and Dystonia.

Neurotrophins, particularly brain-derived neurotrophic factor (BDNF), act as key regulators of neuronal development, survival, and plasticity. BDNF is necessary for neuronal and functional maintenance in the striatum and the substantia nigra, both structures involved in the pathogenesis of Parkinson's Disease (PD). Depletion of BDNF leads to striatal degeneration and defects in the dendritic arborization of striatal neurons. Activation of tropomyosin receptor kinase B (TrkB) by BDNF is necessary for the induction of long-term potentiation (LTP), a form of synaptic plasticity, in the hippocampus and striatum. PD is characterized by the degeneration of nigrostriatal neurons and altered striatal plasticity has been implicated in the pathophysiology of PD motor symptoms, leading to imbalances in the basal ganglia motor pathways. Given its essential role in promoting neuronal survival and meditating synaptic plasticity in the motor system, BDNF might have an important impact on the pathophysiology of neurodegenerative diseases, such as PD. In this review, we focus on the role of BDNF in corticostriatal plasticity in movement disorders, including PD and dystonia. We discuss the mechanisms of how dopaminergic input modulates BDNF/TrkB signaling at corticostriatal synapses and the involvement of these mechanisms in neuronal function and synaptic plasticity. Evidence for alterations of BDNF and TrkB in PD patients and animal models are reviewed, and the potential of BDNF to act as a therapeutic agent is highlighted. Advancing our understanding of these mechanisms could pave the way toward innovative therapeutic strategies aiming at restoring neuroplasticity and enhancing motor function in these diseases.

Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer's disease.

BACKGROUND: Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer's disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations. METHODS: Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-ß (Aß) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs. RESULTS: ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aß-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αß toxicity and prevent synapse loss after Aß treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aß toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq. CONCLUSIONS: Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer's disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.

Combining Network Pharmacology and Experimental Verification to Ascertain the Mechanism of Action of Asparagus officinalis Against the Brain Damage Caused by Fluorosis.

Asparagus officinalis (ASP) has antioxidation, anti-inflammatory, antiaging, and immune system-enhancing effects. We explored the preventive and therapeutic consequences of ASP on the brain damage elicited by fluorosis through network pharmacology and in vivo experimental validation. We ascertained the pharmaceutically active ingredients and drug targets of ASP from the Traditional Chinese Medicine Systems Pharmacology database, predicted the disease targets of fluorosis-induced brain injury using GeneCards and Online Mendelian Inheritance in Man databases, obtained target protein-protein interaction networks in the Search Tool for the Retrieval of Interacting Genes/Proteins database, used Cytoscape to obtain key targets and active ingredients, and conducted enrichment analyses of key targets in the Database for Annotation, Visualization and Integrated Discovery. Enrichment analyses showed that "mitogen-activated protein kinase" (MAPK), "phosphoinositide 3-kinase/protein kinase B" (PI3K-Akt), "nuclear factor-kappa B" (NF-κB), and the "neurotrophin signaling pathway" were the most enriched biological processes and signaling pathways. ASP could alleviate fluorosis-based injury, improve brain-tissue damage, increase urinary fluoride content, and improve oxidation levels and inflammatory-factor levels in the body. ASP could also reduce dental fluorosis, bone damage, fluoride concentrations in blood and bone, and accumulation of lipid peroxide. Upon ASP treatment, expression of silent information regulator (SIRT)1, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), MAPK, NF-κB, PI3K, Akt, and B-cell lymphoma-2 in rat brain tissue increased gradually, whereas that of Bax, caspase-3, and p53 decreased gradually. We demonstrated that ASP could regulate the brain damage caused by fluorosis through the SIRT1/BDNF/TrkB signaling pathway, and reported the possible part played by ASP in preventing and treating fluorosis.

BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases.

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and overall neuronal health by binding to its receptor, tyrosine receptor kinase B (TrkB). This review delves into the intricate mechanisms through which BDNF-TrkB signaling influences mitochondrial function and potentially influences pathology in neurodegenerative diseases. This review highlights the BDNF-TrkB signaling pathway which regulates mitochondrial bioenergetics, biogenesis, and dynamics, mitochondrial processes vital for synaptic transmission and plasticity. Furthermore, we explore how the BDNF-TrkB-PKA signaling in the cytosol and in mitochondria affects mitochondrial transport and distribution and mitochondrial content, which is crucial for supporting the energy demands of synapses. The dysregulation of this signaling pathway is linked to various neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by mitochondrial dysfunction and reduced BDNF expression. By examining seminal studies that have characterized this signaling pathway in health and disease, the present review underscores the potential of enhancing BDNF-TrkB signaling to mitigate mitochondrial dysfunction in neurodegenerative diseases, offering insights into therapeutic strategies to enhance neuronal resilience and function.