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Ageing‐related neuromuscular dysfunction is associated with reduced tropomyosin‐related kinase receptor subtype B (TrkB) signalling and accumulation of damaged cytoplasmic aggregates in motor neurons. Autophagy functions to remove these damaged aggregates, and we previously reported increased cervical motor neuron expression of LC3 and p62 in old age. We hypothesized that inhibition of TrkB kinase activity results in an increase in the relative expression of both LC3 and p62 in cervical motor neurons, consistent with impaired progression of autophagy. TrkBF616A mice, which possess a mutation that renders TrkB kinase activity susceptible to rapid inhibition by 1NMPP1, were treated at 6, 18 or 24 months of age with vehicle or 1NMPP1 for 7 days. Immunofluorescence intensity was measured to determine LC3 and p62 expression in choline acetyltransferase‐positive motor neurons in the cervical spinal cord. The effect of inhibiting TrkB kinase activity on progression of autophagy was age dependent. In 6‐month‐old mice, inhibiting TrkB kinase activity increased cervical motor neuron expression of LC3 by 11% (P < 0.001) and p62 by 8% (P = 0.019) compared with vehicle treatment. In 18‐ and 24‐month‐old mice, there was no effect of inhibiting TrkB kinase activity on motor neuron LC3 or p62 expression. We provide evidence that inhibition of TrkB signalling impairs progression of autophagy in motor neurons of young mice, similar to the response to ageing. Accordingly, a reduction of TrkB signalling in old age might contribute to neuromuscular dysfunction by impairing progression of autophagy in motor neurons. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) often leads to significant functional impairment. Here, we investigated the impact of epidermal growth factor‐like domain‐containing protein 7 (EGFL7) on angiogenesis and nerve regeneration following PNI. Using a sciatic nerve injury model, we assessed nerve function using the sciatic nerve function index. We analyzed the expression levels of EGFL7, forkhead box proteins A1 (FOXA1), nerve growth factor (NGF), brain‐derived neurotrophic factors (BDNF), Neurofilament 200 (NF200), myelin protein zero (P0), cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), and NOTCH‐related proteins in tissues and cells. Cell proliferation, migration, and angiogenesis were evaluated through cell counting kit assays, 5‐ethynyl‐2′deoxyuridine staining, and Transwell assays. We investigated the binding of FOXA1 to the EGFL7 promoter using dual‐luciferase assays and chromatin immunoprecipitation. We observed decreased EGFL7 expression and increased FOXA1 expression in PNI, and EGFL7 overexpression alleviated gastrocnemius muscle atrophy, increased muscle weight, and improved motor function. Additionally, EGFL7 overexpression enhanced Schwann cell and endothelial cell proliferation and migration, promoted tube formation, and upregulated NGF, BDNF, NF200, P0, CD31, and VEGF expression. FOXA1 was found to bind to the EGFL7 promoter region, inhibiting EGFL7 expression and activating the NOTCH signaling pathway. Notably, FOXA1 overexpression counteracted the effects of EGFL7 on Schwann cells and endothelial cells. In conclusion, EGFL7 holds promise as a therapeutic molecule for treating sciatic nerve injury. [ABSTRACT FROM AUTHOR]

Hippocampal area CA2 has garnered attention in recent times owing to its significant involvement in social memory and distinctive plasticity characteristics. Research has revealed that the CA2 region demonstrates a remarkable resistance to plasticity, particularly in the Schaffer Collateral (SC)‐CA2 pathway. In this study we investigated the role of Nogo‐A, a well‐known axon growth inhibitor and more recently discovered plasticity regulator, in modulating plasticity within the CA2 region. The findings demonstrate that blocking Nogo‐A in male rat hippocampal slices facilitates the establishment of both short‐term and long‐term plasticity in the SC‐CA2 pathway, while having no impact on the Entorhinal Cortical (EC)‐CA2 pathway. Additionally, the study reveals that inhibiting Nogo‐A enables association between the SC and EC pathways. Mechanistically, we confirm that Nogo‐A operates through its well‐known co‐receptor, p75 neurotrophin receptor (p75NTR), and its downstream signaling factor such as Rho‐associated protein kinase (ROCK), as their inhibition also allows plasticity induction in the SC‐CA2 pathway. Additionally, the induction of long‐term depression (LTD) in both the EC and SC‐CA2 pathways led to persistent LTD, which was not affected by Nogo‐A inhibition. Our study demonstrates the involvement of Nogo‐A mediated signaling mechanisms in limiting synaptic plasticity within the CA2 region. [ABSTRACT FROM AUTHOR]

The important role that the neurotrophin tyrosine kinase receptor ‐ TrkB has in the pathogenesis of several neurodegenerative conditions such are Alzheimer's disease, Parkinson's disease, Huntington's disease, has been well described. This shouldn't be a surprise, since in the physiological conditions, once activated by brain‐derived neurotrophic factor (BDNF) and neurotrophin‐4/5 (NT‐4/5), the TrkB receptor promotes neuronal survival, differentiation and synaptic function. Considering that the natural ligands for TrkB receptor are large proteins, it is a challenge to discover small molecule capable to mimic their effects. Even though, the surface of receptor that is interacting with BDNF or NT‐4/5 is known, there was always a question which pocket and interaction is responsible for activation of it. In order to answer this challenging question, we have used molecular dynamic (MD) simulations and Pocketron algorithm which enabled us to detect, for the first time, a pocket network existing in the interacting domain (d5) of the receptor; to describe them and to see how they are communicating with each other. This new discovery gave us potential new areas on receptor that can be targeted and used for structure‐based drug design approach in the development of the new ligands. [ABSTRACT FROM AUTHOR]

The differentiation of bone marrow stromal cells (BMSCs) into Schwann‐like cells (SCLCs) has the potential to promote the structural and functional restoration of injured axons. However, the optimal induction protocol and its underlying mechanisms remain unclear. This study aimed to compare the effectiveness of different induction protocols in promoting the differentiation of rat BMSCs into SCLCs and to explore their potential mechanisms. BMSCs were induced using two distinct methods: a composite factor induction approach (Protocol‐1) and a conditioned culture medium induction approach (Protocol‐2). The expression of Schwann cells (SCs) marker proteins and neurotrophic factors (NTFs) in the differentiated cells was assessed. Cell proliferation and apoptosis were also measured. During induction, changes in miR‐21 and Sprouty RTK signaling antagonist 2 (SPRY2) mRNA were analyzed. Following the transfection of BMSCs with miR‐21 agomir or miR‐21 antagomir, induction was carried out using both protocols, and the expression of SPRY2, ERK1/2, and SCs marker proteins was examined. The results revealed that NTFs expression was higher in Protocol‐1, whereas SCs marker proteins expression did not significantly differ between the two groups. Compared to Protocol‐1, Protocol‐2 exhibited enhanced cell proliferation and fewer apoptotic and necrotic cells. Both protocols showed a negative correlation between miR‐21 and SPRY2 expression throughout the induction stages. After induction, the miR‐21 agomir group exhibited reduced SPRY2 expression, increased ERK1/2 expression, and significantly elevated expression of SCs marker proteins. This study demonstrates that Protocol‐1 yields higher NTFs expression, whereas Protocol‐2 results in stronger SCLCs proliferation. Upregulating miR‐21 suppresses SPRY2 expression, activates the ERK1/2 signaling pathway, and promotes BMSC differentiation into SCLCs. [ABSTRACT FROM AUTHOR]

Endosomal trafficking of TrkA is a critical process for nerve growth factor (NGF)‐dependent neuronal cell survival and differentiation. The small GTPase ADP‐ribosylation factor 6 (Arf6) is implicated in NGF‐dependent processes in PC12 cells through endosomal trafficking and actin cytoskeleton reorganization. However, the regulatory mechanism for Arf6 in NGF signaling is largely unknown. In this study, we demonstrated that EFA6A, an Arf6‐specific guanine nucleotide exchange factor, was abundantly expressed in PC12 cells and that knockdown of EFA6A significantly inhibited NGF‐dependent Arf6 activation, TrkA recycling from early endosomes to the cell surface, prolonged ERK1/2 phosphorylation, and neurite outgrowth. We also demonstrated that EFA6A forms a protein complex with TrkA through its N‐terminal region, thereby enhancing its catalytic activity for Arf6. Similarly, we demonstrated that EFA6A forms a protein complex with TrkA in cultured dorsal root ganglion (DRG) neurons. Furthermore, cultured DRG neurons from EFA6A knockout mice exhibited disturbed NGF‐dependent TrkA trafficking compared with wild‐type neurons. These findings provide the first evidence for EFA6A as a key regulator of NGF‐dependent TrkA trafficking and signaling. [ABSTRACT FROM AUTHOR]

Methylmercury (MeHg) causes selective neuronal damage to cerebrocortical neurons (CCNs) in the central nervous system, but not to hippocampal neurons (HiNs), which are highly vulnerable to neurodegenerative diseases. In our previous study using cultured rat neurons, we performed a comprehensive gene expression analysis and found that the brain‐derived neurotrophic factor (BDNF), a neurotrophin (NT), was specifically expressed in HiNs. Therefore, to elucidate the causal factors of MeHg toxicity resistance in HiNs, we conducted a comparative study of the protein expression and function of several NTs, including BDNF, using CCNs showing vulnerability to MeHg toxicity and HiNs showing resistance. BDNF was specifically expressed in HiNs, whereas nerve growth factor was barely detectable in either neuron type. In addition, other NTs, NT3 and NT4/5, were expressed in small but nearly equal amounts in both neuron types. Furthermore, among the various pathways involved in MeHg neurotoxicity, the p44/42 MAPK pathway was specifically activated in HiNs, even without MeHg treatment. siRNAs were used to reduce NTs in both neuron types. Only a specific reduction in BDNF attenuated the resistance to MeHg toxicity and p44/42 MAPK activation in HiNs. In addition, the external addition of BDNF and NT4/5, which act on the same tyrosine receptor kinase (Trk), TrkB, suppressed MeHg neurotoxicity in both neuron types. These results suggest that BDNF, expressed specifically in HiNs, is involved in the resistance to MeHg neurotoxicity via TrkB. Additionally, the activation of the p44/42 MAPK pathway may contribute to the inhibitory effect of BDNF on MeHg neurotoxicity. [ABSTRACT FROM AUTHOR]

Toll‐like receptors (TLRs) are key mediators of inflammation in intervertebral disc (IVD) degeneration. TLR‐2 activation contributes to the degenerative process by increasing the expression of extracellular matrix‐degrading enzymes, pro‐inflammatory cytokines, and neurotrophins. As potent post‐transcriptional regulators, microRNAs can modulate intracellular mechanisms, and their dysregulation is known to contribute to numerous pathologies. This study aims to investigate the impact of TLR‐2 signaling on miRNA dysregulation in the context of IVD degeneration. Small‐RNA sequencing of degenerated IVD cells shows the dysregulation of ten miRNAs following TLR‐2 activation by PAM2CSK4. The miR‐155‐5p is most significantly upregulated in degenerated and non‐degenerated annulus fibrosus and nucleus pulposus cells. Sequence‐based target and pathway prediction shows the involvement of miR‐155‐5p in inflammation‐ and cell fate‐related pathways and TLR‐2‐induced miR‐155‐5p expression leads to the downregulation of its target c‐FOS. Furthermore, changes specific to the activation of TLR‐2 through fragmented fibronectin are seen in miR‐484 and miR‐487. Lastly, miR‐100‐3p, miR‐320b, and miR‐181a‐3p expression exhibit degeneration‐dependent changes. These results show that TLR‐2 signaling leads to the dysregulation of miRNAs in IVD cells as well as their possible downstream effects on inflammation and degeneration. The identified miRNAs provide important opportunities as potential therapeutic targets for IVD degeneration and low back pain. [ABSTRACT FROM AUTHOR]

The neurotrophin nerve growth factor (NGF) and its precursor proNGF are both bioactive and exert similar or opposite actions depending on the cell target and its milieu. The balance between NGF and proNGF is crucial for cell and tissue homeostasis and it is considered an indicator of pathological conditions. Proteolytical cleavage of proNGF to the mature form results in different fragments, whose function and/or bioactivity is still unclear. The present study was conducted to investigate the distribution of proNGF fragments derived from endogenous cleavage in brain and peripheral tissues of adult rats in the healthy condition and following inflammatory lipopolysaccharide (LPS) challenge. Different anti‐proNGF antibodies were tested and the presence of short peptides corresponding to the prodomain sequence (pdNGFpep) was identified. Processing of proNGF was found to be tissue‐specific and accumulation of pdNGFpeps was found in inflamed tissues, mainly in testis, intestine and heart, suggesting a possible correlation between organ functions and a response to insults and/or injury. The bioactivity of pdNGFpep was also demonstrated in vitro by using primary hippocampal neurons. Our study supports a biological function for the NGF precursor prodomain and indicates that short peptides from residues 1–60, differing from the 70–110 sequence, induce apoptosis, thereby opening the way for identification of new molecular targets to study pathological conditions. [ABSTRACT FROM AUTHOR]

The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1β into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below. [ABSTRACT FROM AUTHOR]

Aims: To explore the effect of blocking galectin‐3 in the bladder pain syndrome associated with interstitial cystitis. Methods: A galectin‐3 inhibitor was used to treat mice with cyclophosphamide‐induced cystitis. The expression of galectin‐3 in bladder tissues and urine was examined by immunohistochemistry and enzyme‐linked immunosorbent assay (ELISA), respectively. Suprapubic‐pelvic pain, bladder voiding, bladder pain‐like nociceptive behavior, and referred hyperalgesia were assessed. The weights of the bladders were also measured, and inflammatory cell infiltration and inflammatory cytokine levels were examined by histopathological evaluation. The inflammatory cytokines interleukin 1β (IL‐1β), nerve growth factor (NGF), IL‐6, and tumor necrosis factor α (TNF‐α) were measured by ELISA. Results: Increases in galectin‐3 levels, inflammation, bladder weight, and bladder pain‐related symptoms were observed in bladders with cyclophosphamide‐induced cystitis. Administration of the galectin‐3 inhibitor significantly mitigated bladder pain‐related symptoms and inflammatory response. In response to the 500 μM dose of the galectin‐3 inhibitor, nociceptive behaviors, nociceptive score, and bladder‐to‐body weight ratios were reduced by 65.1%, 65.3%, and 40.3%, respectively, while 500 μM Gal‐3 inhibitor increased pelvic pain threshold by 86.7%. Moreover, galectin‐3 inhibitor treatment inhibited the inflammation. Compared to untreated CYP‐induced mice, there were significant changes in the levels of IL‐1β (41.72 ± 2.05 vs. 18.91 ± 2.26 pg/mg tissues), NGF (9.64 ± 0.38 vs. 1.88 ± 0.05 pg/mg tissues), IL‐6 (42.67 + 1.51 vs. 21.26 + 2.78 pg/mg tissues, and TNF‐α (22.02 ± 1.08 vs. 10.70 ± 0.80 pg/mg tissues) in response to the highest dose of the Gal‐3 inhibitor subgroup (500 μM), and 500 μM Gal‐3 inhibitor reduced mast cell infiltration ratios by 71.8%. Conclusions: The galectin‐3 inhibitor relieved pelvic pain, urinary symptoms, and bladder inflammation in mice with cyclophosphamide‐induced cystitis. Thus, galectin‐3 inhibitors may be novel agents in interstitial cystitis treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Cognitive impairment is a prevalent adverse consequence of traumatic brain injury (TBI). The neuroprotective effects of nicorandil (N‐(2‐hydroxyethyl)‐nicotinamide nitrate) has been previously documented, yet its protective effects against cognitive dysfunction post‐TBI remain unclear. Hence, the present study was aimed to evaluate whether nicorandil attenuates cognitive dysfunction in TBI rats and the underlying mechanism behind this process. Methods: The TBI model was established with a controlled cortical impact (CCI). The effects of nicorandil on cognitive dysfunction of rats with TBI were examined through Novel object recognition (NOR) test, Y‐maze test, and Morris water maze (MWM) task. After behavioral tests, hippocampal tissue was collected for Quantitative real‐time PCR, Western blot analysis, and Enzyme‐linked immunosorbent assay (ELISA) assay. Results: We observed that nicorandil administration effectively ameliorates learning and memory impairment in TBI rats. Alongside, nicorandil treatment attenuated oxidative stress in the hippocampus of TBI rats, characterized by the decreased reactive oxygen species generation, malondialdehyde, and protein carbonyls levels, and concurrent promotion of antioxidant‐related factors (including superoxide dismutase, glutathione peroxidase, and catalase) activities. Additionally, nicorandil treatment attenuated the inflammatory response in the hippocampus of TBI rat, as evidenced by the upregulated levels of interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐α (TNF‐α), as well as the downregulated level of IL‐10. Mechanistically, nicorandil treatment significantly enhanced the mRNA and protein levels of neurotrophic factors, brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of TBI rats. Conclusion: These findings suggest that nicorandil mitigates cognitive impairment after TBI by suppressing oxidative stress and inflammation, potentially through enhancing BDNF and NGF levels. [ABSTRACT FROM AUTHOR]

Background: The impact of cannabis uses on blood levels of brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) remains uncertain, with conflicting findings reported in the literature. BDNF and NGF both are essential proteins for neuron's growth, and their dysregulation is seen in various mental disorders. This study aims to evaluate the relationship between cannabis usage and BDNF and NGF levels due to their potential implications for mental health. Methods: A comprehensive search of electronic databases was performed using appropriate MeSH terms and keywords. Inclusion criteria comprised human studies investigating the relationship between cannabis use and BDNF and NGF levels. Results: A total of 11 studies met the inclusion criteria and were included. The pooled analysis revealed a nonsignificant association between cannabis use and dysregulated blood levels of BDNF (random‐effects model, standardized mean differences [SMD] =.26, 95% CI −.34 to.76, p =.40). The results of our subgroup analysis based on BDNF source showed a nonsignificant between‐group difference. For NGF levels, four studies were included, the pooled analysis revealed a nonsignificant association between cannabis use and dysregulated blood levels of NGF (random‐effects model, SMD = −.60, 95% CI −1.43 to –.23, p =.16). In both analyses, high heterogeneity was observed among the included studies which is a notable limitation to current meta‐analysis. Conclusion: This systematic review highlights the need for further research to elucidate the relationship between cannabis use and these neurotrophic factors. A better understanding of these associations can contribute to our knowledge of the neurobiological effects of cannabis and inform potential implications for mental health, cognitive function, and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Aim: Schizophrenia onset in the developmental age has a strong neurodevelopmental burden and is associated with a poorer prognosis. The approach to diagnosis is still based on symptomatic description without objective validation. In this study, we aimed to compare the peripheral blood levels of hypothesized biomarker proteins: brain‐derived neurotrophic factor (BDNF), proBDNF, p75 neurotrophin receptor (p75NTR) and S100B between early‐onset schizophrenia‐spectrum adolescents (n = 45) and healthy controls (n = 34). Methods: Clinical assessment of the participants encompassed symptomatic description with the use of structured interviews and executive function objective measurement. Plasma levels of BDNF protein were significantly lower in schizophrenia patients than in controls both at admission (p =.003) and 6–8 weeks follow‐up (p =.007). Results: We observed significant correlations between BDNF, proBDNF and p75NTR levels and positive and negative symptoms scale (PANSS) scores, p75NTR and S100B levels and suicidal parameters, as well as a correlation of BDNF plasma level with the risky decision‐making style in Iowa Gambling Task (IGT). Conclusions: The results indicate a potential value of studied proteins as a biomarker in the diagnosis and monitoring of the disease's course. [ABSTRACT FROM AUTHOR]

To study the process of neuronal differentiation, the human neuroblastoma (SH‐SY5Y) and the murine neuroblastoma (Neuro2a) cell lines have proven to be effective models. For this approach, different protocols involving known neurotrophic factors and other molecules, such as retinoic acid (RA), have been assessed to better understand the neuronal differentiation process. Thus, the goal of this manuscript was to provide a brief overview of recent studies that have used protocols to promote neurodifferentiation in SH‐SY5Y and Neuro2a cell lines and used acquired morphology and neuronal markers to validate whether differentiation was effective. The published results supply some guidance regarding the relationship between RA and neurotrophins for SH‐SY5Y, as well a serum concentrations for both cell lines. Furthermore, they demonstrate the potential application of Neuro2a, which is critical for future research on neuronal differentiation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex form of neurodegenerative dementia. Growing body of evidence supports the cardinal role of sirtuin1 (SIRT1) in neurodegeneration and AD development. Recently, adipose tissue‐derived mesenchymal stem cells (Ad‐MSCs) have made their mark for a wide array of regenerative medicine applications, including neurodegenerative disorders. Therefore, the present study aimed to investigate the therapeutic potential of Ad‐MSCs in AD rat model, and to explore the possible implication of SIRT1. Ad‐MSCs were isolated from rat epididymal fat pads and properly characterized. Aluminum chloride was used to induce AD in rats, and afterward, a group of AD‐induced rats received a single dose of Ad‐MSCs (2 × 106cell, I.V per rat). One month after Ad‐MSCs transplantation, behavioral tests were done, brain tissues were collected, then histopathological and biochemical assessments were performed. Amyloid beta and SIRT1 levels were determined by enzyme‐linked immunosorbent assay. Whereas expression levels of neprilysin, BCL2 associated X protein, B‐cell lymphoma‐2, interleukin‐1β, interleukin‐6, and nerve growth factor in hippocampus and frontal cortex brain tissues were assessed using reverse transcriptase quantitative polymerase chain reaction. Our data demonstrated that transplantation of Ad‐MSCs alleviated cognitive impairment in AD rats. Additionally, they exhibited anti‐amyloidogenic, antiapoptotic, anti‐inflammatory, as well as neurogenic effects. Furthermore, Ad‐MSCs were found to possibly mediate their therapeutic effects, at least partially, via modulating both central and systemic SIRT1 levels. Hence, the current study portrays Ad‐MSCs as an effective therapeutic approach for AD management and opens the door for future investigations to further elucidate the role of SIRT1 and its interrelated molecular mediators in AD. [ABSTRACT FROM AUTHOR]

The article discusses the concept of intra-tumoral heterogeneity in oral cancer and its impact on cancer diagnosis and therapy. Intra-tumoral heterogeneity refers to the presence of diverse populations of cells within a tumor, which exhibit variations in molecular expressions and cellular characteristics. This heterogeneity contributes to the resistance of cancer therapies and poses challenges for personalized medicine. The article specifically focuses on perineural invasion (PNI), which occurs when cancer cells invade and spread through nerve fibers, leading to high rates of recurrence. The interaction between cancer cells and nerve cells in the perineural niche plays a crucial role in promoting PNI and contributing to intra-tumoral heterogeneity. Understanding these mechanisms can help develop effective cancer therapies based on tumor heterogeneity. [Extracted from the article]

Tanezumab is a monoclonal antibody against nerve growth factor (NGF). We investigated tanezumab pharmacokinetic (PK)‐NGF relationships and predicted the extent of systemic free NGF suppression with target‐mediated drug disposition (TMDD) modeling using data from three pivotal phase III interventional studies (NCT02697773, NCT02709486, and NCT02528188) in patients with osteoarthritis. Patients received tanezumab 2.5 mg or 5 mg every 8 weeks (q8w) subcutaneously. A TMDD model using a previously established population PK model was used to describe plasma tanezumab and serum total NGF concentration data, and simulations were performed to predict "unobserved" free NGF versus time profiles and dose–response relationships for free NGF. A total of 2992 patients had available data for plasma tanezumab or serum total NGF concentrations and were included in the analysis; 706 of these had data for both tanezumab and total NGF concentrations. The model generally performed well to predict observed total NGF concentrations up to ~24 weeks after each dose. Simulations suggested free NGF concentration would be suppressed by ~75% (median) near the peak of tanezumab concentration and by less than 5% (median) around the trough tanezumab concentration with a tanezumab 2.5 mg q8w regimen. Free NGF concentration was predicted to return to baseline level at ~8 weeks (95% prediction interval: 5–16 weeks) after the last tanezumab dose. This model adequately described plasma tanezumab and serum total NGF concentrations following s.c. administration of tanezumab 2.5 or 5 mg q8w, allowed prediction of relative change in systemic free NGF following s.c. administration of tanezumab. [ABSTRACT FROM AUTHOR]

Background and Purpose: Traumatic brain injury (TBI) comprises a primary injury directly induced by impact, which progresses into a secondary injury leading to neuroinflammation, reactive astrogliosis, and cognitive and motor damage. To date, treatment of TBI consists solely of palliative therapies that do not prevent and/or limit the outcomes of secondary damage and only stabilize the deficits. The neurotrophin, nerve growth factor (NGF), delivered to the brain parenchyma following intranasal application, could be a useful means of limiting or improving the outcomes of the secondary injury, as suggested by pre‐clinical and clinical data. Experimental Approach: We evaluated the effect of acute intranasal treatment of young (20‐postnatal day) rats, with NGF in a TBI model (weight drop/close head), aggravated by hypoxic complications. Immediately after the trauma, rats were intranasally treated with human recombinant NGF (50 μg·kg−1), and motor behavioural test, morphometric and biochemical assays were carried out 24 h later. Key Results: Acute intranasal NGF prevented the onset of TBI‐induced motor disabilities, and decreased reactive astrogliosis, microglial activation and IL‐1β content, which after TBI develops to the same extent in the impact zone and the hypothalamus. Conclusion and Implications: Intranasal application of NGF was effective in decreasing the motor dysfunction and neuroinflammation in the brain of young rats in our model of TBI. This work forms an initial pre‐clinical evaluation of the potential of early intranasal NGF treatment in preventing and limiting the disabling outcomes of TBI, a clinical condition that remains one of the unsolved problems of paediatric neurology. [ABSTRACT FROM AUTHOR]

Background and purpose: Elevated plasma concentrations of neural cell adhesion molecule 1 (NCAM1) and p75 neurotrophin receptor (p75) in patients with peripheral neuropathy have been reported. This study aimed to determine the specificity of plasma concentration elevation of either NCAM1 or p75 in a subtype of Charcot–Marie–Tooth disease (CMT) and its correlation with pathologic nerve status and disease severity. Methods: Blood samples were collected from 138 patients with inherited peripheral neuropathy and 51 healthy controls. Disease severity was measured using Charcot–Marie–Tooth Neuropathy Score version 2 (CMTNSv2), and plasma concentrations of NCAM1 and p75 were analyzed by enzyme‐linked immunosorbent assay. Eight sural nerves from CMT patients were examined to determine the relation of histopathology and plasma NCAM1 levels. Results: Plasma concentration of NCAM1, but not p75, was specifically increased in demyelinating subtypes of CMT (median = 7100 pg/mL, p < 0.001), including CMT1A, but not in axonal subtype (5964 pg/mL, p > 0.05), compared to the control (3859 pg/mL). CMT1A patients with mild or moderate severity (CMTNSv2 < 20) showed higher levels of plasma NCAM1 than healthy controls. Immunofluorescent NCAM1 staining for the sural nerves of CMT patients showed that NCAM1‐positive onion bulb cells and possible demyelinating Schwann cells might be associated with the specific increase of plasma NCAM1 in demyelinating CMT. Conclusions: The plasma NCAM1 levels in demyelinating CMT might be a surrogate biomarker reflecting pathological Schwann cell status and disease progression. [ABSTRACT FROM AUTHOR]

43 Gähwiler, B. H., Capogna, M., Debanne, D., McKinney, R. A., & Thompson, S. M. (1997). 65 Scanziani, M., Capogna, M., Gähwiler, B. H., & Thompson, S. M. (1992). 70 Thompson, S. M., Capogna, M., & Scanziani, M. (1993). 2 Edited by: John Foxe Marco Capogna's main publications 1 Ahluwalia, J., Urban, L., Bevan, S., Capogna, M., & Nagy, I. (2002). [Extracted from the article]

Background: Nerve growth factor (NGF) is a neurotrophin that is increased in osteoarthritic joints of horses. In humans, NGF has been associated with pain, and both synovial and serum NGF concentrations are increased in osteoarthritic patients. Studies in humans also have shown that serum NGF concentration can increase with stress. Serum NGF concentration should be evaluated in horses with osteoarthritis‐associated lameness. Objectives: Quantify and compare serum NGF concentration in horses with osteoarthritis‐associated lameness and sound horses. Additionally, the impact of short‐term stress on serum NGF concentration was investigated. Animals: Lame horses with radiographic evidence of osteoarthritis (n = 20), lame horses without radiographic changes in the affected joint (n = 20) and sound horses (n = 20). In addition, horses with acute fractures (n = 9) were sampled. To determine the effect of stress, serum from horses subjected to a stressful event (transportation, n = 5; stress confirmed by increased serum cortisol concentration) was analyzed. Methods: Cross‐sectional clinical study (lame, sound, and fracture cohorts) and experimental longitudinal study (stress cohort). Serum NGF concentration was determined using a quantitative sandwich ELISA. Results: Serum NGF concentration was increased in lame horses with radiographic evidence of osteoarthritis (P <.0001; median, 238 pg/mL; interquartile range [IQR], 63‐945 pg/mL) and in lame horses without radiographic evidence of osteoarthritis in the painful joint (P <.05; median, 31 pg/mL; IQR, 31‐95 pg/mL) compared with sound horses (median, 31 pg/mL; IQR, 31‐46 pg/mL). Serum NGF concentration did not increase with short‐term stress and was low in horses with fracture‐associated pain. Conclusions and Clinical Importance: Serum NGF concentration was high in the cohort with advanced osteoarthritis and should be investigated as a marker for osteoarthritis‐associated pain. [ABSTRACT FROM AUTHOR]

Background and Purpose: Peripheral sensitization contributes to pathological pain. While prostaglandin E2 (PGE2) and nerve growth factor (NGF) sensitize peptidergic C‐nociceptors (TRPV1+), glial cell line‐derived neurotrophic factor (GDNF) sensitizes non‐peptidergic C‐neurons (IB4+). The sigma‐1 receptor (sigma‐1R) is a Ca2+‐sensing chaperone known to modulate opoid analgesia. This receptor binds both to TRPV1 and the μ opioid receptor, although the functional repercussions of these physical interactions in peripheral sensitization are unknown. Experimental Approach: We tested the effects of sigma‐1 antagonism on PGE2‐, NGF‐, and GDNF‐induced mechanical and heat hyperalgesia in mice. We used immunohistochemistry to determine the presence of endomorphin‐2, an endogenous μ receptor agonist, on dorsal root ganglion (DRG) neurons. Recombinant proteins were used to study the interactions between sigma‐1R, μ‐ receptor, and TRPV1. We used calcium imaging to study the effects of sigma‐1 antagonism on PGE2‐induced sensitization of TRPV1+ nociceptors. Key Results: Sigma1 antagonists reversed PGE2‐ and NGF‐induced hyperalgesia but not GDNF‐induced hyperalgesia. Endomorphin‐2 was detected on TRPV1+ but not on IB4+ neurons. Peripheral opioid receptor antagonism by naloxone methiodide or administration of an anti‐endomorphin‐2 antibody to a sensitized paw reversed the antihyperalgesia induced by sigma‐1 antagonists. Sigma‐1 antagonism transfers sigma‐1R from TRPV1 to μ receptors, suggesting that sigma‐1R participate in TRPV1‐μ receptor crosstalk. Moreover, sigma‐1 antagonism reversed, in a naloxone‐sensitive manner, PGE2‐induced sensitization of DRG neurons to the calcium flux elicited by capsaicin, the prototypic TRPV1 agonist. Conclusion and Implications: Sigma‐1 antagonism harnesses endogenous opioids produced by TRPV1+ neurons to reduce hyperalgesia by increasing μ receptor activity. [ABSTRACT FROM AUTHOR]

In this review, an attempt was made to substantiate the possibility for neurotrophins to be involved in the development of immune tolerance based on data accumulated on neurotrophin content and receptor expression in the trophoblast and immune cells, in particular, in natural killer cells. Numerous research results are reviewed to show that the expression and localization of neurotrophins along with their high‐affinity tyrosine kinase receptors and low‐affinity p75NTR receptor in the mother‐placenta‐fetus system indicate the important role of neurotrophins as binding molecules in regulating the crosstalk between the nervous, endocrine, and immune systems in pregnancy. An imbalance between these systems can occur with tumor growth and pathological processes observed in pregnancy complications and fetal development anomalies. [ABSTRACT FROM AUTHOR]

Proline‐rich polypeptides (PRPs complex also known as COLOCO®, Colostrinin®) consist of low‐molecular weight peptides ranging up to 10 kDa, isolated from the bovine colostrum obtained up to 48 h postpartum. PRPs have been shown to affect processes involved in inflammation, brain aging, and neurodegeneration. The aim of this study was to investigate the effect of Colostrinin® (COLOCO®) on the cognitive abilities of healthy volunteers in three different age groups using the CANTAB tool in a double‐blind randomized placebo‐controlled study. BDNF serum level was used as a physicochemical marker of improvement of the cognitive skills. Three hundred and sixty‐one healthy volunteers were divided into three study groups aged 18–24, 25–54, and 55–75; each group was then divided into two subgroups which took either placebo or tested lozenge with 120 μg of PRPs for the period of 4 months. The CANTAB battery test was used to measure the efficacy of PRP in the context of cognitive functioning. After the treatment with COLOCO®, we observed differences within MoCA score in the oldest patients, improvement in DMS and drop in PAL scores within the youngest group, drop in RTI and improvement in RVP scores within the middle‐aged group. It was observed that serum BDNF level increased in all study groups which confirms cognitive improvement. In conclusion, we have shown that Colostrinin® exhibits cognitive enhancing effects, probably through the modulation of BDNF concentrations. [ABSTRACT FROM AUTHOR]

Background and Purpose: Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti‐inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)‐induced schizophrenia. Experimental Approach: Male Sprague–Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain‐derived neurotrophic factor expression and phosphorylation of extracellular signal‐regulated kinase were determined using western blot analysis. Key Results: Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose‐dependent manner in PCP‐treated rats. Fingolimod treatment exerted anti‐inflammatory effects by inhibiting microglial activation and IL‐6 and IL‐1β pro‐inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain‐derived neurotrophic factor protein expression and activation of the ERK signalling pathway. Conclusion and Implications: This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

Nicotine has been used during pregnancy and lactation as a tobacco harm reduction strategy. However, it is unclear whether nicotine exposure during a critical development period negatively impacts stress responses in adulthood. This study investigated how nicotine, administered via breastfeeding, affects the brain-derived neurotrophic factor (BDNF), synaptic proteins levels, and anxiety-like behavior in adult female mice subjected to stress. Female Swiss mice were exposed to saline or nicotine (8 mg/kg/day) through breastfeeding between their fourth and 17th postnatal days (P) via implanted osmotic mini pumps. The unpredictable chronic mild stress (UCMS) protocol was performed during their adulthood (P65) for 10 consecutive days, followed by the elevated plus maze (EPM) test 1 day after the protocol. Animals were euthanized and their blood, collected for plasma corticosterone measurements and their brain structures, dissected for BDNF and synaptic proteins analyses. We found no significant differences in corticosterone levels between groups (Saline/Nonstress, Nicotine/Non-stress, Saline/Stress, and Nicotine/Stress). The UCMS protocol hindered weight gain. Mice exposed to nicotine through breastfeeding with or without the UCMS protocol in adulthood showed higher grooming and head dipping frequency; decreased BDNF levels in cerebellum and striatum; increased postsynaptic density protein 95 (PSD-95), synapsin I, and synaptophysin levels in cerebellum; and decreased PSD-95 and synapsin I levels in brainstem. Our results indicate that nicotine exposure through breastfeeding leads to long-lasting behavioral effects and synaptic protein changes, most of which were independent of the UCMS protocol, even after a long nicotine-free period, highlighting the importance of further studies on nicotine exposure during development. [ABSTRACT FROM AUTHOR]

The interaction of neurotrophins with their receptors is involved in the pathogenesis and progression of various neurological diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury and acute and chronic cerebral damage. The p75 neurotrophin receptor (p75NTR) plays a pivotal role in the development of neurological dysfunctions as a result of its high expression, abnormal processing and signalling. Therefore, p75NTR represents as a vital therapeutic target for the treatment of neurodegeneration, neuropsychiatric disorders and cerebrovascular insufficiency. This review summarizes the current research progress on the p75NTR signalling in neurological deficits. We also summarize the present therapeutic approaches by genetically and pharmacologically targeting p75NTR for the attenuation of pathological changes. Based on the evolving knowledge, the role of p75NTR in the regulation of tau hyperphosphorylation, Aβ metabolism, the degeneration of motor neurons and dopaminergic neurons has been discussed. Its position as a biomarker to evaluate the severity of diseases and as a druggable target for drug development has also been elucidated. Several prototype small molecule compounds were introduced to be crucial in neuronal survival and functional recovery via targeting p75NTR. These small molecule compounds represent desirable agents in attenuating neurodegeneration and cell death as they abolish activation‐induced neurotoxicity of neurotrophins via modulating p75NTR signalling. More comprehensive and in‐depth investigations on p75NTR‐based drug development are required to shed light on effective treatment of numerous neurological disorders. [ABSTRACT FROM AUTHOR]

Age‐related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age‐related IHC synaptopathy can be prevented, and if this impacts the time‐course of ARHL, we tested the effects of cochlear overexpression of neurotrophin‐3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC‐SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound‐evoked neural potentials compared with age‐matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3‐overexpressing mice have milder ARHL, with larger sound‐evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age‐matched controls. Our results also provide evidence that an age‐related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age‐related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a destructive traumatic disease of the central nervous system without satisfying therapy efficiency. Bone marrow mesenchymal stem cells (BMMSCs) therapy promotes the neurotrophic factors' secretion and axonal regeneration, thereby promoting recovery of SCI. Pulsed electromagnetic fields (PEMF) therapy has been proven to promote neural growth and regeneration. Both BMMSCs and PEMF have shown curative effects for SCI; PEMF can further promote stem cell differentiation. Thus, we explored the combined effects of BMMSCs and PEMF and the potential interaction between these two therapies in SCI. Compared with the SCI control, BMMSCs, and PEMF groups, the combinational therapy displayed the best therapeutic effect. Combinational therapy increased the expression levels of nutritional factors including brain‐derived neurotrophic factor (BDNF), nerve growth factors (NGF) and vascular endothelial growth factor (VEGF), enhanced neuron preservation (NeuN and NF‐200), and increased axonal growth (MBP and myelin sheath). Additionally, PEMF promoted the expression levels of BDNF and VEGF in BMMSCs via Wnt/β‐catenin signaling pathway. In summary, the combined therapy of BMMSCs and PEMF displayed a more satisfactory effect than BMMSCs and PEMF therapy alone, indicating a promising application of combined therapy for the therapy of SCI. [ABSTRACT FROM AUTHOR]

Background: Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl‐L‐carnitine (ALCAR) has been proven to promote nerve repair. Objectives: To investigate the effect and potential mechanism of ALCAR in the treatment of NED. Materials and methods: Thirty‐two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower‐dose ALCAR (50 mg/kg/day) group, BCNI + higher‐dose (100 mg/kg/day) group, and sham‐operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro. Results: We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR‐LD and BCNI+ALCAR‐HD groups. Also, we observed decreased smooth muscle and increased collagen content in the corpus cavernosum in the BCNI group. The expressions of fibrosis markers transforming growth factor‐beta (TGF‐β), connective tissue growth factor (CTGF), and Smad 2/3 were significantly up‐regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher‐dose ALCAR. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate pathway (cGMP) was promoted and the Ras homolog gene family member A (RhoA)/Rho‐associated protein kinase (ROCK) pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased neuronal nitric oxide synthase (nNOS) and down‐regulated tyrosine hydroxylase (TH). In vitro, ALCAR promoted the migration and proliferation of SC and increased the expression of 22‐kD peripheral myelin protein and nerve growth factor (NGF). Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site. Discussion and conclusion: ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED. [ABSTRACT FROM AUTHOR]

Cucurbitacin E (CuE) shows potential to handle airway remodelling. In the current study, the effects of CuE on nicotine‐induced airway remodelling were explored by focussing on its interaction with let‐7c‐5p/NGF axis. The potential microRNA (miR) as the therapeutic target for CuE treatment was determined using a microarray assay. Changes in viability, inflammation and let‐7c‐5p/NGF pathway in nicotine‐treated bronchial epithelial cells (BECs) were detected under CuE treatment (5 μM). The pathways were manipulated with let‐7c‐5p inhibitor. Mice were subjected to nicotine treatment and handled with CuE. Changes in pulmonary function and structure were detected. Based on the microarray data, let‐7c‐5p was selected as the therapeutic target. Viability and inflammation of BECs were induced by nicotine and then restored by CuE. At molecular level, nicotine suppressed let‐7c‐5p while induced NGF, FN1 and COLIA levels. The effects of CuE were counteracted by let‐7c‐5p inhibition. In a mouse model, nicotine impaired the function and structure of lung, which was attenuated by CuE and then re‐impaired by let‐7c‐5p antagomir. Collectively, CuE protected against nicotine‐induced airway remodelling and partially depended on the induction of let‐7c‐5p; our future work would pay more attention to other downstream effectors of the miR to promote the treatment of nicotine‐induced pulmonary disorders. [ABSTRACT FROM AUTHOR]

In the central nervous system, most neurons co‐express TrkB and TrkC, the tyrosine kinase receptors for brain‐derived neurotrophic factor (BDNF) and neurotrophin‐3 (NT3). As NT3 can also activate TrkB, it has been difficult to understand how NT3 and TrkC can exert unique roles in the assembly of neuronal circuits. Using neurons differentiated from human embryonic stem cells expressing both TrkB and TrkC, we compared Trk activation by BDNF and NT3. To avoid the complications resulting from TrkB activation by NT3, we also generated neurons from stem cells engineered to lack TrkB. We found that NT3 activates TrkC at concentrations lower than those of BDNF needed to activate TrkB. Downstream of Trk activation, the changes in gene expression caused by TrkC activation were found to be similar to those resulting from TrkB activation by BDNF, including a number of genes involved in synaptic plasticity. At high NT3 concentrations, receptor selectivity was lost as a result of TrkB activation. In addition, TrkC was down‐regulated, as was also the case with TrkB at high BDNF concentrations. By contrast, receptor selectivity as well as reactivation were preserved when neurons were exposed to low neurotrophin concentrations. These results indicate that the selectivity of NT3/TrkC signalling can be explained by the ability of NT3 to activate TrkC at concentrations lower than those needed to activate TrkB. They also suggest that in a therapeutic perspective, the dosage of Trk receptor agonists will need to be taken into account if prolonged receptor activation is to be achieved. [ABSTRACT FROM AUTHOR]

Neuropathic pain is an unbearable condition caused by nervous system damage. As distinct acute pain, neuropathic pain is chronic, and it severely influences quality of life. N,N‐Dimethyl‐d‐erythro‐sphingosine (DMS), a neuropathic pain inducer, is metabolited de novo from sphingosine. In a recent study, metabolomics showed an increased concentration level of DMS in the spinal cord in mice with neuropathic pain. Nerve growth factor (NGF) is one of the peripheral nervous system targeted pain factors that interact with tropomyosin receptor kinase A (trkA). On the basis of this information, we were interested in the possibility that DMS may induce neuropathic pain‐like behavior through an increase of NGF activity. In this study, we showed that DMS can enhance the binding of NGF to trkA, followed by neurite outgrowth of epidermal nerve fibers and phosphorylation of trkA. In addition, a stereoisomer, N,N‐dimethyl‐l‐erythro‐sphingosine, did not any show such biological activities. The results suggest that DMS can enhance the binding of NGF to trkA and that its stereochemistry is an essential factor for exhibiting its activity. [ABSTRACT FROM AUTHOR]

Engineered proteases are promising tools to address physiological and pathophysiological questions as well as to develop new therapeutic approaches. Here we introduce a new genetically encoded engineered single‐chain tobacco etch virus protease, allowing to control proprotein cleavage in different compartments of living mammalian cells. We demonstrated a set of controllable proteolytic effects, including cytosolic protein cleavage, inducible gene expression, and maturation of brain‐derived neurotrophic factor (BDNF) in the secretory pathway thus showing the versatility of this technique. Of note, the secretory pathway exhibits different characteristics from the cytosol and it is difficult to target because inaccessible to some small molecules. We were able to induce ligand‐mediated BDNF maturation and monitor its effects on dendritic spines in hippocampal pyramidal cells and in the mouse brain. This strategy paves the way to dissect proteolytic cleavage product signaling in various processes as well as for future therapeutic applications. [ABSTRACT FROM AUTHOR]

A motor unit (MU) comprises the neuron cell body, its corresponding axon and each of the muscle fibres it innervates. Many studies highlight age‐related reductions in the number of MUs, yet the ability of a MU to undergo remodelling and to expand to rescue denervated muscle fibres is also a defining feature of MU plasticity. Remodelling of MUs involves two coordinated processes: (i) axonal sprouting and new branching growth from adjacent surviving neurons, and (ii) the formation of key structures around the neuromuscular junction to resume muscle–nerve communication. These processes rely on neurotrophins and coordinated signalling in muscle–nerve interactions. To date, several neurotrophins have attracted focus in animal models, including brain‐derived neurotrophic factor and insulin‐like growth factors I and II. Exercise in older age has demonstrated benefits in multiple physiological systems including skeletal muscle, yet evidence suggests this may also extend to peripheral MU remodelling. There is, however, a lack of research in humans due to methodological limitations which are easily surmountable in animal models. To improve mechanistic insight of the effects of exercise on MU remodelling with advancing age, future research should focus on combining methodological approaches to explore the in vivo physiological function of the MU alongside alterations of the localised molecular environment. [ABSTRACT FROM AUTHOR]

Disordered copper metabolism has been suggested to occur to several neurological conditions, including Alzheimer's disease and Parkinson's disease. However, the underlying mechanism was still unclear. This might link to copper‐induced hippocampal neuronal apoptosis and decrease in neurons viability. Our vitro experiment showed copper exposure induced oxidative stress and promoted apoptosis of HT22 murine hippocampal neuronal cell. Mechanistically, we found copper, on the one hand, prevented phosphorylation of cAMP response element binding protein (CREB) to decrease expression its downstream target protein Brain‐derived neurotrophic factor (BDNF), and to decrease mitochondrial membrane potential and Bcl‐2/Bax ratio; on the other hand, copper‐induced reactive oxygen species (ROS), promoted lipid peroxidation, reduced antioxidant enzyme activity of GSH‐Px. Copper‐induced oxidative damage further decreased the phosphorylation of CREB, decreased expression of Bcl‐2, enhanced expression of Bax, and accelerated the dissociation of keap1‐Nrf2 complex, promoted the nuclear translocation of Nrf2, stimulate the expression of antioxidant molecules HO‐1 and NQO1. In conclusion, we found copper inhibited pCREB/BDNF signaling pathway by prevent CREB from phosphorylation, further found that oxidative damage not only inhibited neuroprotective signaling pathways and induced apoptosis, but activated antioxidant protection signals Nrf2/HO‐1/NQO1 signaling pathway. HT22 cells were used to investigate neuronal damage and oxidative stress after copper exposure. The results showed copper treatment increased intracellular copper content, inhibited proliferation and promoted apoptosis of HT22 cells. Copper‐induced neuronal apoptosis was probably mediated by p‐CREB/BNDF and mitochondrial‐ dependent. In addition, copper‐induced oxidative stress activated anti‐oxidative damage signals Nrf2/HO‐1/NQO1 pathways. [ABSTRACT FROM AUTHOR]

Objective. Mindfulness-based cognitive therapy (MBCT) is a cost-effective psychosocial program that prevents relapse/recurrence in major depression. The present study aimed to analyze the effects of augmented MBCT along with standard treatment dominated by pharmacotherapy on psychological state, compliance, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) expression levels in patients with depression. Methods. A total of 160 eligible patients with depression in The First Affiliated Hospital of Zhengzhou University were included in this study. The study randomly assigned the patients to the experimental group (n = 80) and control group (n = 80). All participants were assessed with the questionnaires including the 17-item Hamilton Depression Rating Scale (HAMD-17), Rosenberg Self-esteem Scale (RSES), Self-Acceptance Questionnaire (SAQ), and Stigma Scale (Scale of Stigma in People with Mental Illness, SSPM). The serum levels of BDNF and NGF were detected by enzyme-linked immunosorbent assay (ELISA). Results. After 8 weeks of treatment, the experimental group showed significant lower HAMD-17 score, higher RSES, and SAQ score, as well as lower SSPM score compared with the control group (P < 0.01). Furthermore, ELISA revealed that the serum levels of BDNF and NGF remarkably increased in the experimental group after treatment (P < 0.001). Conclusions. Our data showed that augmented MBCT combined with pharmacotherapy contributed to improvement on patients' psychological state, compliance, and disease recurrence. [ABSTRACT FROM AUTHOR]

Airway smooth muscle (ASM) cells modulate the local airway milieu via production of inflammatory mediators and growth factors including classical neurotrophins, such as brain‐derived neurotrophic factor (BDNF). The glial cell‐derived neurotrophic factor (GDNF) family of ligands (GFLs) are nonclassical neurotrophins and their role in the airway is barely understood. The major GFLs, GDNF and Neurturin (NRTN) bind to GDNF family receptor (GFR) α1 and α2 respectively that pair with Ret receptor to accomplish signaling. In this study, we found GDNF is expressed in human lung and increased in adult asthma, while human ASM expresses GDNF and its receptors. Accordingly, we used human ASM cells to test the hypothesis that ASM expression and autocrine signaling by GFLs regulate [Ca2+]i. Serum‐deprived ASM cells from non‐asthmatics were exposed to 10 ng/ml GDNF or NRTN for 15 min (acute) or 24 h (chronic). In fura‐2 loaded cells, acute GDNF or NRTN alone induced [Ca2+]i responses, and further enhanced responses to 1 µM ACh or 10 µM histamine. Ret inhibitor (SPP86; 10 µM) or specific GDNF chelator GFRα1‐Fc (1 µg/ml) showed roles of these receptors in GDNF effects. In contrast, NRTN did not enhance [Ca2+]i response to histamine. Furthermore, conditioned media of nonasthmatic and asthmatic ASM cells showed GDNF secretion. SPP86, Ret inhibitor and GFRα1‐Fc chelator markedly decreased [Ca2+]i response compared with vehicle, highlighting autocrine effects of secreted GDNF. Chronic GDNF treatment increased histamine‐induced myosin light chain phosphorylation. These novel data demonstrate GFLs particularly GDNF/GFRα1 influence ASM [Ca2+]i and raise the possibility that GFLs are potential targets of airway hyperresponsiveness. [ABSTRACT FROM AUTHOR]

β‐caryophyllene (BCP), a natural sesquiterpene present in plants, is a selective agonist of cannabinoid receptor type‐2 (CB2) of the endocannabinoid system. In this study, we have prepared an extract from Piper nigrum (black pepper) seeds using supercritical fluid extraction, standardized to contain 30% BCP (ViphyllinTM). The beneficial effects of prophylactic treatment with Viphyllin on cognitive functions were demonstrated in Scopolamine‐induced dementia model mice. Male Swiss albino mice (25–30 g) were administered with Viphyllin (50 mg and 100 mg/kg body weight p.o.) or donepezil (1.60 mg/kg) for 14 days. Subsequently, cognitive deficits were induced by treating the animals intraperitoneally with Scopolamine (0.75 mg/kg). The cognitive behavior of mice was evaluated using a novel object recognition test (NORT) and Morris water maze (MWM) test. The brain homogenates were studied for biochemical parameters including cholinesterase activities and antioxidant status. Western blot analysis was performed to investigate the mechanism of action. Viphyllin dose dependently improved the recognition and spatial memory and cholinergic functions in Scop‐treated mice. The extract was found protective against Scop‐induced oxidative damage and histopathologic changes in the brain. At 100 mg/kg Viphyllin markedly reduced the proBDNF/mBDNF ratio (p <.05) and augmented the TrkB expression (p <.01). Viphyllin (100 mg/kg) was found to be neuroprotective by reducing the Scop‐induced upregulation of p‐JNK and p‐p38 MAPK proteins, Bax/Bcl‐2 ratio, and caspase activation in the brain. Viphyllin also exerted anti‐inflammatory effects by downregulating Cox‐2, TNF‐α, and NOS‐2 in Scop‐induced mice (p <.05). To summarize, our data encourage Viphyllin as a functional ingredient/dietary supplement for brain health and cognition. Practical applications: Black pepper is a culinary spice having several medicinal attributes. Essential oils in the seeds of the plant give aroma and flavor to it. Here we have prepared an extract from the seeds of black pepper using supercritical fluid extraction, characterized for the presence of β‐caryophyllene (not <30%). This research work further validates the neuroprotective mechanism of the extract in Scopolamine‐induced cognitive impairment model mice. The findings from this study strongly suggest the beneficial neuroactive properties of black pepper seed extract having the presence of BCP, a CB2 receptor agonist. It can thus be used potentially as a functional food ingredient for cognition and brain function. [ABSTRACT FROM AUTHOR]

To overcome the limitations of the clinical use of neurotrophins nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF), scientists have been trying to create their low‐molecular‐weight mimetics having improved pharmacokinetic properties and lacking side effects of full‐sized proteins since the 90s of the last century. The efforts of various research groups have led to the production of peptide and nonpeptide mimetics, being agonists or modulators of the corresponding Trk or p75 receptors that reproduced the therapeutic effects of full‐sized proteins. This review discusses different strategies and approaches to the design of such compounds. The relationship between the structure of the mimetics obtained and their action mechanisms and pharmacological properties are analyzed. Special attention is paid to the dipeptide mimetics of individual NGF and BDNF loops having different patterns of activation of Trk receptors signal transduction pathways, phosphoinositide 3‐kinase/protein kinase B and mitogen‐activated protein kinase/extracellular signal‐regulated kinase, which allowed to evaluate the contribution of each pathway to different pharmacological effects. In conclusion, data on therapeutically promising compounds being at different stages of preclinical and clinical studies are summarized. [ABSTRACT FROM AUTHOR]

Synapse degeneration correlates strongly with cognitive impairments in Alzheimer's disease (AD) patients. Soluble Amyloid‐beta (Aβ) oligomers are thought as the major trigger of synaptic malfunctions. Our earlier studies have demonstrated that Aβ oligomers interfere with synaptic function through N‐methyl‐D‐aspartate receptors (NMDARs). Our recent in vitro study found the neuroprotective role of astrocytic GluN2A in the promotion of synapse survival and identified nerve growth factor (NGF) derived from astrocytes, as a likely mediator of astrocytic GluN2A buffering against Aβ synaptotoxicity. Our present in vivo study focused on exploring the precise mechanism of astrocytic GluN2A influencing Aβ synaptotoxicity through regulating NGF. We generated an adeno‐associated virus (AAV) expressing an astrocytic promoter (GfaABC1D) shRNA targeted to Grin2a (the gene encoding GluN2A) to perform astrocyte‐specific Grin2a knockdown in the hippocampal dentate gyrus, after 3 weeks of virus vector expression, Aβ were bilaterally injected into the intracerebral ventricle. Our results showed that astrocyte‐specific knockdown of Grin2a and Aβ application both significantly impaired spatial memory and cognition, which associated with the reduced synaptic proteins PSD95, synaptophysin and compensatory increased NGF. The reduced astrocytic GluN2A can counteract Aβ‐induced compensatory protective increase of NGF through regulating pNF‐κB, Furin and VAMP3, which modulating the synthesis, mature and secretion of NGF respectively. Our present data reveal, for the first time, a novel mechanism of astrocytic GluN2A in exerting protective effects on synapses at the early stage of Aβ exposure, which may contribute to establish new targets for AD prevention and early therapy. [ABSTRACT FROM AUTHOR]

Multiple human and animal studies suggest that the upregulation of inflammatory cytokines and other pain‐related molecules in degenerated or injured intervertebral discs (IVDs) may cause discogenic low back pain (LBP). We previously reported that macrophages in injured IVD in mice produced inflammatory cytokines, but not other pain‐related molecules. CD14 is a monocyte marker expressed mainly by macrophages. The aim of the current study was to evaluate the role of CD14‐positive cells in inflammatory cytokine and pain‐related molecule expression in human degenerated IVD. IVD samples were harvested from 14 patients, including 10 with lumbar spinal stenosis, four with adult spinal deformity, and one with lumbar disc herniation during spinal interbody fusion surgery. Harvested IVD‐derived mononuclear cells were obtained and CD14‐positive (+) and CD14‐negative (−) cells were separated using CD14 antibody and streptavidin‐labeled magnetic beads. Inflammatory cytokines messenger RNA (mRNA) in the CD14(+) and CD14(−) cells, including tumor necrosis factor ɑ (TNFA), in, terleukin‐1β (IL1B) and IL6, were determined using quantitative polymerase chain reaction (qPCR) and their expression levels were compared. To evaluate factors controlling the regulation of pain‐related molecules mRNA expression, cultured CD14(−) and CD14(+) cells from IVDs were stimulated with recombinant human TNF‐ɑ and IL‐1β and levels of pain‐related molecules, including calcitonin gene‐related peptide (CGRP) and nerve growth factor (NGF) were determined using qPCR. Levels of TNFA, IL1B, IL6, and NGF in CD14(+) cells were significantly increased compared with those in CD14(−) cells (TNFA, p = 0.006; IL1B, p =.017; IL6, p =.010; NGF, p =.027). Following TNFA stimulation, NGF levels were significantly increased in CD14(−) and CD14(+) cells (CD14(−), p =.003; CD14(+), p <.001) and CGRP was significantly increased in CD14(−) IVD cells (p =.040). Following IL1B stimulation, NGF levels were significantly increased in CD14(−) cells (p =.004). CD14(+) cells had higher TNFA, IL1B, IL6, and NGF expressions than CD14(−) cells in human degenerated IVDs. Additionally, TNFA stimulation promoted the upregulation of NGF and CGRP in CD14(−) cells. These findings suggested that CD14(+) cells directly and indirectly contributed to inflammatory cytokine and pain‐related molecule expression in human degenerated IVD. CD14(+) cells might be important in the pathological mechanism of chronic discogenic LBP in humans. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays important roles in the pathogenesis and progression of altered neurodevelopment, sensorineural hearing loss, and certain neurodegenerative diseases. Hyperoside (quercetin-3-O-β-D-galactoside) is an active compound isolated from Hypericum plants. In this study, we investigate the protective effect of hyperoside on neuroinflammation and its possible molecular mechanism. Lipopolysaccharide (LPS) and hyperoside were used to treat HT22 cells. The cell viability was measured by MTT assay. The cell apoptosis rate was measured by flow cytometry assay. The mRNA expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) were determined by quantitative reverse transcription polymerase chain reaction. The levels of oxidative stress indices superoxide dismutase (SOD), reactive oxygen species (ROS), catalase (CAT), glutathione (GSH), and malondialdehyde (MDA) were measured by the kits. The expression of neurotrophic factor and the relationship among hyperoside, silent mating type information regulation 2 homolog-1 (SIRT1) and Wnt/β-catenin, and sonic hedgehog was examined by western blotting. In the LPS-induced HT22 cells, hyperoside promotes cell survival; alleviates the level of IL-1β, IL-6, IL-8, TNF-α, ROS, MDA, Bax, and caspase-3; and increases the expression of CAT, SOD, GSH, Bcl-2, BDNF, TrkB, and NGF. In addition, hyperoside upregulated the expression of SIRT1. Further mechanistic investigation showed that hyperoside alleviated LPS-induced inflammation, oxidative stress, and apoptosis by upregulating SIRT1 to activate Wnt/β-catenin and sonic hedgehog pathways. Taken together, our data suggested that hyperoside acts as a protector in neuroinflammation. [ABSTRACT FROM AUTHOR]

Objective: Neurotrophins are known to influence the development and maturation of the feto‐placental unit and affect fetal growth trajectories. This study reports the levels of nerve growth factor (NGF) and brain‐derived growth factor (BDNF) in the placenta of women with gestational diabetes mellitus (GDM). Methods: A total number of 60 women with GDM and 70 women without GDM (non‐GDM) were included in the study. Placental NGF and BDNF levels were measured using commercially available ELISA kits. Results: Placental NGF levels were lower (p <.05) in women with GDM compared to non‐GDM women. Maternal body mass index (BMI), mode of delivery, and the gender of the baby influenced the placental NGF levels. Placental BDNF levels were similar in GDM and non‐GDM women. There was an influence of baby gender on the placental BDNF levels while maternal BMI and mode of delivery did not show any effect. In regression models adjusted for maternal age at delivery, gestational age, maternal BMI, mode of delivery, and baby gender, the placental NGF levels in the GDM group were lower (−0.144 pg/ml [95% CI −0.273, 22120.016] p =.028) as compared to the non‐GDM group. However, there was no difference in the BDNF levels between the groups. Conclusion: This study for the first time demonstrates differential effects on neurotrophic factors such as BDNF and NGF in the placenta in pregnancies complicated by GDM. Alterations in the levels of placental neurotrophins in GDM deliveries may affect placental development and fetal brain growth. This has implications for increased risk for neurodevelopmental pathologies in later life. [ABSTRACT FROM AUTHOR]

Laminins (LMs) are important structural proteins of the extracellular matrix (ECM). The abundance of every LM isoform is tissue‐dependent, suggesting that LM has tissue‐specific roles. LM binds growth factors (GFs), which are powerful cytokines widely used in tissue engineering due to their ability to control stem cell differentiation. Currently, the most commonly used ECM mimetic material in vitro is Matrigel, a matrix of undefined composition containing LM and various GFs, but subjected to batch variability and lacking control of physicochemical properties. Inspired by Matrigel, a new and completely defined hydrogel platform based on hybrid LM‐poly(ethylene glycol) (PEG) hydrogels with controllable stiffness (1–25 kPa) and degradability is proposed. Different LM isoforms are used to bind and efficiently display GFs (here, bone morphogenetic protein (BMP‐2) and beta‐nerve growth factor (β‐NGF)), enabling their solid‐phase presentation at ultralow doses to specifically target a range of tissues. The potential of this platform to trigger stem cell differentiation toward osteogenic lineages and stimulate neural cells growth in 3D, is demonstrated. These hydrogels enable 3D, synthetic, defined composition, and reproducible cell culture microenvironments reflecting the complexity of the native ECM, where GFs in combination with LM isoforms yield the full diversity of cellular processes. [ABSTRACT FROM AUTHOR]

Reduced nerve growth factor (NGF) is associated with cardiac sympathetic nerve denervation in heart failure (HF) which is characterized by increased oxidative stress. Apocynin is considered an antioxidant agent which inhibits NADPH oxidase activity and improves reactive oxygen species scavenging. However, it is unclear whether apocynin prevents reduced myocardial NGF, leading to improvement of cardiac function in HF. In this study, we tested the hypothesis that apocynin prevents reduced myocardial NGF, contributing to amelioration of myocardial apoptosis and failure. Rabbits with myocardial infarction (MI) or sham operation were randomly assigned to receive apocynin or placebo for 4 weeks. MI rabbits exhibited left ventricular (LV) dysfunction, and elevation in oxidative stress, as evidenced by a decreased reduced‐to‐oxidized glutathione ratio and an increased 4‐hydroxynonenal expression, and reduction in NGF and NGF receptor tyrosine kinase A (TrKA) expression in the remote non‐infarcted myocardium. Apocynin treatment ameliorated LV dysfunction, reduced oxidative stress, prevented decreases in NGF and TrKA expression and reduced cardiomyocyte apoptosis after MI. In cultured H9C2 cardiomyocytes, hypoxia or hydrogen peroxide decreased NGF expression, and apocynin normalized hypoxia‐induced reduction of NGF. Recombinant NGF attenuated hypoxia‐induced apoptosis. Apocynin prevented hypoxia‐induced apoptosis, and the suppressive effect of apocynin on apoptosis was abolished by NGF receptor TrKA inhibitor K252a. We concluded that apocynin prevented reduced myocardial NGF, leading to attenuation of cardiomyocyte apoptosis and LV remodelling and dysfunction in HF after MI. These findings suggest that strategies to prevent NGF reduction by inhibition of oxidative stress may be of value in amelioration of LV dysfunction in HF. [ABSTRACT FROM AUTHOR]

Background: Brain‐derived neurotrophic factor (BDNF) and neurotrophin receptors have been recognized as fundamental regulators of normal brain development, homeostasis, and plasticity. They have also been studied in the behavior of central nervous system tumors. Here, we studied the pattern of BDNF, TrkB and p75NTR immunoexpression in peripheral benign and malignant neural lesions in head and neck. Methods: This cross‐sectional analytical study included 79 cases of head and neck neural lesions. Nineteen cases of traumatic neuromas (TN), 20 cases of granular cell tumors (GCT), 16 cases of neurofibromas (NF), 20 cases of schwannomas (SC), and 4 malignant peripheral nerve sheath tumor (MPNST) were submitted to immunohistochemistry with BDNF, TrkB, and p75NTR antibodies. A semi‐quantitative analysis was performed. Results: The analysis of BDNF demonstrated a high percentage of positive cells in TN, GCT and SC with a decrease in cases of NF and MPNST. TrkB presented a lower significant immunoexpression in GCT in relation to the TN, NF, SC, and MPNST (P <.0001); and TN showed less percentage of positive cell compared to SC (P =.0017). Regarding p75NTR, the percentage of positive cell was significantly reduced in MPNST compared GCT (P =.009), NF (P =.0138) and SC (P =.0069). Also, a decrease in TN compared to GCT (P =.007) was observed. Conclusions: Our results showed the immunoreactivity of BDNF, TrkB, and p75NTR in head and neck peripheral neural lesions. Reduction of BDNF and p75NTR in MPNST might suggest down‐regulation during the acquisition of malignant phenotype. [ABSTRACT FROM AUTHOR]

Late thrombosis and restenosis remain major challenges to the safety of drug-eluting stents. Biofunctional modification to endow the surface with selective anticoagulation and promote endothelium regeneration has become a hotpot recently. In this study, chitosan and heparin were found to form three-dimensional nanoparticles by spontaneous electrostatic interaction. Based on the specific binding properties between heparin and nerve growth factor (NGF), a new type of NGF-loaded heparin/chitosan nanoparticles was constructed for surface modification. The results of material characterization show that the nanoparticles are successfully immobilized on the surface of the material. In vitro blood compatibility and endothelial cell compatibility assay showed that the modified surface could selectively inhibit platelet adhesion and smooth muscle cell overproliferation, while accelerating endothelialization via promoting endothelial cell proliferation and enhancing endothelial progenitor cell mobilization. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the expression of genes and proteins involved in the urethral components: vessels, nerves, and extracellular matrix, in female rats after trauma by vaginal distension (VD) and after electrical stimulation therapy (electrotherapy). Methods: We analyzed the urethras of three groups of 18 female rats 30 days posttrauma by VD: control (no interventions); trauma (animals that had VD); and electrotherapy group (those that had VD and were treated with electrical stimulation). We compared the expression of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), collagen types I and III (COL1a1 and COL3a1), and lysyl‐oxidase like 1 (LOXL1) among the groups. Real‐time reverse transcription‐polymerase chain reaction, Western blot, and immunohistochemistry were used for molecule quantification. We used the Kruskal–Wallis test and analysis of variance for statistical analyses with p < 0.05 for significance. Results: The COL1a1 gene expression was higher in the electrotherapy group than the trauma group (p = 0.036). COL3a1, VEGF, NGF, LOXL1 messenger RNA (mRNA) expression did not differ among the groups (p ≥ 0.05). COL1a1, COL3a1, VEGF, NGF, LOXL1 protein levels did not significantly differ among the groups (p ≥ 0.05) in Western blot analysis or immunohistochemistry assays. Conclusions: Electrotherapy caused a long‐term increase in the COL1a1 mRNA level but did not change COL1a1 protein expression or VEGF, NGF, COL3a1, and LOXL1 genes and proteins in the urethras of rats after trauma by VD. [ABSTRACT FROM AUTHOR]