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Introduction: Cancer stem cells (CSCs) shape the tumor microenvironment via neuroendocrine signaling and orchestrate drug resistance and metastasis. Cytokine antibody array demonstrated the upregulation of neurotrophin-3 (NT-3) in lung CSCs. This study aims to dissect the role of NT-3 in lung CSCs during tumor innervation. Methods: Western blotting, quantitative reverse transcription-PCR, and flow cytometry were used to determine the expression of the NT-3 axis in lung CSCs. NT-3-knockdown and NT-3-overexpressed cells were derived lung CSCs, followed by examining the stemness gene expression, tumorsphere formation, transwell migration and invasion, drug resistance, soft agar colony formation, and in vivo tumorigenicity. Human lung cancer tissue microarray and bioinformatic databases were used to investigate the clinical relevance of NT-3 in lung cancer. Results: NT-3 and its receptor tropomyosin receptor kinase C (TrkC) were augmented in lung tumorspheres. NT-3 silencing (shNT-3) suppressed the migration and anchorage-independent growth of lung cancer cells. Further, shNT-3 abolished the sphere-forming capability, chemo-drug resistance, invasion, and in vivo tumorigenicity of lung tumorspheres with a decreased expression of CSC markers. Conversely, NT-3 overexpression promoted migration and anchorage-independent growth and fueled tumorsphere formation by upregulating the expression of CSC markers. Lung cancer tissue microarray analysis revealed that NT-3 increased in patients with advanced-stage, lymphatic metastasis and positively correlated with Sox2 expression. Bioinformatic databases confirmed a co-expression of NT-3/TrkC-axis and demonstrated that NT-3, NT-3/TrkC, NT-3/Sox2, and NT-3/CD133 worsen the survival of lung cancer patients. Conclusion: NT-3 conferred the stemness features in lung cancer during tumor innervation, which suggests that NT-3-targeting is feasible in eradicating lung CSCs. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum lipoprotein-associated phospholipase A2 (Lp-PLA2), neurotrophin-3 (NT-3) levels and rapid eye movement sleep behavior disorder (RBD) in patients with Parkinson’s disease (PD). Methods: 150 PD patients admitted to Zigong Hospital Affiliated to Southwest Medical University were selected as the PD group from January 2021 to December 2022, and at the same time, selected 55 healthy individuals who underwent physical examinations in our hospital as the control group. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum levels of Lp-PLA2 and NT-3. The PD group was divided into RBD group and non RBD group based on the physical signs and RBD questionnaire Hong Kong version (RBDQ-HK) score. Univariate and multivariate logistic regression were used to analyze the influencing factors in PD patients concomitant with RBD, and the predictive efficacy of serum Lp-PLA2 and NT-3 in PD patients concomitant with RBD was analyzed by receiver operating characteristic curve (ROC) curve. Results: The serum Lp-PLA2 level in the control group was lower than that in the PD group (P＜0.05), and the serum NT-3 level was higher than that in the PD group (P＜0.05). The results of univariate analysis showed that the PD patients concomitant with RBD was associated with age, course of disease, and serum levels of Lp-PLA2 and NT-3 (P＜0.05). Multivariate logistic regression analysis showed that prolonged course of disease, elevated Lp-PLA2 levels were independent risk factors for PD with RBD, while elevated NT-3 levels were protective factors for PD concomitant with RBD (P＜0.05). The area under the curve (AUC) of serum Lp-PLA2, NT-3,and combined detection for predicting PD concomitant with RBD were 0.830, 0.766, and 0.866, respectively. Conclusion: Serum Lp-PLA2 and NT-3 are associated with PD patients concomitant with RBD. Elevated serum Lp-PLA2 is an independent risk factor, while elevated serum NT-3 is a protective factor. The combined detection of these two indicators has high predictive value for PD concomitant with RBD. [ABSTRACT FROM AUTHOR]

The goal of this work was to design a polymer-based platform capable of localized, long-term delivery of biologically active neurotropic factors using an affinity-based approach. Here, we synthesized hyaluronic acid-methylfuran (HA-mF) hydrogels that provide sustained, affinity-based release of neurotrophin-3 (NT-3), a growth factor that promotes axon growth for 28 days. A Diels-Alder crosslinking reaction between HA-mF and polyethylene glycol (PEG)-dimaleimide occurs within 15 min under physiological conditions, resulting in hydrogels that can be polymerized in the presence of cells and growth factors. We also tuned the hydrogel's storage modulus to match that of native rat spinal cord tissue, providing a platform not only for localized drug delivery but also a suitable vehicle for cellular transplantation. The NT-3 released from the HAmF hydrogels remains bioactive for at least 14 days, promoting axonal growth from primary sensory neurons as well as stem cell-derived V2a interneurons and motoneurons in vitro. The hydrogels also supported cell growth allowing for 3-dimensional axonal extensions within the scaffold matrix. Here we confirm the protective role of HA-mF on matrix-bound NT-3 activity and show that these hydrogels are an excellent platform for growth factor delivery for neural applications. [ABSTRACT FROM AUTHOR]

Hemodialyzed patients have innate immunity activation and adaptive immunity senescence. Diabetes mellitus is a frequent cause for chronic kidney disease and systemic inflammation. We studied the immunological pattern (innate and acquired immunity) and the tissular regeneration capacity in two groups of hemodialyzed patients: one comprised of diabetics and the other of non-diabetics. For inflammation, the following serum markers were determined: interleukin 6 (IL-6), interleukin 1β (IL-1β), tumoral necrosis factor α (TNF-α), IL-6 soluble receptor (sIL-6R), NGAL (human neutrophil gelatinase-associated lipocalin), and interleukin 10 (IL-10). Serum tumoral necrosis factor β (TNF-β) was determined as a cellular immune response marker. Tissue regeneration capacity was studied using neurotrophin-3 (NT-3) and vascular endothelial growth factor β (VEGF-β) serum levels. The results showed important IL-6 and sIL-6R increases in both groups, especially in the diabetic patient group. IL-6 generates trans-signaling at the cellular level through sIL-6R, with proinflammatory and anti-regenerative effects, confirmed through a significant reduction in NT-3 and VEGF-β. Our results suggest that the high serum level of IL-6 significantly influences IL-1β, TNF-β, NT-3, VEGF-β, and IL-10 behavior. Our study is the first that we know of that investigates NT-3 in this patient category. Moreover, we investigated VEGF-β and TNF-β serum behavior, whereas most of the existing data cover only VEGF-α and TNF-α in hemodialyzed patients. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells (iPSCs) can be personalized and differentiated into neural stem cells (NSCs), thereby effectively providing a source of transplanted cells for spinal cord injury (SCI). To further improve the repair efficiency of SCI, we designed a functional neural network tissue based on TrkC-modified iPSC-derived NSCs and a CBD-NT3-modified linear-ordered collagen scaffold (LOCS). We confirmed that transplantation of this tissue regenerated neurons and synapses, improved the microenvironment of the injured area, enhanced remodeling of the extracellular matrix, and promoted functional recovery of the hind limbs in a rat SCI model with complete transection. RNA sequencing and metabolomic analyses also confirmed the repair effect of this tissue from multiple perspectives and revealed its potential mechanism for treating SCI. Together, we constructed a functional neural network tissue using human iPSCs-derived NSCs as seed cells based on the interaction of receptors and ligands for the first time. This tissue can effectively improve the therapeutic effect of SCI, thus confirming the feasibility of human iPSCs-derived NSCs and LOCS for SCI repair and providing a valuable direction for SCI research.

Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and the therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (Nt3) mRNA and NT3 protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking NT3 upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking this increase produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, NT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C–C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, NT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. NT3 may be thus a potential target for CINP treatment. Synopsis: Neurotrophin-3 (NT3) activates tropomyosin receptor kinase C (TrkC) to elevate C–C chemokine ligand 2 (CCL2) in dorsal root ganglion neurons contributing to paclitaxel-induced neuropathic pain. NT3 expression is increased in DRG neurons after systemic paclitaxel injection. Blocking this increase inhibits paclitaxel-induced nociceptive hypersensitivity. The inhibitory effect is mediated by preventing NT3-triggered TrkC activation and subsequent CCL2 production in DRG neurons. Neurotrophin-3 (NT3) activates tropomyosin receptor kinase C (TrkC) to elevate C-C chemokine ligand 2 (CCL2) in dorsal root ganglion neurons contributing to paclitaxel-induced neuropathic pain. [ABSTRACT FROM AUTHOR]

A dimeric dipeptide mimetic based on the β-turn of the 4th loop of neurotrophin-3, bis-(N-monosuccinyl-L-asparaginyl-L-asparagine)hexamethylenediamide (GTS-301LL), was recently designed and synthesized by us. GTS-301, like the full-length neurotrophin, activated TrkC and TrkB receptors and exhibited neuroprotective activity on HT22 cells under oxidative stress conditions in the concentration range 10–5 – 10–12 M and antidepressant-like activity in the forced swimming test in mice (10 – 40 mg/kg, intraperitoneally). The stereospecificity of the pharmacological effects of GTS-301LL was revealed by synthesizing the LD, DL, and DD stereoisomers of GTS-301LL and studying their neuroprotective and antidepressant-like properties under the same conditions as for GTS-301LL. Both activities were found to disappear on going from the LL to the DL and DD stereoisomers and were retained on going to the LD stereoisomer. Thus, the stereospecificity of the neuroprotective and antidepressant-like activities of the dipeptide mimetic of neurotrophin-3 GTS-301LL at the N-terminal asparagine residue was proven, which indicated the key role of that amino-acid residue in the interaction with the receptor. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to determine the effect of regular exercise on aerobic capacity, strength values, and plasma levels of Nerve Growth Factor (NGF) and Neurotrophin-3 (NT-3) in patients with multiple sclerosis (MS) and investigate its effects on MS symptoms including cognitive impairment, fatigue, balance disorders, and quality of life (QOL). Methods: Forty-three relapsing-remitting MS patients with an Expanded Disability Status Scale (EDSS) score of 4 or less participated in the study. Participants were divided into three groups: aerobic group, strength group, and control group. The patients in the exercise groups had exercise programs three days a week for three months. Aerobic capacity (maximum VO2 value), strength measurements, and balance tests were done, and NGF and NT-3 plasma levels were analyzed in all participants at the beginning and end of the study. Multiple Sclerosis Quality of Life- 54 (MSQoL-54), fatigue impact scale, Pittsburgh Sleep Quality Index (PSQI) and, to evaluate cognitive functions, BICAMS scale were applied. Results: Aerobic exercise and strength exercise groups had significant increases in VO2 max, back and leg strength values, and NGF and NT-3 plasma levels (p<0.01). Cognitive functions, fatigue, sleep quality, and QOL significantly improved in the exercise groups (p<0.01). The balance values were also significantly improved in the aerobic group (p<0.01), and although improvement although improvement was observed in the strength group, it was not statistically significant (p>0.05). Conclusions: Our study provides evidence that regular exercise improves quality of life, cognitive functions, fatigue, and sleep quality in MS patients. The levels of NGF and NT-3, which are important factors in neural regeneration and remyelination, were increased post exercise. It can be suggested that exercise may have a potential effect on MS and slow down the disease process with these results. [ABSTRACT FROM AUTHOR]

Abstract Background Maintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms. Methods Western blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote peripheral nerve regeneration after chronic denervation. Results After peripheral nerve injury, c-Jun expression progressively increased until week 5 and then began to decrease in the distal nerve following denervation. NT-3 upregulated the expression of c-Jun in denervated Schwann cells, both in vitro and in vivo. NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The TrkC receptor was consistently presented on denervated Schwann cells and served as NT-3 receptors following chronic denervation. NT-3 mainly upregulated c-Jun through the TrkC/ERK pathway. Conclusion NT-3 promotes peripheral nerve regeneration by maintaining the repair phenotype of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. It provides a potential target for the clinical treatment of peripheral nerve injury after chronic denervation.

Hemodialyzed patients have innate immunity activation and adaptive immunity senescence. Diabetes mellitus is a frequent cause for chronic kidney disease and systemic inflammation. We studied the immunological pattern (innate and acquired immunity) and the tissular regeneration capacity in two groups of hemodialyzed patients: one comprised of diabetics and the other of non-diabetics. For inflammation, the following serum markers were determined: interleukin 6 (IL-6), interleukin 1β (IL-1β), tumoral necrosis factor α (TNF-α), IL-6 soluble receptor (sIL-6R), NGAL (human neutrophil gelatinase-associated lipocalin), and interleukin 10 (IL-10). Serum tumoral necrosis factor β (TNF-β) was determined as a cellular immune response marker. Tissue regeneration capacity was studied using neurotrophin-3 (NT-3) and vascular endothelial growth factor β (VEGF-β) serum levels. The results showed important IL-6 and sIL-6R increases in both groups, especially in the diabetic patient group. IL-6 generates trans-signaling at the cellular level through sIL-6R, with proinflammatory and anti-regenerative effects, confirmed through a significant reduction in NT-3 and VEGF-β. Our results suggest that the high serum level of IL-6 significantly influences IL-1β, TNF-β, NT-3, VEGF-β, and IL-10 behavior. Our study is the first that we know of that investigates NT-3 in this patient category. Moreover, we investigated VEGF-β and TNF-β serum behavior, whereas most of the existing data cover only VEGF-α and TNF-α in hemodialyzed patients.

Treatment of patients with NTRK fusion-positive cancers using first-generation tropomyosin-related kinase (Trk) inhibitors is associated with high response rates, regardless of tumor histology. However, there have been few studies on neurotrophin-3 (NTF3) and TrkC ligands in hepatocellular carcinoma (HCC). We used immunohistochemistry to evaluate NTF3 and TrkC expression levels in tissue samples. Gene expression profiling interactive analysis was used to determine TrkC and NTF3 expression in HCC. Western blotting, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assays were utilized to analyze TrkC and NTF3 levels in HCC cell lines. Proliferation tests and cell migration were also explored. NTF3 and TrkC levels were lower in HCC tissue (median H- scores 149.09 and 54.60, respectively) than those in para-cancerous tissue (192.69 and 71.70, respectively); no statistical difference was found in the survival rate. Positive correlations were observed between NTF3 and TrkC levels in both HCC and para-cancerous tissues. Alpha-fetoprotein was the only clinical characteristic associated with TrkC levels. The transcription of NTF3 was lower in HCC samples compared to normal samples. NTF3 overexpression inhibited the proliferation of MHCC97-L and HepG2 cells but did not significantly affect cell migration. The transcription of NTF3 was lower in HCC samples compared to normal samples, indicating a potential association with disease-free survival and overall survival in HCC. NTF3 and TrkC expression levels were lower in HCC tissues than those in para-cancerous tissues. Our results indicate that NTF3 may be a prognostic factor for HCC. [ABSTRACT FROM AUTHOR]

[Display omitted] A novel neurotrophin-3 loop 4 dipeptide mimetic, bis(N -γ-hydroxybutyryl-L-glutamyl-L-asparagine) hexamethylenedi-amide (GTS-302), was designed and synthesized. Compound GTS-302 activated the tyrosine kinase receptors TrkC and TrkB, exhibited cytoprotective activity (10-8–10-5 M) in oxidative stress model in HT-22 cells and in 6-hydroxy-dopamine-induced SH-SY5Y cell damage. It also demon- strated an antidepressant-like activity in the forced swim test in mice (0.5–10.0 mg kg–1, intraperitoneally). [ABSTRACT FROM AUTHOR]

Postoperative cognitive decline (POCD) is a common and serious complication following anesthesia and surgery; however, the precise mechanisms of POCD remain unclear. Our previous research showed that sevoflurane impairs adult hippocampal neurogenesis (AHN) and thus cognitive function in the aged brain by affecting neurotrophin‐3 (NT‐3) expression; however, the signaling mechanism involved remains unexplored. In this study, we found a dramatic decrease in the proportion of differentiated neurons with increasing concentrations of sevoflurane, and the inhibition of neural stem cell differentiation was partially reversed after the administration of exogenous NT‐3. Understanding the molecular underpinnings by which sevoflurane affects NT‐3 is key to counteracting cognitive dysfunction. Here, we report that sevoflurane administration for 2 days resulted in upregulation of histone deacetylase 9 (HDAC9) expression, which led to transcriptional inactivation of cAMP‐response element binding protein (CREB). Due to the colocalization of HDAC9 and CREB within cells, this may be related to the interaction between HDAC9 and CREB. Anyway, this ultimately led to reduced NT‐3 expression and inhibition of neural stem cell differentiation. Furthermore, knockdown of HDAC9 rescued the transcriptional activation of CREB after sevoflurane exposure, while reversing the downregulation of NT‐3 expression and inhibition of neural stem cell differentiation. In summary, this study identifies a unique mechanism by which sevoflurane can inhibit CREB transcription through HDAC9, and this process reduces NT‐3 levels and ultimately inhibits neuronal differentiation. This finding may reveal a new strategy to prevent sevoflurane‐induced neuronal dysfunction. [ABSTRACT FROM AUTHOR]

Background: Maintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms. Methods: Western blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote peripheral nerve regeneration after chronic denervation. Results: After peripheral nerve injury, c-Jun expression progressively increased until week 5 and then began to decrease in the distal nerve following denervation. NT-3 upregulated the expression of c-Jun in denervated Schwann cells, both in vitro and in vivo. NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The TrkC receptor was consistently presented on denervated Schwann cells and served as NT-3 receptors following chronic denervation. NT-3 mainly upregulated c-Jun through the TrkC/ERK pathway. Conclusion: NT-3 promotes peripheral nerve regeneration by maintaining the repair phenotype of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. It provides a potential target for the clinical treatment of peripheral nerve injury after chronic denervation. [ABSTRACT FROM AUTHOR]

The semi-permeable round window membrane (RWM) is the gateway to the cochlea. Although the RWM is considered a minimally invasive and clinically accepted route for localised drug delivery to the cochlea, overcoming this barrier is challenging, hindering development of effective therapies for hearing loss. Neurotrophin 3 (NT3) is an emerging treatment option for hearing loss, but its therapeutic effect relies on sustained delivery across the RWM into the cochlea. Silica supraparticles (SPs) are drug delivery carriers capable of providing long-term NT3 delivery, when injected directly into the guinea pig cochlea. However, for clinical translation, a RWM delivery approach is desirable. Here, we aimed to test approaches to improve the longevity and biodistribution of NT3 inside the cochlea after RWM implantation of SPs in guinea pigs and cats. Three approaches were tested (i) coating the SPs to slow drug release (ii) improving the retention of SPs on the RWM using a clinically approved gel formulation and (iii) permeabilising the RWM with hyaluronic acid. A radioactive tracer (iodine 125: 125I) tagged to NT3 (125I NT3) was loaded into the SPs to characterise drug pharmacokinetics in vitro and in vivo. The neurotrophin-loaded SPs were coated using a chitosan and alginate layer-by-layer coating strategy, named as '(Chi/Alg)SPs', to promote long term drug release. The guinea pigs were implanted with 5× 125I NT3 loaded (Chi/Alg) SPs on the RWM, while cats were implanted with 30× (Chi/Alg) SPs. A cohort of animals were also implanted with SPs (controls). We found that the NT3 loaded (Chi/Alg)SPs exhibited a more linear release profile compared to NT3 loaded SPs alone. The 125I NT3 loaded (Chi/Alg)SPs in fibrin sealant had efficient drug loading (~5 μg of NT3 loaded per SP that weights ~50 μg) and elution capacities (~49% over one month) in vitro. Compared to the SPs in fibrin sealant, the (Chi/Alg)SPs in fibrin sealant had a significantly slower 125I NT3 drug release profile over the first 7 days in vitro (~12% for (Chi/Alg) SPs in fibrin sealant vs ~43% for SPs in fibrin sealant). One-month post-implantation of (Chi/Alg) SPs, gamma count measurements revealed an average of 0.3 μg NT3 remained in the guinea pig cochlea, while for the cat, 1.3 μg remained. Histological analysis of cochlear tissue revealed presence of a 125I NT3 signal localised in the basilar membrane of the lower basal turn in some cochleae after 4 weeks in guinea pigs and 8 weeks in cats. Comparatively, and in contrast to the in vitro release data, implantation of the SPs presented better NT3 retention and distribution inside the cochlea in both the guinea pigs and cats. No significant difference in drug entry was observed upon acute treatment of the RWM with hyaluronic acid. Collectively, our findings indicate that SPs and (Chi/Alg)SPs can facilitate drug transfer across the RWM, with detectable levels inside the cat cochlea even after 8 weeks with the intracochlear approach. This is the first study to examine neurotrophin pharmacokinetics in the cochlea for such an extended period of times in these two animal species. Whilst promising, we note that outcomes between animals were variable, and opposing results were found between in vitro and in vivo release studies. These findings have important clinical ramifications, emphasising the need to understand the physical properties and mechanics of this complex barrier in parallel with the development of therapies for hearing loss. [Display omitted] • Supraparticles are a viable approach to deliver neurotrophin to the cochlea. • Neurotrophin was detected in the cochlea 8 weeks post-supraparticle implantation. • Variable drug distribution after round membrane implantation of supraparticles. • Coated supraparticles improve the longevity of drug elution in vitro , but not in vivo. [ABSTRACT FROM AUTHOR]

Bio-factor stimulation is essential for axonal regeneration in the central nervous system. Thus, persistent and efficient factor delivery in the local microenvironment is an ideal strategy for spinal cord injury repair. We developed a biomimetic hydrogel scaffold to load biofactors in situ and release them in a controlled way as a promising therapeutic modality. Hyaluronic acid and silk fibroin were cross-linked as the basement of the scaffolds, and poly-dopamine coating was used to further increase the loading of factors and endow the hydrogel scaffolds with ideal physical and chemical properties and proper biocompatibility. Notably, neurotrophin-3 release from the hydrogel scaffolds was prolonged to 28 days. A spinal cord injury model was constructed for hydrogel scaffold transplantation. After eight weeks, significant NF200-positive nerve fibers were observed extending across the glial scar to the center of the injured area. Due to the release of neurotrophin-3, spinal cord regeneration was enhanced, and the cavity area of the injury graft site and inflammation associated with CD68 positive cells were reduced, which led to a significant improvement in hind limb motor function. The results show that the hyaluronic acid/silk fibroin/poly-dopamine-coated biomimetic hydrogel scaffold achieved locally slow release of neurotrophin-3, thus facilitating the regeneration of injured spinal cord. Hydrogels have received great attention in spinal cord regeneration. Current research has focused on more efficient and controlled release of bio-factors. Here, we adopted a mussel-inspired strategy to functionalize the hyaluronic acid/silk fibroin hydrogel scaffold to increase the load of neurotrophin-3 and extend the release time. The hydrogel scaffolds have ideal physiochemical properties, proper release rate, and biocompatibility. Owing to the continuous neurotrophin-3 release from implanted scaffolds, cavity formation is reduced, inflammation alleviated, and spinal cord regeneration enhanced, indicating great potential for bio-factor delivery in soft tissue regeneration applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Microglial cells play an important role in neuroinflammation and secondary damages after spinal cord injury (SCI). Progressive microglia/macrophage inflammation along the entire spinal axis follows SCI, and various factors may determine the microglial activation profile. Neurotrophin-3 (NT-3) is known to control the survival of neurons, the function of synapses, and the release of neurotransmitters, while also stimulating axon plasticity and growth. We examined the effects of whole-body vibration (WBV) and forms of assisted locomotor therapy, such as passive flexion–extension (PFE) therapy, at the neuronal level after SCI, with a focus on changes in NT-3 expression and on microglia/macrophage reaction, as they play a major role in the reconstitution of CNS integrity after injury and they may critically account for the observed structural and functional benefits of physical therapy. More specifically, the WBV therapy resulted in the best overall functional recovery when initiated at day 14, while inducing a decrease in Iba1 and the highest increase in NT-3. Therefore, the WBV therapy at the 14th day appeared to be superior to the PFE therapy in terms of recovery. Functional deficits and subsequent rehabilitation depend heavily upon the inflammatory processes occurring caudally to the injury site; thus, we propose that increased expression of NT-3, especially in the dorsal horn, could potentially be the mediator of this favorable outcome.

Introduction: Neurotrophin-3 (NT3) is a neuroprotective growth factor that induces the development, maintenance and survival of neurons. This study aims to localize NT3-expressing cells in the adult zebrafish brain and examine the role of NT3 in a zebrafish Parkinson’s disease (PD) model.Methods: Cellular localization of NT3 in adult zebrafish brains was conducted using in situ hybridization. Subsequently, adult zebrafish were injected intraperitoneally with 100 μg/g of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 400 ng/g body weight of recombinant NT3 (rNT3) via intracranial injection 24 h following MPTP injection. The fish were assessed for neurobehavioral, gene expression, immunohistology, and protein analysis on days 3, 5 and 10 post-MPTP injection.Results: Our findings showed that NT3 was extensively expressed throughout the adult zebrafish brain in neurons. Administration of rNT3 has significantly improved locomotor activity, with upregulation of th1, dat, ntf3 and bdnf gene expressions compared to MPTP-induced zebrafish. Dopaminergic neurons were also significantly increased in the zebrafish brain following rNT3 treatment. ELISA analysis reported raised GST and decreased caspase-3 levels on day 3 of assessment. The trophic changes of rNT3, however, decline as the assessment day progresses.Conclusion: This study is the first to examine the role of NT3 in the adult zebrafish PD model. NT3 has remarkable trophic effects in the zebrafish PD model. However, further study is needed to examine the dosage requirements and long-term effects of NT3 in PD.

Objectives: Synaptic plasticity markers are known to alter in schizophrenia. The objective of the study was to investigate the genotype and allele frequency of neurotrophin-3 (NT-3) gene polymorphism (rs6489630, rs6332, and rs11063714) and plasma NT-3 levels in schizophrenia and their relation with cognitive status. Materials and Methods: The study was conducted on 216 Schizophrenia patients and 216 controls. Single-nucleotide polymorphism (SNP) of NT-3 and its plasma levels were assessed in both groups. Cognitive status was evaluated using Addenbrooke Cognitive examination-III scores. Results: The rs6489630 polymorphism was found to be significantly associated with the severity of schizophrenia (P = 0.004). The CT genotype (P = 0.02, OR = 1.631 [1.10-2.43]) and minor allele T (P = 0.004, OR = 1.58 [1.16-2.16]) of rs6489630 conferred an increased susceptibility to develop schizophrenia. The rs6332 variant was found to affect cognitive status significantly in schizophrenia (P = 0.040), and memory dysfunction was seen in individuals with AG (P < 0.01) and AA variant (P = 0.03) of rs6332. Conclusion: We conclude that SNPs of NT-3 enhance the risk of schizophrenia and are related to cognitive dysfunction. [ABSTRACT FROM AUTHOR]

BACKGROUND: Non-invasive treatment of spinal cord injury needs to be developed urgently. Nanomaterials have obvious advantages, which can deliver drugs and improve the therapeutic effect. OBJECTIVE: To fabricate sustained-release nanospheres containing neurotrophin-3 and ganglioside GD1a by poly(lactic-co-glycolic acid) and investigate their effects on the repair of spinal cord injury in rats. METHODS: Poly(lactic-co-glycolic acid) nanospheres encapsulated with neurotrophin-3 and ganglioside GD1a were prepared using oil-water emulsion volatile organic solvent method. The sustained release properties of microspheres were tested. Sixty female adult SD rats were randomly divided into five groups with 12 rats in each group. In the sham operation group, the lamina was opened and sutured directly. In the spinal cord injury group, a spinal cord T9 impingement injury model was established. In the neurotrophin group, the nanosphere suspension of slow-release neurotrophin-3 was injected into the injured area of spinal cord T9. In the ganglioside GD1a group, the sustained-release ganglioside GD1a nanosphere suspension was injected into the spinal cord T9 injury area. The experimental group was injected with nanosphere suspension of sustained-release neurotrophin-3 and ganglioside GD1a in the injured area of spinal cord T9. Open field test and BBB scoring were conducted weekly after operation. The sections were taken 4 and 8 weeks after surgery for morphological observation. RESULTS AND CONCLUSION: (1) After soaking in PBS for 14 days in vitro, the sustained-release nanospheres could continuously release neurotrophin-3 and ganglioside GD1a. (2) At 7 and 8 weeks after surgery, compared with the spinal cord injury group, the BBB score and the total open field distance of the rats increased in the neurotrophin group and the experimental group (P < 0.05). The results of Nissl staining showed that at 4 and 8 weeks after surgery, the number of motor neurons increased in the anterior horn of caudal gray matter in the experimental group compared with the spinal cord injury group (P < 0.05). At 8 weeks after surgery, the number of motor neurons increased in the anterior horn of caudal gray matter in the neurotrophin group compared with the spinal cord injury group (P < 0.05). The results of immunofluorescence staining showed that compared with the spinal cord injury group, the neurotrophin group at 8 weeks and the experimental group at 4 and 8 weeks had increased spinal white matter ventral nerve fibers (P < 0.05); the expression of myelin basic protein on the ventral side of the spinal cord white matter increased at 4 and 8 weeks in the ganglioside GD1a and experimental groups (P < 0.05); the expression of myelin basic protein in the neurotrophin group increased at 8 weeks after operation (P < 0.05); the descending propriospinal tract increased in the neurotrophin group and the experimental group at 8 weeks (P < 0.05). (3) The results showed that neurotrophin-3 microspheres alone or in combination with ganglioside GD1a microspheres could promote the survival of motor neurons and nerve fibers around the spinal cord injury site and improve the motor function of the hind limbs of rats. [ABSTRACT FROM AUTHOR]

Damage to the peripheral nervous system (PNS) is a common complication of breast cancer (BC) treatment, with 60 to 80% of breast cancer survivors experiencing symptoms of PNS damage. In the current study, the levels of brain-derived neurotrophic factor (BDNF), galectin-3 (Gal-3), and neurotrophin-3 (NT-3) were measured in the blood serum of BC patients by ELISA as potential biomarkers that might indicate the PNS damage. Sixty-seven patients were enrolled in this multi-center trial and compared to the aged-matched healthy female volunteers (control group) (n = 25). Intergroup comparison of biomarker levels (i.e., Gal-3 and BDNF) did not show significant differences in any of the studied subgroups. However, intriguingly, NT-3 levels were significantly higher in BC patients as compared to healthy volunteers, constituting 14.85 [10.3; 18.0] and 5.74 [4.56; 13.7] pg/mL, respectively (p < 0.001). In conclusion, NT-3 might be employed as a potential biomarker in BC patients with clinical manifestations of PNS damage. However, further studies to validate its correlation to the degree of peripheral nervous system lesions are of high value. [ABSTRACT FROM AUTHOR]

Background : Epilepsy is one of the most common neurological disorders, and it places a significant economic strain on the healthcare system around the world. Although the exact mechanism of epilepsy has yet to be illustrated, various pathogenic cascades involving neurotransmitters and trace elements have been reported. We aimed to investigate the serum levels of growth-associated protein-43 (GAP-43) and neurotrophin-3 (NT-3) among cohort of Egyptian children with epilepsy and correlate these biomarkers with their zinc levels. Methods: This case–control study included 50 pediatric patients with epilepsy who were comparable with 50 controls. Neurological assessment and electroencephalogram (EEG) were done to all included children. Biochemical measurements of serum GAP-43 and NT-3 using enzyme linked immunosorbent assays (ELISA), and total antioxidant capacity (TAC) and zinc using colorimetric assays, were performed to all participants. Results: There was significantly frequent positive parental consanguinity among cases with significantly frequent generalized onset seizures (94%) than simple partial seizure (6%). There were significantly lower serum GAP-43 and zinc levels with significantly higher TAC among cases vs. the controls, p˂0.05 for all. There was no significant difference in the serum levels of NT-3 among epileptic children vs. the controls, p = 0.269. Serum Zn was positively correlated with GAP-43 level among epileptic children (r = 0.381, p = 0.006). Serum GAP-43 in diagnosing childhood epilepsy at cut-off point ≤ 0.6 ng/mL showed 78% sensitivity, 62% specificity, positive predictive value (PPV) = 50.6%, negative predictive value (NPP) = 84.9% with AUC = 0.574. Conclusion: GAP-43 can be considered a sensitive good negative biomarker in childhood epilepsy which correlated positively with the zinc status. [ABSTRACT FROM AUTHOR]

The disturbances in neurotrophic support are thought to be one of the main causes of depression, which depend not only on the neurotrophins themselves but also on the molecules regulating their synthesis and effector functions. One such molecule is cAMP responsive element binding protein (CREB), which role in depression and antidepressant drugs mechanism of action has been extensively studied. However, CREB's effects vary depending on brain structure, necessitating specific transgenic models for studying its function. Moreover, deletion of CREB enhances cAMP response element modulator (CREM) expression, suspected to compensate for CREB in its absence. Previously, mice lacking CREB in noradrenergic neurons and CREM (Creb1 DbhCre Crem-/-) showed to be insensitive to acute desipramine, whereas mice lacking only CREB (Creb1 DbhCre ) showed similar effects as wild type animals (w/t). As neurotrophic changes require chronic antidepressant treatment, in current study mice (w/t, Creb1 DbhCre and Creb1 DbhCre Crem-/-; both males and females) were given desipramine for 21 days, to assess the effects of the drug on CREB, neurotrophins and their receptors in the hippocampus and prefrontal cortex. Interestingly, desipramine had no effect on CREB in neither of studied groups. However, both male and female mice lacking CREB and CREM displayed alterations in neurotrophin-3 (NTF3) expression or protein levels, modulated by desipramine. These findings suggest NTF3 is connected with inhibited response to acute and probably chronic desipramine administration in Creb1 DbhCre Crem-/- mice, although in w/t chronic desipramine had no effect on NTF3. Nevertheless, our findings give insight into the role of non-BDNF neurotrophins in the mechanism of antidepressant drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Neuropathies, which encompass a wide array of peripheral nervous system disorders, present significant challenges due to their varied causes, such as metabolic diseases, toxic exposures, and genetic mutations. This review article, focused on the critical role of neurotrophins in peripheral neuropathy, highlights the intricate balance of neurotrophins necessary for nerve health and the pathophysiological consequences when this balance is disturbed. Neurotrophins, including Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin- 3 (NT-3), and Neurotrophin-4 (NT-4), are essential for neuronal survival, axonal growth, and synaptic plasticity. Their signaling pathways are crucial for maintaining peripheral nervous system integrity, primarily via the Tropomyosin receptor kinase (Trk) receptors and the p75 neurotrophin receptor p75(NTR). Dysregulation of neurotrophins is implicated in various neuropathies, such as diabetic neuropathy and chemotherapy-induced peripheral neuropathy, leading to impaired nerve function and regeneration. Understanding neurotrophin signaling intricacies and their alterations in neuropathic conditions is crucial for identifying novel therapeutic targets. Recent advancements illuminate neurotrophins' potential as therapeutic agents, promising diseasemodifying treatments by promoting neuronal survival, enhancing axonal regeneration, and improving functional recovery post-nerve injury. However, translating these molecular insights into effective clinical applications faces challenges, including delivery methods, target specificity, and the instability of protein-based therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction, which may be help guide neuroengineering to boost stem cell-based neural regeneration for the structural and functional repair of spinal cord injury. Herein, we hypothesized that supplying spinal cord defects with an exogenous neural network in the NT-3/fibroin-coated gelatin sponge (NF-GS) scaffold might improve tissue repair efficacy. To test this, we engineered tropomyosin receptor kinase C (TrkC)-modified neural stem cell (NSC)-derived neural network tissue with robust viability within an NF-GS scaffold. When NSCs were genetically modified to overexpress TrkC, the NT-3 receptor, a functional neuronal population dominated the neural network tissue. The pro-regenerative niche allowed the long-term survival and phenotypic maintenance of the donor neural network tissue for up to 8 weeks in the injured spinal cord. Additionally, host nerve fibers regenerated into the graft, making synaptic connections with the donor neurons. Accordingly, motor function recovery was significantly improved in rats with spinal cord injury (SCI) that received TrkC-modified NSC-derived neural network tissue transplantation. Together, the results suggested that transplantation of the neural network tissue formed in the 3D bioactive scaffold may represent a valuable approach to study and develop therapies for SCI.

The dimeric dipeptide mimetic hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301) was created on the basis of the structure of the exposed region of the neurotrophin-3 4th loop. The new compound, as well as the full-length neurotrophin, activated the TrkC and TrkB receptors. GTS-301 showed neuroprotective activity in experiments on HT-22 mouse hippocampal cells under conditions of oxidative stress and glutamate toxicity at concentrations of 10–12 and 10–8 M, respectively, and antidepressant-like activity in the forced swimming test on mice with 7-day intraperitoneal administration in doses of 10–40 mg/kg. [ABSTRACT FROM AUTHOR]

Even though earlier studies have reported alteration in the markers of synaptic plasticity (Matrix metalloproteinase-9 [MMP-9] and Neurotrophin-3 [NT-3]), there are no reports about the effect of risperidone on the same. The present study was designed to assess the effect of risperidone on NT-3 and MMP-9 levels in patients with schizophrenia spectrum of disorder and to investigate whether these markers can be used to predict the treatment response in these patients. 62 schizophrenia spectrum of disorder patients were enrolled in the study and were treated with 4 mg of risperidone OD. Serum NT-3 and MMP-9 levels were compared at baseline and after 6 weeks following risperidone treatment. Severity of the disease was assessed using Positive and Negative Syndrome Scale (PANSS). MMP-9 was significantly reduced and NT-3 was significantly increased in schizophrenia spectrum of disorder after treatment with risperidone. We also found a significant reduction in MMP-9 levels in the non-responders group. At a cut off of 1225 ng/mL, MMP-9 can predict response to treatment with 64% sensitivity and 62% specificity and at a cut off of 957 pg/mL, NT-3 predicted the response to treatment with 60% sensitivity and 62% specificity. We conclude that risperidone decreases the serum levels of MMP-9 and increases the NT-3 levels in schizophrenia spectrum of disorder. MMP-9 and NT-3 can predict the response to treatment with risperidone. [ABSTRACT FROM AUTHOR]

Immunolocalization of brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial cell line-derived neurotrophic factor (GDNF) in the parietal cortex of rats in a model of focal stroke caused by permanent occlusion of the middle cerebral artery was studied. The spatial density of marked cells constantly varies by cortex layer and at different stages of the ischemic process, demonstrating opposite topographical trends in the stroke nucleus and penumbra. A significant reduction of immunoreactive cells in cortex layers IV–VI on the first and third days of ischemia is typical for all studied neurotrophins. In supragranular layers, their amount remains relatively stable or is slightly reduced as compared with the control. On the eighth day of ischemia, neurotrophins are almost not detected in neurons in the stroke nucleus, while the induction of immunoreactivity occurs in the penumbra. In the penumbra, NT-3-immunoreactive neurons prevail in layers II–III, BDNF is detected in neurons of layers II–III and V, while astrocytes constitute the main population of GDNF-immunoreactive cells. The topography of neurotrophins in the contralateral hemisphere repeats the pattern of their localization in the area of the penumbra. A heterogeneous stratification of neurotrophins and their selective response to ischemic injury are determined by their different involvement in maintaining cytoprotective and neurodestructive effects. [ABSTRACT FROM AUTHOR]

Febrile seizures (FSs) are a common occurrence in young children and a serious concern in pediatric practice; nevertheless, the causes and mechanisms of FS are still unknown. We hypothesized a relation of neuropeptides such as neurotrophin-3 (NT-3) and growth-associated protein-43 (GAP-43) as well as zinc and the oxidant/antioxidant system with pediatric FS. The study included 100 infants categorized into 50 infants with FS and 50 febrile infants without seizures as controls. Clinical assessments, biochemical assays of NT-3 and GAP-43 using ELISA assay kits, and colorimetric measurements of TAC and Zn were performed to all participants. Overall, significant rises of the values of NT-3 and insignificant increases of GAP-43 were detected in children with FS. At the same time, zinc values and the total antioxidant capacity in serum samples were found to be decreased significantly. In addition, a negative correlation was estimated between NT-3 and zinc levels. Serum NT-3 in diagnosing febrile seizures at cutoff point > 49.62 ng/L showed 100% sensitivity, 46% specificity, positive predictive value (PPV) = 48.1%, and negative predictive value (NPP) = 100% with AUC = 0.678. Significant altered circulating NT-3 and zinc levels in FS may indicate their possible role in the pathogenesis of FS. This may open a way for further research and warrants enlightening of the pathophysiological details of FS. [ABSTRACT FROM AUTHOR]

Abstract Background Efficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect. Method NT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation. Results The engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group. Conclusion In this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration.

Abstract Acute myocardial infarction (MI) resulting from coronary ischemia is a major cause of disability and death worldwide. Transplantation of human embryonic stem cell (hESC)‐derived cardiovascular progenitor cells (hCVPCs) promotes the healing of infarcted hearts by secreted factors. However, the hCVPC‐secreted proteins contributing to cardiac repair remain largely unidentified. In this study, we investigated protective effects of neurotrophin (NT)‐3 secreted from hCVPCs in hearts against myocardial ischemia/reperfusion (I/R) injury and explored the underlying mechanisms to determine the potential of using hCVPC products as a new therapeutic strategy. The implantation of hCVPCs into infarcted myocardium at the beginning of reperfusion following 1 hour of ischemia improved cardiac function and scar formation of mouse hearts. These beneficial effects were concomitant with reduced cardiomyocyte death and increased angiogenesis. Moreover, hCVPCs secreted a rich abundance of NT‐3. The cardioreparative effect of hCVPCs in the I/R hearts was mimicked by human recombinant NT‐3 (hNT‐3) but canceled by NT‐3 neutralizing antibody (NT‐3‐Ab). Furthermore, endogenous NT‐3 was detected in mouse adult cardiomyocytes and its level was enhanced in I/R hearts. Adenovirus‐mediated NT‐3 knockdown exacerbated myocardial I/R injury. Mechanistically, hNT‐3 and endogenous NT‐3 inhibited I/R‐induced cardiomyocyte apoptosis through activating the extracellular signal‐regulated kinase (ERK) and reducing the Bim level, resulting in the cardioreparative effects of infarcted hearts together with their effects in the improvement of angiogenesis. These results demonstrate for the first time that NT‐3 is a cardioprotective factor secreted by hCVPCs and exists in adult cardiomyocytes that reduces I/R‐induced cardiomyocyte apoptosis via the ERK‐Bim signaling pathway and promotes angiogenesis. As a cell product, NT‐3 may represent as a noncell approach for the treatment of myocardial I/R injury.

To date, no studies have addressed the role of neurotrophins (NTs) in Acanthamoeba spp. infections in the brain. Thus, to clarify the role of NTs in the cerebral cortex and hippocampus during experimental acanthamoebiasis in relation to the host immune status, the purpose of this study was to determine whether Acanthamoeba spp. may affect the concentration of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in brain structures. Our results suggest that at the beginning of infection in immunocompetent hosts, BDNF and NT-3 may reflect an endogenous attempt at neuroprotection against Acanthamoeba spp. infection. We also observed a pro-inflammatory effect of NGF during acanthamoebiasis in immunosuppressed hosts. This may provide important information for understanding the development of cerebral acanthamoebiasis related to the immunological status of the host. However, the pathogenesis of brain acanthamoebiasis is still poorly understood and documented and, therefore, requires further research. [ABSTRACT FROM AUTHOR]

Neurotrophin-3 enhances the effectiveness of human olfactory ensheathing cells in improving hind limb mobility in rats with post-traumatic cysts of the spinal cord. Transplantation of olfactory ensheathing cells into spinal cord cysts reduced their size; neurotrophin-3 did not modulate this effect. Combined preparation of human olfactory ensheathing cells and neurotrophin- 3 can be used in neurosurgery for the treatment of patients with spinal cord injuries. [ABSTRACT FROM AUTHOR]

Cochlear hair cell damage and spiral ganglion neuron (SGN) degeneration are the main causes of sensory neural hearing loss. Cochlear implants (CIs) can replace the function of the hair cells and stimulate the SGNs electrically. The condition of the SGNs and their spatial distance to the CI are key factors for CI-functionality. For a better performance, a high number of neurons and a closer contact to the electrode are intended. Neurotrophic factors are able to enhance SGN survival and neurite outgrowth, and thereby might optimize the electrode-nerve interaction. This would require chronic factor treatment, which is not yet established for the inner ear. Investigations on chronic drug delivery to SGNs could benefit from an appropriate in vitro model. Thus, an inner ear inspired Neurite Outgrowth Chamber (NOC), which allows the incorporation of a mini-osmotic pump for long-term drug delivery, was designed and three-dimensionally printed. The NOC's function was validated using spiral ganglion explants treated with ciliary neurotrophic factor, neurotrophin-3, or control fluid released via pumps over two weeks. The NOC proved to be suitable for explant cultivation and observation of pump-based drug delivery over the examined period, with neurotrophin-3 significantly increasing neurite outgrowth compared to the other groups. [ABSTRACT FROM AUTHOR]

Sevoflurane anesthesia induces cognitive impairment, which may lead to perioperative neurocognitive disorders (PND). However, the factors and molecular mechanism underlying this impairment remains unclear. Adult hippocampal neurogenesis (AHN) in the subgranular zone of the hippocampus has been implicated in cognitive processes. Nonetheless, the direct role of AHN in sevoflurane-induced cognitive impairment has never been demonstrated. In this study, we explored the age and the concentration factors and the role of AHN inhibition in sevoflurane-induced cognitive impairment in sevoflurane inhalation model mice. We found that 3% sevoflurane exposure induced significant cognitive impairment and inhibition of AHN in aged mice but not adult mice. Expression of BDNF/TrkB and NT-3/TrkC was also decreased by 3% sevoflurane exposure in aged mice. Hippocampal brain-derived neurotrophic factor (BDNF) or Neurotrophin-3 (NT-3) microinjection could partially improve the sevoflurane-induced cognitive impairment and AHN inhibition, respectively. These results demonstrate that the cognitive impairment caused by sevoflurane inhalation is related to patient age and sevoflurane concentration. In conclusion, the molecular mechanism of cognitive impairment in the elderly is related to the inhibition of AHN through the BDNF/TrkB and NT-3/TrkC pathways. Thus, sevoflurane inhalation anesthesia may be safe for adult patients, but caution should be exercised when administering it to the elderly. [ABSTRACT FROM AUTHOR]

Dental pulp stem cells (DPSCs) secrete neurotrophic factors which may play an important therapeutic role in neural development, maintenance and repair. To test this hypothesis, DPSCs-conditioned medium (DPSCs-CM) was collected from 72 hours serum-free DPSCs cultures. The impact of DPSCs-derived factors on PC12 survival, growth, migration and differentiation was investigated. PC12 cells were treated with nerve growth factor (NGF), DPSCs-CM or co-cultured with DPSCs using Transwell inserts for 8 days. The number of surviving cells with neurite outgrowths and the length of neurites were measured by image analysis. Immunocytochemical staining was used to evaluate the expression of neuronal markers NeuN, microtubule associated protein 2 (MAP-2) and cytoskeletal marker βIII-tubulin. Gene expression levels of axonal growth-associated protein 43 and synaptic protein Synapsin-I, NeuN, MAP-2 and βIII-tubulin were analysed by quantitative polymerase chain reaction (qRT-PCR). DPSCs-CM was analysed for the neurotrophic factors (NGF, brain-derived neurotrophic factor [BDNF], neurotrophin-3, and glial cell-derived neurotrophic factor [GDNF]) by specific ELISAs. Specific neutralizing antibodies against the detected neurotrophic factors were used to study their exact role on PC12 neuronal survival and neurite outgrowth extension. DPSCs-CM significantly promoted cell survival and induced the neurite outgrowth confirmed by NeuN, MAP-2 and βIII-tubulin immunostaining. Furthermore, DPSCs-CM was significantly more effective in stimulating PC12 neurite outgrowths than live DPSCs/PC12 co-cultures over the time studied. The morphology of induced PC12 cells in DPSCs-CM was similar to NGF positive controls; however, DPSCs-CM stimulation of cell survival was significantly higher than what was seen in NGF-treated cultures. The number of surviving PC12 cells treated with DPSCs-CM was markedly reduced by the addition of anti-GDNF, whilst PC12 neurite outgrowth was significantly attenuated by anti-NGF, anti-GDNF and anti-BDNF antibodies. These findings demonstrated that DPSCs were able to promote PC12 survival and differentiation. DPSCs-derived NGF, BDNF and GDNF were involved in the stimulatory action on neurite outgrowth, whereas GDNF also had a significant role in promoting PC12 survival. DPSCs-derived factors may be harnessed as a cell-free therapy for peripheral nerve repair. All experiments were conducted on dead animals that were not sacrificed for the purpose of the study. All the methods were carried out in accordance with Birmingham University guidelines and regulations and the ethical approval is not needed.

Axon regeneration and remyelination of the damaged region is the most common repair strategy for spinal cord injury. However, achieving good outcome remains difficult. Our previous study showed that porcine decellularized optic nerve better mimics the extracellular matrix of the embryonic porcine optic nerve and promotes the directional growth of dorsal root ganglion neurites. However, it has not been reported whether this material promotes axonal regeneration in vivo. In the present study, a porcine decellularized optic nerve was seeded with neurotrophin-3-overexpressing Schwann cells. This functional scaffold promoted the directional growth and remyelination of regenerating axons. In vitro, the porcine decellularized optic nerve contained many straight, longitudinal channels with a uniform distribution, and microscopic pores were present in the channel wall. The spatial micro topological structure and extracellular matrix were conducive to the adhesion, survival and migration of neural stem cells. The scaffold promoted the directional growth of dorsal root ganglion neurites, and showed strong potential for myelin regeneration. Furthermore, we transplanted the porcine decellularized optic nerve containing neurotrophin-3-overexpressing Schwann cells in a rat model of T10 spinal cord defect in vivo. Four weeks later, the regenerating axons grew straight, the myelin sheath in the injured/transplanted area recovered its structure, and simultaneously, the number of inflammatory cells and the expression of chondroitin sulfate proteoglycans were reduced. Together, these findings suggest that porcine decellularized optic nerve loaded with Schwann cells overexpressing neurotrophin-3 promotes the directional growth of regenerating spinal cord axons as well as myelin regeneration. All procedures involving animals were conducted in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Sun Yat-sen University (approval No. SYSU-IACUC-2019-B034) on February 28, 2019.

Sevoflurane anesthesia induces cognitive impairment, which may lead to perioperative neurocognitive disorders (PND). However, the factors and molecular mechanism underlying this impairment remains unclear. Adult hippocampal neurogenesis (AHN) in the subgranular zone of the hippocampus has been implicated in cognitive processes. Nonetheless, the direct role of AHN in sevoflurane-induced cognitive impairment has never been demonstrated. In this study, we explored the age and the concentration factors and the role of AHN inhibition in sevoflurane-induced cognitive impairment in sevoflurane inhalation model mice. We found that 3% sevoflurane exposure induced significant cognitive impairment and inhibition of AHN in aged mice but not adult mice. Expression of BDNF/TrkB and NT-3/TrkC was also decreased by 3% sevoflurane exposure in aged mice. Hippocampal brain-derived neurotrophic factor (BDNF) or Neurotrophin-3 (NT-3) microinjection could partially improve the sevoflurane-induced cognitive impairment and AHN inhibition, respectively. These results demonstrate that the cognitive impairment caused by sevoflurane inhalation is related to patient age and sevoflurane concentration. In conclusion, the molecular mechanism of cognitive impairment in the elderly is related to the inhibition of AHN through the BDNF/TrkB and NT-3/TrkC pathways. Thus, sevoflurane inhalation anesthesia may be safe for adult patients, but caution should be exercised when administering it to the elderly.

Hearing loss is the most prevalent sensory disorder affecting nearly half a billion people worldwide. Aside from devices to assist hearing, such as hearing aids and cochlear implants, a drug treatment for hearing loss has yet to be developed. The neurotrophin family of growth factors has long been established as a potential therapy, however delivery of these factors into the inner ear at therapeutic levels over a sustained period of time has remained a challenge restricting clinical translation. We previously demonstrated that direct delivery of exogenous neurotrophin-3 (NT3) in the guinea pig cochleae via a bolus injection was rapidly cleared from the inner ear, with almost complete elimination 3 days post-treatment. Here, we explored the potential of suprapaticles (SPs) for NT3 delivery to the inner ear to achieve sustained delivery over time. SPs are porous spheroid structures comprised of smaller colloidal silica nanoparticles that provide a platform for long-term controlled release of therapeutics. This study aimed to assess the pharmacokinetics and biodistribution of SP-delivered NT3. We used a radioactive tracer (iodine 125: 125I) to label the NT3 to determine the loading, retention and distribution of NT3 delivered via SPs. Gamma measurements taken from 125I NT3 loaded SPs revealed high drug loading (an average of 5.3 μg of NT3 loaded per SP weighing 50 μg) and elution capacities in vitro (67% cumulative release over one month). Whole cochlear gamma measurements from SP-implanted cochleae harvested at various time points revealed detection of 125I NT3 in the guinea pig cochlea after one month, with 3.6 and 10% of the loaded drug remaining in the intracochlear and round window-implanted cochleae respectively. Autoradiography analysis of cochlear micro-sections revealed widespread 125I NT3 distribution after intracochlear SP delivery, but more restricted distribution with the round window delivery approach. Collectively, drug delivery into the inner ear using SPs support sustained, long-term availability and release of neurotrophins in the inner ear. [Display omitted] [ABSTRACT FROM AUTHOR]

Rapid endothelialization is an effective way to treat intimal hyperplasia after intravascular stent implantation. Blood vessels and nerves coordinate with each other in function, while neurotrophin-3 (NT-3) is an important class of nerve growth factors. Our study found that NT-3 promoted endothelial progenitor cell (EPC) mobilization, and the proportion of EPCs in peripheral blood was increased by 1.774 times compared with the control group. Besides, NT-3 promoted the expression of stromal cell-derived factor-1α (SDF-1α), matrix metalloproteinase-9 (MMP9), and chemokine (C-X-C motif) receptor 4 (CXCR4) in EPCs, which increased by 59.89%, 74.46%, and 107.7%, respectively, compared with the control group. Transwell experiments showed that NT-3 enhanced the migration of EPCs by 1.31 times. Flow chamber experiments demonstrated that NT-3 captured more circulating EPCs. As shown by ELISA results, NT-3 can promote the paracrine of vascular endothelial growth factor, interleukin-8, MMP-9, and SDF-1 from EPCs. Such increased angiogenic growth factors further accelerated the closure of endothelial cell scratches. Additionally, EPC-conditioned medium in the NT-3 group significantly inhibited the proliferation of vascular smooth muscle cells. Then animal experiments also illustrated that NT-3 prominently accelerated the endothelialization of injured carotid artery. In short, NT-3 accelerated rapid reendothelialization of injured carotid artery through promoting EPC mobilization and homing.

Neurotrophins play a major role in the regulation of neuronal growth such as neurite sprouting or regeneration in response to nerve injuries. The role of nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor in maintaining the survival of peripheral neurons remains poorly understood. In regenerative medicine, different modalities have been investigated for the delivery of growth factors to the injured neurons, in search of a suitable system for clinical applications. This study was to investigate the influence of nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor on the growth of neurites using two in vitro models of dorsal root ganglia explants and dorsal root ganglia-derived primary cell dissociated cultures. Quantitative data showed that the total neurite length and tortuosity were differently influenced by trophic factors. Nerve growth factor and, indirectly, brain-derived neurotrophic factor stimulate the tortuous growth of sensory fibers and the formation of cell clusters. Neurotrophin-3, however, enhances neurite growth in terms of length and linearity allowing for a more organized and directed axonal elongation towards a peripheral target compared to the other growth factors. These findings could be of considerable importance for any clinical application of neurotrophic factors in peripheral nerve regeneration. Ethical approval was obtained from the Regione Piemonte Animal Ethics Committee ASLTO1 (file # 864/2016-PR) on September 14, 2016.

The goal of this work was to design a polymer-based platform capable of localized, long-term delivery of biologically active neurotropic factors using an affinity-based approach. Here, we synthesized hyaluronic acid-methylfuran (HA-mF) hydrogels that provide sustained, affinity-based release of neurotrophin-3 (NT-3), a growth factor that promotes axon growth for 28 days. A Diels-Alder crosslinking reaction between HA-mF and polyethylene glycol (PEG)-dimaleimide occurs within 15 min under physiological conditions, resulting in hydrogels that can be polymerized in the presence of cells and growth factors. We also tuned the hydrogel's storage modulus to match that of native rat spinal cord tissue, providing a platform not only for localized drug delivery but also a suitable vehicle for cellular transplantation. The NT-3 released from the HAmF hydrogels remains bioactive for at least 14 days, promoting axonal growth from primary sensory neurons as well as stem cell-derived V2a interneurons and motoneurons in vitro. The hydrogels also supported cell growth allowing for 3-dimensional axonal extensions within the scaffold matrix. Here we confirm the protective role of HA-mF on matrix-bound NT-3 activity and show that these hydrogels are an excellent platform for growth factor delivery for neural applications., (© 2023 Wiley Periodicals LLC.)

Percutaneous treatment of low‐intensity pulsed ultrasound (LIPUS) to the site of inferior alveolar nerve (IAN) transection promotes functional regeneration, but the detailed mechanism is unknown. We examined the involvement of neurotrophin‐3 (NT‐3), which primarily binds with tropomyosin receptor kinase C (TrkC), in functional transected IAN regeneration following LIPUS treatment in rats. Daily LIPUS treatment to the transected IAN was performed, and the mechanical sensitivity of the facial skin was measured for 14 d. On day 5 after IAN transection, the expression of NT‐3 in the transected IAN and TrkC‐positive trigeminal ganglion neurons were immunohistochemically examined. Further, the effect of TrkC neutralization on the acceleration of facial mechanosensory disturbance restoration due to LIPUS treatment was analyzed. LIPUS treatment to the site of IAN transection significantly facilitated functional recovery from sensory disturbance on facial skin. Schwann cells in the transected IAN expressed NT‐3, and LIPUS treatment increased the amount of NT‐3. The facilitated recovery from the mechanosensory disturbance by continuous LIPUS treatment was inhibited by the ongoing TrkC neutralization at the IAN transection site. These results suggest that LIPUS treatment accelerates the recovery of orofacial mechanosensory function following IAN transection through the enhancement of NT‐3 signaling in the transected IAN. [ABSTRACT FROM AUTHOR]

Purpose: To compare the effects of 12-week high-intensity interval training (HIIT) and vigorous-intensity continuous training (VICT) on cognitive function, physical fitness, VO2max, serum neurotransmitters and neurotrophic factors in overweight and obese elderly individuals. Methods: Twenty-nine physically inactive older adults (18 males and 11 females) with a mean age of 64.8 ± 3.9 years were randomly divided into a control group (CON, n = 9), an HIIT group (4 × 3 min at 90% VO2max interspersed with 3 min at 60% VO2max, n = 10) and a VICT group (25 min at 70% VO2max, n = 10) and submitted to 12 weeks of training. Cognitive function questionnaires, physical fitness, VO2max, serum neurotransmitters and neurotrophic factors were determined at baseline and post training. Results: Twelve weeks of HIIT and VICT improved the VO2max (4.19 ± 2.21 and 1.84 ± 1.63 mL/kg/min, respectively, p = 0.005), sit-and-reach distance (8.7 ± 3.0 and 7.8 ± 3.8 cm, p = 0.033), choice reaction time (− 0.115 ± 0.15 and − 0.09 ± 0.15 s, p = 0.004) and one-leg stand time (4.4 ± 3.4 and 4.2 ± 4.0 s, p < 0.001) of the elderly participants. The serum concentrations of brain-derived neurotrophic factor (375.5 ± 247.9 and 227.0 ± 137.1 pg/ml, p = 0.006), nerve growth factor (33.9 ± 16.7 and 23.3 ± 14.5 pg/ml, p = 0.037), neurotrophin-3 (24.2 ± 9.33 and 16.3 ± 5.91 pg/ml, p = 0.006) and neurotrophin-4 (10.4 ± 3.8 and 7.8 ± 5.0 pg/ml, p = 0.029) increased significantly in the HIIT and VICT groups after training. In addition, compared to VICT, HIIT significantly increased VO2max and the serum neurotrophin-3 concentration. Serum concentrations of the neurotransmitters acetylcholine, dopamine and serotonin trended upward with training. No significant change was observed in the cognitive function questionnaire scores (p > 0.05). Conclusion: HIIT is suitable for elderly adults and is more effective than VICT for improving VO2max and serum neurotrophin-3 concentrations. Chinese Clinical Trial Registry number: No. ChiCTR1900022315, date of registration: 4 April 2019 [ABSTRACT FROM AUTHOR]

Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo, in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro. Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone.

Background: Efficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect. Method: NT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation. Results: The engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group. Conclusion: In this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration. [ABSTRACT FROM AUTHOR]

Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo , in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro. Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone. [ABSTRACT FROM AUTHOR]

Aims: This study was aimed to investigate whether electroacupuncture (EA) would increase the secretion of neurotrophin‐3 (NT‐3) from injured spinal cord tissue, and, if so, whether the increased NT‐3 would promote the survival, differentiation, and migration of grafted tyrosine kinase C (TrkC)‐modified mesenchymal stem cell (MSC)‐derived neural network cells. We next sought to determine if the latter would integrate with the host spinal cord neural circuit to improve the neurological function of injured spinal cord. Methods: After NT‐3‐modified Schwann cells (SCs) and TrkC‐modified MSCs were co‐cultured in a gelatin sponge scaffold for 14 days, the MSCs differentiated into neuron‐like cells that formed a MSC‐derived neural network (MN) implant. On this basis, we combined the MN implantation with EA in a rat model of spinal cord injury (SCI) and performed immunohistochemical staining, neural tracing, electrophysiology, and behavioral testing after 8 weeks. Results: Electroacupuncture application enhanced the production of endogenous NT‐3 in damaged spinal cord tissues. The increase in local NT‐3 production promoted the survival, migration, and maintenance of the grafted MN, which expressed NT‐3 high‐affinity TrkC. The combination of MN implantation and EA application improved cortical motor‐evoked potential relay and facilitated the locomotor performance of the paralyzed hindlimb compared with those of controls. These results suggest that the MN was better integrated into the host spinal cord neural network after EA treatment compared with control treatment. Conclusions: Electroacupuncture as an adjuvant therapy for TrkC‐modified MSC‐derived MN, acted by increasing the local production of NT‐3, which accelerated neural network reconstruction and restoration of spinal cord function following SCI. [ABSTRACT FROM AUTHOR]

Introduction: Accumulating studies demonstrate that neurotrophins may play a crucial role in a variety of neurodevelopmental disorders. However, little data are available regarding the potential role of neurotrophins in language disorder (LD). This study aimed to investigate serum brain-derived neurotrophic factor (BDNF), glialderived neurotrophic factor (GDNF), nerve growth factor (NGF) and neurotrophin-3 (NTF3) levels in preschool children with LD. Methods: A total of 43 cases with LD and 43 healthy controls aged 18 to 60 months were enrolled in the study. The development levels and psychiatric symptoms of the children were determined by the Ankara Developmental Screening Inventory and Child Behavior Checklist 1.5-5, respectively. Serum neurotrophin levels were assessed by enzyme-linked immunosorbent assay kits. Results: Serum GDNF and NGF levels were significantly higher, serum BDNF and NTF3 levels were significantly lower in the LD group than in the control group. However, with logistic regression analyses, only negative relationship of BDNF and NTF3 levels with the presence of LD remained significant after accounting for the confounders including development level and coexisting psychiatric symptoms. Conclusions: These results suggest that low BDNF and NTF3 levels have independent negative relationships with LD, which could be contribute to etiopathogenesis of the disorder. [ABSTRACT FROM AUTHOR]

Memory consolidation is an essential process of long-term memory formation. Neurotrophins have been suggested as key regulators of activity dependent changes in the synaptic efficacy and morphology, which are considered the downstream mechanisms of memory consolidation. The neurotrophin 3 (NT-3), a member of the neurotrophin family, and its high affinity receptor TrkC, are widely expressed in the insular cortex (IC), a region with a critical role in the consolidation of the conditioned taste aversion (CTA) paradigm, in which an animal associates a novel taste with nausea. Nevertheless, the role of this neurotrophin in the cognitive processes that the IC mediates remains unexamined. To answer whether NT-3 is involved in memory consolidation at the IC, adult male Wistar rats were administered with NT-3 or NT-3 in combination with the Trk receptors inhibitor K252a into the IC, immediately after CTA acquisition under two different conditions: a strong-CTA (0.2 M lithium chloride i.p.) or a weak-CTA (0.1 M lithium chloride i.p.). Our results show that NT-3 strengthens the memory trace of CTA, transforming a weak conditioning into a strong one, in a Trk-dependent manner. The present evidence suggests that NT-3 has a key role in the consolidation process of an aversive memory in a neocortical region. • NT-3 into the IC strengthens the CTA memory. • NT-3 enhances the CTA memory in a Trk dependent manner. • NT-3 is a key molecular actor of the consolidation process in the adult neocortex. [ABSTRACT FROM AUTHOR]