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Background: This study aimed to investigate the effect of four weeks of selected endurance training on neurotrophin-3 (NT-3) and tropomyosin receptor kinase C (TrkC) gene expression in hippocampal areas of rats with spinal cord injury (SCI). Methods: In this experimental study, the rats were separated into six equal groups. First, the animals were put under general anesthesia and had their SCI. Then, for four weeks, they were subjected to two kinds of endurance training programs. However, the control injury group received no intervention or training. Following the completion of the training regimes, molecular tests were done using the qRT-PCR technique to evaluate changes in the gene expression of NT-3 and TrkC from the animals' hippocampus. Results: The expression of NT-3 and TrkC genes were significantly reduced in the SCI model compared to the healthy control group, but it was increased in the SCI + exercise 1 and SCI + exercise 2 groups compared to the SCI group. NT-3 levels did not vary significantly between the SCI + exercise 1 and SCI + exercise 2 groups, although alterations in TrkC levels altered. Conclusion: In addition to enhancing locomotion in animals with SCI, the endurance training regimens in this research were effective on the expression of NT-3 and TrkC genes and may play a role in axonal development and neuronal survival in SCI recovery.

Introduction: Anorexia nervosa (AN) is an eating disorder characterized by restricted energy intake leading to weight loss below the healthy range. It is accompanied by anxiety and distorted body perception. While the disorder often manifests during adolescence, there is a noted decrease in the average age of onset, with an increasing number of cases in childhood. Successful treatment and maintenance of healthy body weight require an understanding of the complex etiology of AN, encompassing both psychosocial and specific biological factors. Material and methods: For the review, databases PubMed, Cochrane, and Google Scholar were utilized, searching for the following keywords: anorexia nervosa, neurotrophins, neurotrophin 3, neurotrophin 4, BDNF, nerve growth factor, from the inception of the databases until September 2023. Discussion: In the biological context, neurotrophic growth factors such as neurotrophin 3 (NT-3), neurotrophin 4 (NT-4), brainderived neurotrophic factor (BDNF), and nerve growth factor (NGF) may play a significant role in the etiopathogenesis of AN. These substances are involved in processes such as neuroprotection, proliferation, maturation, and survival of neurons in both the central and peripheral nervous systems. They regulate neuronal plasticity, impact the production of neurotransmitters, and control synaptic activity. BDNF and neurotrophin 3 influence the serotoninergic and noradrenergic systems, which may be associated with neurobiological processes responsible for anxiety and mood disorders. Conclusions: Understanding the role of neurotrophins in AN has the potential to lead to more effective and personalized therapies, enabling a better comprehension of the biological mechanisms of this disorder and the development of targeted pharmacological interventions. [ABSTRACT FROM AUTHOR]

Objective. Studying the levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF-β), and neurotrophin 3 (NT3) in the cerebral cortex and subcortical substance of female rats in an experimental model of extracerebral growth of malignant tumor under conditions of induced hypothyroidism.Materials and methods. An experiment was performed on 47 white non-linear female rats: 10 rats each in the intact group, control group 1 (induced hypothyroidism), control group 2 (subcutaneous growth of Guerin’s carcinoma), main group (combination of pathologies); 7 rats in the group with subcutaneous tumor growth to assess life expectancy. Hypothyroidism was induced by per os administration of thiamazole (mercazolil, Akrikhin, Russia), daily dose of 2.5 mg/100 g of body weight, course of 30 days; total thyroxine and thyroid stimulating hormone were determined in blood serum by RIA (Immunotech, Czech Republic). When persistent hypothyroidism was achieved, Guerin’s carcinoma was transplanted under the skin as standard. Aſter decapitation on the 18th day aſter transplantation, the content of BDNF, NGF-β, NT3 (R&D System, RayBiotech, USA) was determined in 10 % homogenates of the cortex and subcortical substance subcortex of the brain (R&D System, RayBiotech, USA).Results. In the cortex in control groups 1 and 2, the level of BDNF was 2.6- and 1.6-fold lower, respectively, and NGF-β was 2.2-fold higher on average than in the intact group. NT3 levels in the control group 1 were 3.0- and 1.6-fold lower in the cortex and subcortical substance, respectively. In the control group 2, the levels of NT3 and NGF-β were higher in the subcortical matter than in the intact group by 2.4-fold and 3.1-fold, respectively. In the cortex and subcortical substance in the main group, only NGF-β levels were higher on average by 1.7 times, with values being intermediate between the corresponding values in control groups 1 and 2.Conclusion. Changes in the levels of all neurotrophins in hypothyroidism were most pronounced in the cortex, while in independent tumor growth, NGF-β in the cortex and subcortical substance and NT3 only in subcortical substance changed the most. When the pathologies were combined, only NGF-β was altered in the cortex and subcortical substance. Apparently, there is an interaction of the tumor and the CNS with changes in the balance of regulatory signals in the subcortical areas of the brain, that reflecting the connection with the biological characteristics of an active or inhibited (in presence of hypothyroidism) tumor growth.

Background: This study aimed to investigate the effect of four weeks of selected endurance training on neurotrophin-3 (NT-3) and tropomyosin receptor kinase C (TrkC) gene expression in hippocampal areas of rats with spinal cord injury (SCI). Methods: In this experimental study, the rats were separated into six equal groups. First, the animals were put under general anesthesia and had their SCI. Then, for four weeks, they were subjected to two kinds of endurance training programs. However, the control injury group received no intervention or training. Following the completion of the training regimes, molecular tests were done using the qRT-PCR technique to evaluate changes in the gene expression of NT-3 and TrkC from the animals' hippocampus. Results: The expression of NT-3 and TrkC genes were significantly reduced in the SCI model compared to the healthy control group, but it was increased in the SCI + exercise 1 and SCI + exercise 2 groups compared to the SCI group. NT-3 levels did not vary significantly between the SCI + exercise 1 and SCI + exercise 2 groups, although alterations in TrkC levels altered. Conclusion: In addition to enhancing locomotion in animals with SCI, the endurance training regimens in this research were effective on the expression of NT-3 and TrkC genes and may play a role in axonal development and neuronal survival in SCI recovery. [ABSTRACT FROM AUTHOR]

Learned fear is orchestrated by a brain fear network that comprises the amygdala, hippocampus and the medial prefrontal cortex. Synaptic plasticity within this network is critical for the formation of proper fear memories. Known for their role in the promotion of synaptic plasticity, neurotrophins position as obvious candidates in the regulation of fear processes. Indeed, recent evidence from our laboratory and others associates dysregulated signalling through neurotrophin-3 and its receptor TrkC with the pathophysiology of anxiety and fear-related disorders. Here, we put wild-type C57Bl/6J mice through a contextual fear conditioning paradigm in order to characterize TrkC activation and expression in the main brain regions involved in (learned) fear – amygdala, hippocampus, and prefrontal cortex – during the formation of a fear memory. We report an overall decreased activation of TrkC in the fear network during fear consolidation and reconsolidation. During reconsolidation, hippocampal TrkC downregulation was accompanied by a decrease in the expression and activation of Erk, a critical signalling pathway in fear conditioning. Moreover, we did not find evidence that the observed decrease of TrkC activation was caused by altered expression of dominant negative form of TrkC, neurotrophin-3, or the PTP1B phosphatase. Our results indicate hippocampal TrkC inactivation through Erk signalling as a potential mechanism in the regulation of contextual fear memory formation. [ABSTRACT FROM AUTHOR]

Hearing impairment is a major health and economic concern worldwide. Currently, the cochlear implant (CI) is the standard of care for remediation of severe to profound hearing loss, and in general, contemporary CIs are highly successful. But there is great variability in outcomes among individuals, especially in children, with many CI users deriving much less or even marginal benefit. Much of this variability is related to differences in auditory nerve survival, and there has been substantial interest in recent years in exploring potential therapies to improve survival of the cochlear spiral ganglion neurons (SGN) after deafness. Preclinical studies using osmotic pumps and other approaches in deafened animal models to deliver neurotrophic factors (NTs) directly to the cochlea have shown promising results, especially with Brain-Derived Neurotrophic Factor (BDNF). More recent studies have focused on the use of NT gene therapy to force expression of NTs by target cells within the cochlea. This could provide the means for a one-time treatment to promote long-term NT expression and improve neural survival after deafness. This review summarizes the evidence for the efficacy of exogenous NTs in preventing SGN degeneration after hearing loss and reviews the animal research to date suggesting that NT gene therapy can elicit long-term NT expression in the cochlea, resulting in significantly improved SGN and radial nerve fiber survival after deafness. In addition, we discuss NT gene therapy in other non-auditory applications and consider some of the remaining issues with regard to selecting optimal vectors, timing of treatment, and place/method of delivery, etc. that must be resolved prior to considering clinical application.

BackgroundAn early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates.MethodsIn response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging-guided surgery (n = 5 per group).ResultsThis discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit.ConclusionsTogether, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.

Introduction: There are several hypotheses of schizophrenia pathogenesis, including the neurodegenerative theory, which is supported by evidence for the decrease of neuroprotective factors' serum levels. The proteins, that exert a protective effect on neurons and are researched concerning schizophrenia pathogenesis, include the brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and glial cell line-derived neurotrophic factor (GDNF). This review aims to discuss the role of neuroprotective factors in the development of schizophrenia and their relevance in clinical trials. Material and methods: This review was performed by search of the PubMed, Google Scholar, and Science Direct databases from December 25th, 2022, through January 31st, 2023, using keywords: 'schizophrenia', 'schizophrenia pathogenesis', 'neuroprotection', 'neurodegeneration', 'BDNF', 'NGF', 'NT3', and 'GDNF'. We considered original research papers and systematic reviews published in English or Polish. Additionally, clinical trials, which included the assessment of neuroprotective factors' levels in schizophrenia as outcome measures, were searched for on clinicaltrials.gov. Results: Lower levels of serum BDNF have been linked to cognitive impairment in schizophrenia. In clinical trials, the assessment of serum BDNF is used as a clinical outcome measure for novel schizophrenia therapies. Schizophrenia has also been associated with reduced peripheral NGF levels. During remission, lower NGF levels correlate with higher severity of negative symptoms. Decreased NT3 and GDNF levels can also be seen, but literature reports are inconsistent. Conclusions: Neuroprotective factors are most likely related to the pathogenesis of schizophrenia. Assessing the serum level of these proteins may prove to be an invaluable element of schizophrenia management. [ABSTRACT FROM AUTHOR]

Introduction: Specific learning disorder (SLD) is a neurodevelopmental disorder that involves complex interactions of genetic, neurobiological and environmental factors, but the definite mechanisms remain mostly unknown. The possible role of neurotrophins has been implicated in the pathophysiology of various neurodevelopmental disorders. This study aimed to investigate whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in children with SLD deviate from those of neurotypical brains. Methods: Forty-four patients with SLD and 44 healthy controls aged 7 - 12 years were included. SLD diagnosis and severity was determined using DSM-5-based interviews and SLD clinical observation battery. Serum neurotrophins were measured using enzyme--linked immunosorbent assay. Results: BDNF (p=0.032), NGF (p=0.029), and NT-3 (p=0.025) serum levels were significantly higher in the SLD group compared to the control group; however, serum levels of GDNF did not show any significant difference between groups. On the other hand, GDNF serum levels were significantly different between mild and severe SLD groups (p=0.007) and were lower in severe SLD subjects than in mild cases. There was also a significant correlation between patients' reading speeds and serum levels of GDNF (p=0.025), and GDNF serum levels were lower in patients with slower reading speeds. Conclusion: These findings suggest that neurotrophins might play a role in the pathophysiology of SLD. Increased serum levels of BDNF, NGF, and NT-3 might reflect compensatory attempts at neuroprotection against neurodevelopmental impairment. [ABSTRACT FROM AUTHOR]

Background: Survival and integrity of the spiral ganglion is vital for hearing in background noise and for optimal functioning of cochlear implants. Numerous studies have demonstrated that supplementation of supraphysiologic levels of the neurotrophins BDNF and NT-3 by pumps or gene therapy strategies supports spiral ganglion survival. The endogenous physiological levels of growth factors within the inner ear, although difficult to determine, are likely extremely low within the normal inner ear. Thus, novel approaches for the long-term low-level delivery of neurotrophins may be advantageous.Objectives: This study aimed to evaluate the long-term effects of gene therapy-based low-level neurotrophin supplementation on spiral ganglion survival. Using an adenovirus serotype 28-derived adenovector delivery system, the herpes latency promoter, a weak, long expressing promoter system, has been used to deliver the BDNF or NTF3 genes to the inner ear after neomycin-induced ototoxic injury in mice.Results: Treatment of the adult mouse inner ear with neomycin resulted in acute and chronic changes in endogenous neurotrophic factor gene expression and led to a degeneration of spiral ganglion cells. Increased survival of spiral ganglion cells after adenoviral delivery of BDNF or NTF3 to the inner ear was observed. Expression of BDNF and NT-3 could be demonstrated in the damaged organ of Corti after gene delivery. Hearing loss due to overexpression of neurotrophins in the normal hearing ear was avoided when using this novel vector–promoter combination.Conclusion: Combining supporting cell-specific gene delivery via the adenovirus serotype 28 vector with a low-strength long expressing promoter potentially can provide long-term neurotrophin delivery to the damaged inner ear.

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.

Spinal cord injury (SCI) is considered incurable because axonal regeneration in the central nervous system (CNS) is extremely challenging, due to harsh CNS injury environment and weak intrinsic regeneration capability of CNS neurons. We discovered that neurotrophin-3 (NT3)-loaded chitosan provided an excellent microenvironment to facilitate nerve growth, new neurogenesis, and functional recovery of completely transected spinal cord in rats. To acquire mechanistic insight, we conducted a series of comprehensive transcriptome analyses of spinal cord segments at the lesion site, as well as regions immediately rostral and caudal to the lesion, over a period of 90 days after SCI. Using weighted gene coexpression network analysis (WGCNA), we established gene modules/programs corresponding to various pathological events at different times after SCI. These objective measures of gene module expression also revealed that enhanced new neurogenesis and angiogenesis, and reduced inflammatory responses were keys to conferring the effect of NT3-chitosan on regeneration.

Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. Multiple channel bridges have been investigated as a means to create a permissive environment for regeneration, with channels supporting axonal growth through the injury. Bridges support robust axon growth and myelination. Here, we investigated the cell types that myelinate axons in the bridges and whether over-expression of trophic factors can enhance myelination. Lentivirus encoding for neurotrophin-3 (NT3), sonic hedgehog (SHH) and the combination of these factors was delivered from bridges implanted into a lateral hemisection defect at T9/T10 in mice, and the response of endogenous progenitor cells within the spinal cord was investigated. Relative to control, the localized, sustained expression of these factors significantly increased growth of regenerating axons into the bridge and enhanced axon myelination 8 weeks after injury. SHH decreased the number of Sox2(+) cells and increased the number of Olig2(+) cells, whereas NT3 alone or in combination with SHH enhanced the numbers of GFAP(+) and Olig2(+) cells relative to control. For delivery of lentivirus encoding for either factor, we identified cells at various stages of differentiation along the oligodendrocyte lineage (e.g., O4(+), GalC(+)). Expression of NT3 enhanced myelination primarily by infiltrating Schwann cells, whereas SHH over-expression substantially increased myelination by oligodendrocytes. These studies further establish biomaterial-mediated gene delivery as a promising tool to direct activation and differentiation of endogenous progenitor cells for applications in regenerative medicine.

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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To encourage re-establishment of functional innervation of ipsilateral lumbar motoneurons by descending fibers after an intervening lateral thoracic (T10) hemisection (Hx), we treated adult rats with the following agents: (i) anti-Nogo-A antibodies to neutralize the growth-inhibitor Nogo-A; (ii) neurotrophin-3 (NT-3) via engineered fibroblasts to promote neuron survival and plasticity; and (iii) the NMDA-receptor 2d (NR2d) subunit via an HSV-1 amplicon vector to elevate NMDA receptor function by reversing the Mg(2+) block, thereby enhancing synaptic plasticity and promoting the effects of NT-3. Synaptic responses evoked by stimulation of the ventrolateral funiculus ipsilateral and rostral to the Hx were recorded intracellularly from ipsilateral lumbar motoneurons. In uninjured adult rats short-latency (1.7-ms) monosynaptic responses were observed. After Hx these monosynaptic responses were abolished. In the Nogo-Ab + NT-3 + NR2d group, long-latency (approximately 10 ms), probably polysynaptic, responses were recorded and these were not abolished by re-transection of the spinal cord through the Hx area. This suggests that these novel responses resulted from new connections established around the Hx. Anterograde anatomical tracing from the cervical grey matter ipsilateral to the Hx revealed increased numbers of axons re-crossing the midline below the lesion in the Nogo-Ab + NT-3 + NR2d group. The combined treatment resulted in slightly better motor function in the absence of adverse effects (e.g. pain). Together, these results suggest that the combination treatment with Nogo-Ab + NT-3 + NR2d can produce a functional 'detour' around the lesion in a laterally hemisected spinal cord. This novel combination treatment may help to improve function of the damaged spinal cord.

BACKGROUND: Due to limited access to exogenous neural stem cells, immune rejection and ethical problems, how to activate endogenous neural stem cells and promote their growth, proliferation and differentiation has become an issue of concern. OBJECTIVE: To investigate the effects of electrical stimulation combined with neurotrophin 3 on the proliferation and differentiation of endogenous neural stem cells into neurons after spinal cord injury in rats. METHODS: Ninety-six rats were randomly divided into sham operation (spinal cord exposed only), spinal cord injury, electrical stimulation, and electrical stimulation+neurotrophin groups, 24 rats in each group. A rat model of spinal cord injury was established by modified Allen method in the latter three groups. After the model was established, the rats in the four groups were given corresponding treatments. At 7, 14, 21, and 28 days after modeling, the motor function of hind limbs was evaluated by Basso-Beattie-Bresnahan score. The latency of motor evoked potential was examined by electrophysiology. At 28 days after modeling, samples of the spinal cord were taken for hematoxylin-eosin staining to observe the pathological changes and for immunohistochemical staining to observe the the proliferation and differentiation of endogenous neural stem cells. The study was approved by the Ethics Committee of the Second Hospital of Lanzhou University. RESULTS AND CONCLUSION: (1) Compared with the sham operation group, the Basso-Beattie-Bresnahan score in the spinal cord injury group was significantly decreased (P < 0.01), and a large number of inflammatory cells infiltrated into the spinal cord tissues with multiple cavities. Compared with the spinal cord injury group, the hind limb function in the electrical stimulation and electrical stimulation+neurotrophin groups began to recover gradually. Basso-Beattie-Bresnahan score in the electrical stimulation+neurotrophin group was significantly higher than that in the electrical stimulation group (P < 0.05). The above pathological changes were significantly improved. (2) No latency of motor evoked potentials in both hind limbs was detected in the spinal cord injury group at 7, 14 days and in the electrical stimulation group at 7 days, respectively. At 21 and 28 days, the latency of motor evoked potential was shorter in the electrical stimulation and electrical stimulation+neurotrophin groups than in the spinal cord injury group (P < 0.05); and the latency of motor evoked potential in the electrical stimulation+neurotrophin group was shorter than that in the electrical stimulation group (P < 0.05). (3) The number of BrdU and Nestin positive cells and the expression of microtubule-associated protein 2 were ranked as follows: electrical stimulation+neurotrophin group > electrical stimulation group > spinal cord injury group. The expression level of glial fibrillary acidic protein was highest in the spinal cord injury group, followed by electrical stimulation group, and lowest in the electrical stimulation+neurotrophin group. These results show that after electrical stimulation plus neurotrophin 3 intervention, endogenous neural stem cells can proliferate and differentiate into neurons. Pathological damage is significantly alleviated and motor function of hind limbs is significantly improved. [ABSTRACT FROM AUTHOR]

Objective: Antrochoanal polyp (ACP) is a benign soft tissue lesion arising from the inner wall of the maxillary sinus that extends into the nasal cavity and choana. Although it was first explained by Killian in 1906, the underlying pathogenesis has not been yet fully understood. Neurotrophins have been demonstrated to have a possible role in the pathogenesis of allergic rhinitis, idiopathic rhinitis and nasal polyps. To date any study has not investigated the function of neuronal inflammation and neurotrophins in the development of ACP. The objective of this study was to investigate the possible effect of neurotrophin-3 (NT-3) in ACP pathogenesis. Method: Twenty adult patients with ACP who underwent endoscopic sinus surgery in our department were included in the study group. The control group included 15 patients with concha bullosa of middle concha who underwent lateral excisional surgery. Nasal tissue NT-3 staining scores were evaluated using immunohistochemical methods. Blood NT-3 levels of both groups were evaluated by enzyme-linked immunosorbent assay (ELISA). Results: There were no statistically significant differences between these two groups regarding tissue NT-3 staining scores (p=0.843) and blood NT-3 levels (p=0.463). In addition, no statistically significant correlation has been observed between tissue NT-3 staining scores and blood NT-3 levels in both ACP (p=0.578) and control (p=0.359) group patients. Conclusion: NT-3-related neuronal inflammation does not seem to have any role in ACP pathogenesis. [ABSTRACT FROM AUTHOR]

A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainstem targets after SCI and an essential role for chemotropic axon guidance in target selection.

Differentiation and maturation of dentate gyrus granule cells requires coordinated interactions of numerous processes. These must be regulated by protein factors capable of integrating signals mediated through diverse signalling pathways. Such integrators of inter and intracellular physiological stimuli include the cAMP-response element binding protein (CREB), a leucine-zipper class transcription factor that is activated through phosphorylation. Neuronal activity and neurotrophic factors, known to be involved in granule cell differentiation, are major physiologic regulators of CREB function. To examine whether CREB may play a role in governing coordinated gene transcription during granule cell differentiation, we determined the spatial and temporal profiles of phosphorylated (activated) CREB throughout postnatal development in immature rat hippocampus. We demonstrate that CREB activation is confined to discrete, early stages of granule cell differentiation. In addition, CREB phosphorylation occurs prior to expression of the neurotrophins BDNF and NT-3. These data indicate that in a signal transduction cascade connecting CREB and neurotrophins in the process of granule cell maturation, CREB is located upstream of neurotrophins. Importantly, CREB may be a critical component of the machinery regulating the coordinated transcription of genes contributing to the differentiation of granule cells and their integration into the dentate gyrus network.

Specific subpopulations of neurons in nerve and sensory systems must be developed and maintained, and this is accomplished in significant part by neurotrophins (NTs) and the signaling receptors on which they act, called tyrosine protein kinase receptors (Trks). The neurotrophins-tyrosine protein kinase receptors (NTs/Trks) system is involved in sensory organ regulation, including the visual system. An NTs/Trks system alteration is associated with neurodegeneration related to aging and diseases, including retinal pathologies. An emergent model in the field of translational medicine, for instance, in aging study, is the annual killifish belonging to the Nothobranchius genus, thanks to its short lifespan. Members of this genus, such as Nothobranchius guentheri , and humans share a similar retinal stratigraphy. Nevertheless, according to the authors' knowledge, the occurrence and distribution of the NTs/Trks system in the retina of N. guentheri has never been investigated before. Therefore, the present study aimed to localize neurotrophin BDNF, NGF, and NT-3 and TrkA, TrkB, and TrkC receptors in the N. guentheri retina using the immunofluorescence method. The present investigation demonstrates, for the first time, the occurrence of the NTs/Trks system in N. guentheri retina and, consequently, the potential key role of these proteins in the biology and survival of the retinal cells.

The present study aimed to study the repair effect of neurotrophic factor III (NT-3) on spinal injury model rats and its mechanism. Wistar rats with spinal injury were established by accelerated compression stroke after the operation and divided into control group, model group, and NT-3 intervention group. The motor function of rats in each group was evaluated at different postoperative time points (3, 7, 14 d). HE staining was used to detect the changes in tissue structure and morphology of the injured spinal column in each group. The changes of SOD, MDA and GSH in serum of rats were detected. The concentrations of inflammatory cytokines IL-1β, IL-6, IL-17 and TNF-α in serum were detected by enzyme-linked immunosorbent assay (ELISA). Western blot was used to detect the expression changes of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax) in injured spinal tissue of rats in each group. Compared with model group, motor function score of NT-3 intervention group increased gradually, and had statistical significance at 7 and 14 days (5.29±1.62 vs 9.33±2.16, 5.92±1.44 vs 14.56±2.45, T =7.386, 9.294, P =0.004, 0.000). The levels of SOD and GSH in serum of NT-3 intervention group were significantly increased (t=9.117, 12.207, P=0.000, 0.000), while the level of MDA was significantly decreased (t=5.089, P=0.011). Serum levels of inflammatory cytokines IL-1β, IL-6, IL-17 and TNF-α in NT-3 intervention group were significantly decreased (T =6.157, 7.958, 6.339, 6.288, P=0.008, 0.005, 0.005, 0.007). In the NT-3 treatment group, Bax protein was significantly decreased (0.24±0.05 vs 0.89±0.12, T =8.579, P=0.001), and the relative expression of Bcl-2 protein was significantly increased (0.75±0.06 vs 0.13±0.05, T =9.367, P=0.001). Neurotrophic factor III can promote spinal injury repair in spinal injury model rats, and play a role by enhancing antioxidant stress ability, inhibiting inflammatory factors, promoting Bcl-2 and decreasing Bax expression.

Objective: To study the effect and mechanism of neurotrophin 3 (NT-3) on inhibiting dexamethasone (DEX)-induced mouse MC3T3-E1 osteoblast apoptosis. Methods: Mouse MC3T3-E1 osteoblasts were cultured and divided into groups. Control group were treated with DMEM without drugs, DEX group were treated with DMEM containing 5µmol/L dexamethasone, and NT-3 group were treated with DMEM containing 5µmol/L dexamethasone and 100ng/mL NT-3. Apoptosis rate, proliferation viability, osteogenesis marker contents as well as apoptosis gene and PI3K/AKT/mTOR signaling pathway molecule expression were detected. Results: The apoptosis rate as well as bax and caspase-3 expression in the cells of DEX group was significantly higher than those of control group, whereas proliferation viability value, ALP, OCN and COL-I contents in the medium as well as bcl-2, p-PI3K, p-AKT and p-mTOR expression in the cells were significantly lower than those of control group (P<0.05); the apoptosis rate as well as bax and caspase-3 expression in the cells of NT-3 group was significantly lower than those of DEX group, whereas proliferation viability value, ALP, OCN and COL-I contents in the medium as well as bcl-2, p-PI3K, p-AKT and p-mTOR expression in the cells were significantly higher than those of DEX group (P<0.05). Conclusion: NT-3 has inhibiting effect on the dexamethasone-induced mouse MC3T3-E1 osteoblast apoptosis, and the possible mechanism of this effect is to activate the PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hyaluronan-methylcellulose hydrogel cannot only be conjugated with short peptide sequences and growth factors to achieve sustained release, but also has a role in blocking dural defects and reducing inflammation. It is an ideal biomaterial for the treatment of spinal cord injury. OBJECTIVE: To investigate the effect of neurotrophin-3 modified hyaluronan-methylcellulose (HAMC-NT-3) hydrogel on the recovery of neurological function in rats with spinal cord injury. METHODS: Fifty-four female Sprague-Dawley rats (provided by the Experimental Animal Center of the Academy of Military Medical Sciences in China) were randomly divided into three groups (n=18 per group). The sham group only underwent T10 laminectomy. In the model group and the experimental group, an aneurysm clip was used to establish spinal cord injury models after T10 laminectomy. The experimental group was locally injected with HAMC-NT-3 hydrogel. The Basso Beattie Bresnahan function scoring was performed at 1 day, 1, 2, 3, 4, 5, 6, 7, and 8 weeks after surgery. The inclined plane test was performed at 4, 6 and 8 weeks after surgery to evaluate the recovery of hindlimb motor function. ELISA was used to detect the concentrations of inflammatory factors in the spinal cord at 1 week after surgery. Immunohistochemical staining was used to observe the area of syringomyelia, glial fibrillary acidic protein expression and nerve regeneration at 8 weeks after surgery. RESULTS AND CONCLUSION: (1) The Basso Beattie Bresnahan scores of the model group and the experimental group were lower than those of the sham group at various time points after surgery (P < 0.05). The Basso Beattie Bresnahan scores of the experimental group were higher than those of the model group at 4-8 weeks after surgery (P < 0.05). (2) In the inclined plane test, the maximum inclined angles of the model group and the experimental group at each time point after surgery were lower than that of the sham group (P < 0.05). The maximum inclined angles of the experimental group at 6 and 8 weeks after surgery were higher than those of the sham group (P < 0.05). (3) The concentrations of tumor necrosis factor-α, interleukin-1β, interleukin-6 and interleukin-10 in the experimental group and the model group were higher than those in the sham group (P < 0.05). The concentrations of tumor necrosis factor-α, interleukin-1β and interleukin-6 in the experimental group were lower than those in the model group (P < 0.05). The concentration of interleukin-10 in the experimental group was higher than that in the model group (P < 0.05). (4) Immunohistochemical staining showed that the expression levels of glial fibrillary acidic protein in the experimental group and the model group were higher than those in the sham group, while the expression of glial fibrillary acidic protein in the experimental group was lower than that in the model group. The area of syringomyelia in the experimental group was smaller than that in the model group (P < 0.05). These results indicate that local injection of HAMC-NT-3 hydrogel can effectively inhibit inflammation as well as astrocyte activation and proliferation, reduce fibrous scar formation, and promote the protection of nerve tissue and the recovery of hindlimb motor function after spinal cord injury. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is known to be associated with an increased risk of dementia, specifically Alzheimer’s disease and vascular dementia. Intermittent fasting (IF) has been proposed to produce neuroprotective effects through the activation of several signaling pathways. In this study, we investigated the effect of IF on rat behavior in type 2 diabetic rats. Forty male Wistar Kyoto rats were divided into four groups (n = 10 for each): the ad libitum (Ad) group, the intermittent fasting group (IF), the streptozotocin-induced diabetic 2 group (T2DM) fed a high-fat diet for 4 weeks followed by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) 25 mg kg−1, and the diabetic group with intermittent fasting (T2DM+IF). We evaluated the impact of 3 months of IF (16 h of food deprivation daily) on the levels of brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), serotonin, dopamine, and glutamate in the hippocampus, and rat behavior was assessed by the forced swim test and elevated plus maze. IF for 12 weeks significantly increased (p < 0.05) the levels of NT3 and BDNF in both control and T2DM rats. Additionally, it increased serotonin, dopamine, and glutamic acid in diabetic rats. Moreover, IF modulated glucose homeostasis parameters, with a significant decrease (p < 0.05) in insulin resistance and downregulation of serum corticosterone level. Interestingly, T2DM rats showed a significant increase in anxiety and depression behaviors, which were ameliorated by IF. These findings suggest that IF could produce a potentially protective effect by increasing the levels of BDNF and NT3 in both control and T2DM rats. IF could be considered as an additional therapy for depression, anxiety, and neurodegenerative diseases.

The olfactory epithelium (OE) of the mouse provides a unique system for understanding how cell birth and cell death interact to regulate neuron number during development and regeneration. We have examined cell death in the OE in normal adult mice; in adult mice subjected to unilateral olfactory bulbectomy (surgical removal of one olfactory bulb, the synaptic target of olfactory receptor neurons (ORNs) of the OE); and in primary cell cultures derived from embryonic mouse OE. In vivo, cells at all stages in the neuronal lineage--proliferating neuronal precursors, immature ORNs, and mature ORNs--displayed signs of apoptotic cell death; nonneuronal cells did not. Bulbectomy dramatically increased the number of apoptotic cells in the OE on the bulbectomized side. Shortly following bulbectomy, increased cell death involved neuronal cells of all stages. Later, cell death remained persistently elevated, but this was due to increased apoptosis by mature ORNs alone. In vitro, apoptotic death of both ORNs and their precursors could be inhibited by agents that prevent apoptosis in other cells: aurintricarboxylic acid (ATA), a membrane-permeant anlog of cyclic AMP (CPT-cAMP), and certain members of the neurotrophin family of growth factors (brain-derived neurotrophic factor, neurotrophin 3, and neurotrophin 5), although no neurotrophin was as effective at promoting survival as ATA or CPT-cAMP. Consistent with observed effects of neurotrophins, immunohistochemistry localized the neurotrophin receptors trkB and trkC to fractions of ORNs scattered throughout neonatal OE. These results suggest that apoptosis may regulate neuronal number in the OE at multiple stages in the neuronal lineage and that multiple factors-potentially including certain neurotrophins--may be involved in this process.

The olfactory epithelium (OE) of the mouse provides a unique system for understanding how cell birth and cell death interact to regulate neuron number during development and regeneration. We have examined cell death in the OE in normal adult mice; in adult mice subjected to unilateral olfactory bulbectomy (surgical removal of one olfactory bulb, the synaptic target of olfactory receptor neurons (ORNs) of the OE); and in primary cell cultures derived from embryonic mouse OE. In vivo, cells at all stages in the neuronal lineage--proliferating neuronal precursors, immature ORNs, and mature ORNs--displayed signs of apoptotic cell death; nonneuronal cells did not. Bulbectomy dramatically increased the number of apoptotic cells in the OE on the bulbectomized side. Shortly following bulbectomy, increased cell death involved neuronal cells of all stages. Later, cell death remained persistently elevated, but this was due to increased apoptosis by mature ORNs alone. In vitro, apoptotic death of both ORNs and their precursors could be inhibited by agents that prevent apoptosis in other cells: aurintricarboxylic acid (ATA), a membrane-permeant anlog of cyclic AMP (CPT-cAMP), and certain members of the neurotrophin family of growth factors (brain-derived neurotrophic factor, neurotrophin 3, and neurotrophin 5), although no neurotrophin was as effective at promoting survival as ATA or CPT-cAMP. Consistent with observed effects of neurotrophins, immunohistochemistry localized the neurotrophin receptors trkB and trkC to fractions of ORNs scattered throughout neonatal OE. These results suggest that apoptosis may regulate neuronal number in the OE at multiple stages in the neuronal lineage and that multiple factors-potentially including certain neurotrophins--may be involved in this process.

Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease that manifests as progressive valvular fibrosis and calcification. An inflammatory milieu in valvular tissue promotes fibrosis and calcification. Aortic valve interstitial cell (AVIC) proliferation and the over-production of the extracellular matrix (ECM) proteins contribute to valvular thickening. However, the mechanism underlying elevated AVIC fibrogenic activity remains unclear. Recently, we observed that AVICs from diseased aortic valves express higher levels of neurotrophin 3 (NT3) and that NT3 exerts pro-osteogenic and pro-fibrogenic effects on human AVICs. Hypothesis: Pro-inflammatory stimuli upregulate NT3 production in AVICs to promote fibrogenic activity in human aortic valves. Methods and Results: AVICs were isolated from normal human aortic valves and were treated with lipopolysaccharide (LPS, 0.20 µg/mL). LPS induced TLR4-dependent NT3 production. This effect of LPS was abolished by inhibition of the Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways. The stimulation of TLR4 in human AVICs with LPS resulted in a greater proliferation rate and an upregulated production of matrix metallopeptidases-9 (MMP-9) and collagen III, as well as augmented collagen deposition. Recombinant NT3 promoted AVIC proliferation in a tropomyosin receptor kinase (Trk)-dependent fashion. The neutralization of NT3 or the inhibition of Trk suppressed LPS-induced AVIC fibrogenic activity. Conclusions: The stimulation of TLR4 in human AVICs upregulates NT3 expression and promotes cell proliferation and collagen deposition. The NT3-Trk cascade plays a critical role in the TLR4-mediated elevation of fibrogenic activity in human AVICs. Upregulated NT3 production by endogenous TLR4 activators may contribute to aortic valve fibrosis associated with CAVD progression.

Background: Neurotrophins (NTs) encompass a group of closely associated proteins regulating various aspects of neuronal growth and survival. The potential association between work-related factors and the levels of circulating NTs has not been extensively examined. In this preliminary investigation, we evaluated plasma concentrations of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in a cohort of healthy individuals from three distinct professional categories, each with unique work environments and lifestyle factors., Methods: The study involved 60 men from three professional fields: airline pilots, construction laborers, and fitness trainers (20 participants per category) recruited during routine occupational health appointments. Plasma levels of NTs were measured using commercially available immunoassays and compared in the three professional groups., Results: Among the professions studied, fitness instructors displayed the highest concentrations of BDNF and NGF, with airline pilots ranking second, and construction workers showing the lowest levels. Significantly decreased NT-3 levels were observed in airline pilots compared to fitness instructors and construction workers, but no differences were found between the latter two occupations. NT-4 levels were similar across all three occupational groups., Conclusions: Our pilot results suggest that plasma concentrations of NTs, which are involved in various aspects of neuronal and cognitive functioning, may display significant differences among healthy individuals depending on their occupation. These observations warrant additional research to explore potential implications for the field of occupational medicine.

POU-homeodomain transcription factor POU3F2 is a critical transcription factor that participates in neuronal differentiation. However, little is known about its downstream mediators. Here genome-wide analyses of a human neuronal differentiation cell model, NT2D1, suggested neurotrophin-3 (NTF3), a key mediator of neuronal development during the early neurogenic period, as a putative regulatory target of POU3F2. Western blot, cDNA microarray, and real-time quantitative PCR analyses showed that POU3F2 and NTF3 were upregulated during neuronal differentiation. Next-generation-sequence-based POU3F2 chromatin immunoprecipitation-sequencing and genome-wide in silico prediction demonstrated that POU3F2 binds to the NTF3 promoter during neuronal differentiation. Furthermore, unidirectional deletion or mutation of the binding site of POU3F2 in the NTF3 promoter decreased promoter-driven luciferase activity, indicating that POU3F2 is a positive regulator of NTF3 promoter activity. While NTF3 knockdown resulted in decreased viability and differentiation of NT2D1 cells, and POU3F2 knockdown downregulated NTF3 expression, recombinant NTF3 significantly rescued viable neuronal cells from NTF3- or POU3F2-knockdown cell cultures. Moreover, immunostaining showed colocalization of POU3F2 and NTF3 in developing mouse neurons. Thus, our data suggest that NTF3 is a novel target gene of POU3F2 and that the POU3F2/NTF3 pathway plays a role in the process of neuronal differentiation. [ABSTRACT FROM AUTHOR]

Abstract Background Surgical brain injury (SBI) which occurs due to the inadvertent injury inflicted to surrounding brain tissue during neurosurgical procedures can potentiate blood brain barrier (BBB) permeability, brain edema and neurological deficits. This study investigated the role of neurotrophin 3 (NT-3) and tropomyosin related kinase receptor C (TrkC) against brain edema and neurological deficits in a rat SBI model. Methods SBI was induced in male Sprague Dawley rats by partial right frontal lobe resection. Temporal expression of endogenous NT-3 and TrkC was evaluated at 6, 12, 24 and 72 h after SBI. SBI rats received recombinant NT-3 which was directly applied to the brain surgical injury site using gelfoam. Brain edema and neurological function was evaluated at 24 and 72 h after SBI. Small interfering RNA (siRNA) for TrkC and Rap1 was administered via intracerebroventricular injection 24 h before SBI. BBB permeability assay and western blot was performed at 24 h after SBI. Results Endogenous NT-3 was decreased and TrkC expression increased after SBI. Topical administration of recombinant NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. Recombinant NT-3 administration increased the expression of phosphorylated Rap1 and Erk5. The protective effect of NT-3 was reversed with TrkC siRNA but not Rap1 siRNA. Conclusions Topical application of NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. The protective effect of NT-3 was possibly mediated via TrkC dependent activation of Erk5. Graphical abstract Unlabelled Image Highlights • Endogenous NT-3 expression decreased after SBI. • TrkC receptor expression increased after SBI. • Topical recombinant NT-3 administration improved SBI outcomes. • NT-3 effects were mediated via Erk5 activation dependent on TrkC receptor. [ABSTRACT FROM AUTHOR]

Background: Although the role of neurotrophins such as nerve growth factor and brain-derived neurotrophic factor in nasal polyps development has been studied, the contribution of neurotrophin-3 has not been evaluated yet. This study aimed to investigate the possible role of neurotrophin-3 in nasal polyps pathogenesis. Methods: The study group comprised 70 non-allergic nasal polyps patients and the control group consisted of 53 patients with middle turbinate concha bullosa. Specimens were taken, during surgery, from the ethmoid sinus nasal polyps in the nasal polyps group and from the lateral part of the middle turbinate concha bullosa in the control group. Tissue and serum levels of neurotrophin-3 were assessed by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. Results: Nasal polyps patients had higher tissue neurotrophin-3 scores (p < 0.001). There was no statistically significant difference between groups regarding serum neurotrophin-3 levels (p = 0.417). Tissue neurotrophin-3 staining scores in the nasal polyps group had no statistically significant correlation with Lund–Mackay scores (p = 0.792). Conclusion: Neurotrophin-3 may have a local effect in nasal polyps pathogenesis, without joining systemic circulation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Either good biocompatibility and biological activity of active biological materials or the potential of multidirectional differentiation of neural stem cells has great application prospect and value. OBJECTIVE: To investigate the effect of neurotrophic factor 3-chitosan active biomaterial scaffolds on the differentiation of neural stem cells and the expression of key proteins of the neurotrophic factor 3 signal pathway in vitro. METHODS: The neural stem cells were extracted and purified, and then divided into pure culture medium group, soluble neurotrophic factor 3 group, pure chitosan group, and neurotrophic factor 3-chitosan group for differentiation induction. The expression of TrkC, Akt / p-Akt and Erk/p-Erk in the neurotrophic factor 3 signaling pathway was detected by western blot after 6 hours of induction. After 7 days of induction, differentiation of neural stem cells was observed by immunocytochemistry of MAP2, MBP, and GFAP. After 14 days of induction, formation of neural network induced by neurotrophic factor 3-chitosan active biomaterials was observed by immunocytochemistry of MAP2, Synapsin-1, and PSD95. RESULTS AND CONCLUSION: The neurotrophic factor 3-chitosan group induced a high proportion of neural stem cells differentiated into neurons, with a ratio of 73.8%, which was significantly higher than that in the other three groups. Meanwhile, the proportion of cells differentiated into glial cells waslower than that in the other three groups. The expression of key proteins TrkC, p-Akt and p-Erk in the neurotrophic factor 3-chitosan group was higher than that in the other three groups. Meanwhile, neurotrophic factor 3-chitosan could induce the in vitro differentiation of neural stem cells to form neural network. [ABSTRACT FROM AUTHOR]

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Transected spinal cord injury (SCT) is a devastating clinical disease that strongly affects a patient’s daily life and remains a great challenge for clinicians. Stem-cell therapy has been proposed as a potential therapeutic modality for SCT. To investigate the effects of hematopoietic stem cells (HSCs) on the recovery of structure and function in SCT rats and to explore the mechanisms associated with recovery, 57 adult Sprague-Dawley rats were randomly divided into sham (n = 15), SCT (n = 24), and HSC transplantation groups (n = 15). HSCs (passage 3) labeled by Hoechst 33342, were transplanted intraspinally into the rostral, scar and caudal sites of the transected lesion at 14 days post-operation. Both in vitro and in vivo, HSCs exhibited a capacity for cell proliferation and differentiation. Following HSC transplantation, the animals’ Basso, Beattie, and Bresnahan (BBB). locomotion scale scores increased significantly between weeks 4 and 24 post-SCT, which corresponded to an increased number of 5-hydroxytryptamine (5-HT) fibers and oligodendrocytes. The amount of astrogliosis indicated by immunohistochemical staining, was markedly decreased. Moreover, the decreased expression of neurotrophin- 3 (NT-3) and mitogen-activated protein kinase kinase-1 (MEK-1) after SCT was effectively restored by HSC transplantation. The data from the current study indicate that intraspinally administered HSCs in the chronic phase of SCT results in an improvement in neurological function. Further, the results indicate that intraspinally administered HSCs benefit the underlying mechanisms involved in the enhancement of 5-HT-positive fibers and oligogenesis, the suppression of excessive astrogliosis and the upregulation of NT3-regulated MEK-1 activation in the spinal cord. These crucial findings reveal not only the mechanism of cell therapy, but may also contribute to a novel therapeutic target for the treatment of spinal cord injury (SCI).