Effects Of Neurotrophins Research Articles

Exogenous NT-3 Promotes Phenotype Switch of Resident Macrophages and Improves Sciatic Nerve Injury through AMPK/NF-κB Signaling Pathway.

Neurotrophin-3 (NT-3) is an important family of neurotrophic factors with extensive neurotrophic activity, which can maintain the survival and regeneration of nerve cells. However, the mechanism of NT-3 on macrophage phenotype transformation after sciatic nerve injury is not clear. In this study, we constructed a scientific nerve compression injury animal model and administered different doses of NT-3 treatment through osmotic minipump. 7 days after surgery, we collected sciatic nerve tissue and observed the distribution of macrophage phenotype through iNOS and CD206 immunofluorescence. During the experiment, regular postoperative observations were conducted on rats. After the experiment, sciatic nerve tissue was collected for HE staining, myelin staining, immunofluorescence staining, and Western blot analysis. To verify the role of the AMPK/NF-κB pathway, we applied the AMPK inhibitor Compound C and the NF-κB inhibitor BAY11-7082 to repeat the above experiment. Our experimental results reveal that NT-3 promotes sciatic nerve injury repair and polarization of M2 macrophage phenotype, promotes AMPK activation, and inhibits NF-κB activation. The repair effect of high concentration NT-3 on sciatic nerve injury is significantly enhanced compared to low concentration. Compound C administration can weaken the effect of NT-3, while BAY 11-7082 can enhance the effect of NT-3. In short, NT-3 significantly improves sciatic nerve injury in rats, promotes sciatic nerve function repair, accelerates M2 macrophage phenotype polarization, and improves neuroinflammatory response. The protective effects of NT-3 mentioned above are partially related to the AMPK/NF-κB signal axis.

Neurotrophins and neural stem cells in posttraumatic brain injury repair.

Traumatic brain injury (TBI) is the main cause of disability, mental health disorder, and even death, with its incidence and social costs rising steadily. Although different treatment strategies have been developed and tested to mitigate neurological decline, a definitive cure for these conditions remains elusive. Studies have revealed that various neurotrophins represented by the brain-derived neurotrophic factor are the key regulators of neuroinflammation, apoptosis, blood-brain barrier permeability, neurite regeneration, and memory function. These factors are instrumental in alleviating neuroinflammation and promoting neuroregeneration. In addition, neural stem cells (NSC) contribute to nerve repair through inherent neuroprotective and immunomodulatory properties, the release of neurotrophins, the activation of endogenous NSCs, and intercellular signaling. Notably, innovative research proposals are emerging to combine BDNF and NSCs, enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI. In this review, we summarize the mechanism of neurotrophins in promoting neurogenesis and restoring neural function after TBI, comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI, and investigate their interaction with NSCs. This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI, thereby promoting the progress of TBI therapeutics.

Neuroprotective effects of Neurotrophin-3 in MPTP-induced zebrafish Parkinson’s disease model

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.

Exploring the Therapeutic Effect of Neurotrophins and Neuropeptides in Neurodegenerative Diseases: at a Glance.

Neurotrophins and neuropeptides are the essential regulators of peripheral nociceptive nerves that help to induce, sensitize, and maintain pain. Neuropeptide has a neuroprotective impact as it increases trophic support, regulates calcium homeostasis, and reduces excitotoxicity and neuroinflammation. In contrast, neurotrophins target neurons afflicted by ischemia, epilepsy, depression, and eating disorders, among other neuropsychiatric conditions. Neurotrophins are reported to inhibit neuronal death. Strategies maintained for "brain-derived neurotrophic factor (BDNF) therapies" are to upregulate BDNF levels using the delivery of protein and genes or compounds that target BDNF production and boosting BDNF signals by expanding with BDNF mimetics. This review discusses the mechanisms of neurotrophins and neuropeptides against acute neural damage as well as highlighting neuropeptides as a potential therapeutic agent against Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease (AD), and Machado-Joseph disease (MJD), the signaling pathways affected by neurotrophins and their receptors in both standard and diseased CNS systems, and future perspectives that can lead to the potent application of neurotrophins and neuropeptides in neurodegenerative diseases (NDs).

The Protective Effects of Neurotrophins and MicroRNA in Diabetic Retinopathy, Nephropathy and Heart Failure via Regulating Endothelial Function.

Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted.

Topography of neurotrophins in the rat neocortex and their role in neuron apoptosis after experimental ischemic stroke

Neuronal loss due to apoptosis after ischemic injury depends on the trophic support of neurons and cytoprotective effects of neurotrophins (NTs). Different NTs may activate both pro- and antiapoptotic factors. Their distribution in the ischemic core (IC) and penumbra (IP) has been poorly studied. The available data on the localization of NTs in the ischemic brain are contradictory and depend to a certain degree on the pathogenetic model used. The distribution of NTs in different layers of the ischemic cortex is also largely unknown hindering our understanding of their exact effects and targets in different zones of the ischemic brain. We examined the immunolocalization of brain-derived neurotrophic factor (BDNF), neurotrophin-3, and glial cell line-derived neurotrophic factor (GDNF) in the parietal cortex using a rat model of ischemic stroke due to permanent occlusion of the middle cerebral artery. The spatial density of immunoreactive (IR) cells varied across the cortical layers and changed with time after ischemic injury. Their distribution in the IC differed considerably from that in the IP. The immunolocalization of neurotrophins in the contralateral hemisphere was similar to that in IP. We also studied the distribution of pro- and anti-apoptotic factors in IC and IP with and without intravenous BDNF administration. In the model without BDNF administration, the proportions of Bcl-2-, p53-, caspase-3-, and Mdm2-IR cells showed different dynamics during the ischemic period. In the model with BDNF administration, Mdm2 immunoreactivity was mainly observed in pyramidal cells of layers V/VI, and Bcl-2, in interneurons of layers II and III. The dynamics of p53 immunoreactivity was opposite to that of caspase-3 throughout the ischemic period. The present results suggest that after ischemic injury, 1) the number of neurotrophin-positive cells increases in the early ischemic period and decreases afterwards; 2) there is a close metabolic relationship between astrocytes and neurons contributing to their adaptation to ischemic conditions; 3) the IP borders undergo constant changes; 4) in the IP, neuronal loss occurs mainly by apoptotic pathway throughout the ischemic period; 5) BDNF may enhance considerably antiapoptotic mechanisms with a predominance of Mdm-2 activity in pyramidal neurons.

The effect of neurotrophin-3 overexpression on adult hippocampal neurogenesis

It is known that stress suppresses neurogenesis in the hippocampus. Neurotrophin-3 (NT-3), a neurotrophic factor, has been reported to be upregulated in the hippocampus of adult mice by stress and corticosterone administration. In order to investigate the effects of increased NT-3 on neurogenesis in the hippocampus and stress-induced behaviors, we generated NT-3 overexpressing mice in the hippocampus by administering adeno-associated virus carrying the NT-3 gene (AAV-NT-3). NT-3 mRNA was expressed more than 7 times higher in the hippocampus by AAV-NT-3 administration compared to control hippocampus. NT-3 expression was mainly localized in hippocampal hilus. After 4 weeks of AAV-NT-3 administration, the number of proliferating cells in the hippocampal dentate gyrus was decreased in the NT-3 overexpression group compared to the control group. This result suggests that high dose of NT-3 may suppress proliferation of neuronal stem cells/progenitors in the dentate gyrus. In the future, we plan to investigate changes in neural differentiation and maturation in the hippocampus of NT-3 overexpressing mice to further clarify the role of NT-3 in neurogenesis. It is also necessary to clarify the effects of NT-3 on stress by examining stress-induced anxiety-like and depression-like behaviors in NT-3 overexpressing mice.

Childhood Onset Strabismus: A Neurotrophic Factor Hypothesis

ABSTRACT Strabismus is a genetically heterogeneous disorder with complex molecular and neurophysiological causes. Evidence in the literature suggests a strong role for motor innervation in the etiology of strabismus, which connects central neural processes to the peripheral extraocular muscles. Current treatments of strabismus through surgery show that an inherent sensorimotor plasticity in the ocular motor system decreases the effectiveness of treatment, often driving eye alignment back toward its misaligned pre-surgical state by altering extraocular muscle tonus. There is recent interest in capitalizing on existing biological processes in extraocular muscles to overcome these compensatory mechanisms. Neurotrophins are trophic factors that regulate survival and development in neurons and muscle, including extraocular muscles. Local administration of neurotrophins to extraocular muscles partially reversed strabismus in an animal model of strabismus. The hypothesis is that sustained release of neurotrophins gives more time for the ocular motor system to adapt to a slow change in alignment in the desired direction. The effect of neurotrophins on extraocular muscles is complex, as different neurotrophic factors have diverse effects on extraocular muscle contraction profiles, patterns of innervation, and density of extraocular muscle precursor cells. Neurotrophic factors show promise as a therapeutic option for strabismus, which may help to improve treatment outcomes and offset devastating amblyopia and psychosocial effects of disease in strabismus patients.

Neurotrophin-3 contributes to benefits of human embryonic stem cell-derived cardiovascular progenitor cells against reperfused myocardial infarction.

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.

Lipid Nanoparticles Vectorized with NFL-TBS.40-63 Peptide Target Oligodendrocytes and Promote Neurotrophin-3 Effects After Demyelination In Vitro.

Promoting remyelination in multiple sclerosis is important to prevent axon degeneration, given the lack of curative treatment. Although some growth factors improve this repair, unspecific delivery to cells and potential side effects limit their therapeutic use. Thus, NFL-TBS.40-63 peptide (NFL)-known to enter specifically myelinating oligodendrocytes (OL)-was used to vectorize 100nm diameter lipid nanoparticles (LNC), and the ability of NFL-LNC to specifically target OL from newborn rat brain was assessed in vitro. Specific uptake of DiD-labeled NFL-LNC by OL characterized by CNP and myelin basic protein was observed by confocal microscopy, as well as DiD colocalization with NFL and with Rab5-a marker of early endosomes. Unvectorized LNC did not significantly penetrate OL and there was no uptake of NFL-LNC by astrocytes. Canonical maturation of OL which extended compacted myelin-like membranes was observed by transmission electron microscopy in cells grown up to 9days with NFL-LNC. Endocytosis of NFL-LNC appeared to depend on several pathways, as demonstrated by inhibitors. In addition, vectorized NFL-LNC adsorbed on neurotrophin-3 (NT-3) potentiated the proremyelinating effects of NT-3 after demyelination by lysophosphatidyl choline, allowing noticeably decreasing NT-3 concentration. Our results if they were confirmed in vivo suggest that NFL-vectorized LNC appear safe and could be considered as putative carriers for specific drug delivery to OL in order to increase remyelination.

Effect of NT-3 on repair of spinal cord injury through the MAPK signaling pathway.

The aim of this study was to explore the effect of neurotrophin-3 (NT-3) on the repair of spinal cord injury (SCI) through the mitogen-activated protein kinase (MAPK) signaling pathway. The rat model of SCI was first successfully established using the impactor (SCI group). Meanwhile, control group and NT-3 treatment group were set up as well. Basso-Beattie-Bresnahan (BBB) score was given and blood, and spinal cord tissues were collected from rats. Subsequently, serum indexes were detected, including glucose (Glu), creatinine (Cr), K+, Na+, the content of interleukin-6 (IL-6), IL-1β, tumor necrosis factor-β (TNF-β), and the level of myeloperoxidase (MPO). Moreover, the morphological changes were observed via hematoxylin-eosin (HE) staining. The gene and protein expressions of glial fibrillary acidic protein (GFAP) and MAPK were determined through Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting, respectively. Furthermore, the effect of the MAPK signaling pathway on SCI was comprehensively observed. In SCI group, the rats could not crawl autonomously with the loss of motor function and paraplegia. Meanwhile, the levels of Glu, Cr, Na+, IL-6, IL-1β, TNF-β, and MPO were all significantly up-regulated. According to the results of HE staining, spinal nerve fibers disappeared with significant syringomyelia in SCI group. Meanwhile, the aggregation of nerve fibers was observed without apparent tissue bleeding, edema, and cell deformation in NT-3 group. QRT-PCR results demonstrated that SCI group showed remarkably higher levels of GFAP, MAPK, and c-Jun N-terminal kinase (JNK) (p<0.05), while it showed a markedly lower level of ERK2 than NT-3 group (p<0.05). In NT-3 group, the protein expression of MAPK in myocardial tissues was remarkably lower than that of SCI group (p<0.05). NT-3 can inhibit the MAPK signaling pathway, thereby promoting the repair of SCI.

Effects of Neurotrophin-3 on Intrinsic Neuronal Properties at a Central Auditory Structure

Neurotrophins, a class of growth factor proteins that control neuronal proliferation, morphology, and apoptosis, are found ubiquitously throughout the nervous system. One particular neurotrophin (NT-3) and its cognate tyrosine receptor kinase (TrkC) have recently received attention as a possible therapeutic target for synaptopathic sensorineural hearing loss. Additionally, research shows that NT-3-TrkC signaling plays a role in establishing the sensory organization of frequency topology (ie, tonotopic order) in the cochlea of the peripheral inner ear. However, the neurotrophic effects of NT-3 on central auditory properties are unclear. In this study we examined whether NT-3-TrkC signaling affects the intrinsic electrophysiological properties at a first-order central auditory structure in chicken, known as nucleus magnocellularis (NM). Here, the expression pattern of specific neurotrophins is well known and tightly regulated. By using whole-cell patch-clamp electrophysiology, we show that NT-3 application to brainstem slices does not affect intrinsic properties of high-frequency neuronal regions but had robust effects for low-frequency neurons, altering voltage-dependent potassium functions, action potential repolarization kinetics, and passive membrane properties. We suggest that NT-3 may contribute to the precise establishment and organization of tonotopy in the central auditory pathway by playing a specialized role in regulating the development of intrinsic neuronal properties of low-frequency NM neurons.

Is There any Possible Role of Neurotrophin 3 in the Pathogenesis of Antrochoanal Polyp?

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.

The role of the TrkB-T1 receptor in the neurotrophin-4/5 antagonism of brain-derived neurotrophic factor on corticostriatal synaptic transmission.

This manuscript reviews the function and fundamental characteristics of the neurotrophins and their receptors to introduce the reader to the differential effects exhibited by the neurotrophins; brain-derived neurotrophic factor and neurotrophin 4/5 when acted together after sequential presentation. The neurotrophin 4/5 exhibits an inhibitory action on the modulatory effect of brain-derived neurotrophic factor in corticostriatal synapses when they are administered sequentially (brain-derived neurotrophic factor to neurotrophin 4/5). This inhibitory effect has not been previously documented and is relevant for these neurotrophins as both of them stimulate the TrkB receptor. The additive effect of these neurotrophins is also discussed and occurs when neurotrophin 4/5 exposure is followed by brain-derived neurotrophic factor in a mouse model of striatal degeneration. Occlusive and additive effects of both neurotrophins are accompanied by changes in the expression of the TrkB receptor isoforms, specifically TrkB-T1 and TrkB-FL, as well as differences in phosphorylation levels of the TrkB receptor. The results of the experiments described raise several questions to inquire about the role that TrkB-T1 receptor plays in striatal physiology, as well as the functional relevance of the interaction of brain-derived neurotrophic factor and neurotrophin 4/5 in the brain and more specifically at the striatal circuits in normal as well as pathological conditions.

NT-3 Promotes Oligodendrocyte Proliferation and Nerve Function Recovery After Spinal Cord Injury by Inhibiting Autophagy Pathway

BackgroundSpinal cord injury (SCI) is a serious medical problem, leading to lifelong disability and increasing the health burden worldwide. Traditional treatments have limited effects on neuronal function recovery. Previous studies showed that neurotrophin-3 (NT-3) promoted oligodendrocyte survival and improved neuronal functional recovery after SCI. However, the mechanism by which NT-3 promotes oligodendrocyte survival after SCI remains unclear, which limits its application. Materials and methodsA total of 75 female Sprague–Dawley rats were randomly divided into three groups: the NS group, NT-3 group, and NT-3 + rapamycin group. After successful modeling, the spinal cord specimens were taken at the corresponding time points. Western blot was used to detect autophagy-related proteins and Olig1 protein expression and combined with pathology, immunohistochemistry, flow cytometry, and other methods to detect the proliferation of oligodendrocytes after NT-3 application. ResultsNT-3 was found to significantly promote the recovery of motor function by Basso–Beattie–Bresnahan scores analysis in the rat SCI model. Furthermore, intraspinal administration of NT-3 could downregulate the expression of Beclin-1 in oligodendrocytes, indicating that NT-3 could inhibit excessive autophagy of oligodendrocytes after SCI. The effects of NT-3 on oligodendrocyte survival could be blocked by an autophagy activator rapamycin. ConclusionsThis study found that NT-3 could promote the recovery of motor function after SCI in rats. The underlying reason may be that NT-3 inhibits the expression of autophagy proteins in oligodendrocytes and promotes oligodendrocyte proliferation. This study provided evidence for the future clinical application of NT-3 in SCI patients.

No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing.

Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain.

Effect of NT-3 on infection-induced memory impairment of neonatal rats.

To explore the effect of neurotrophin-3 (NT-3) messenger ribonucleic acid (mRNA) in the hippocampus on infection-induced memory impairment of neonatal rats. 80 female Sprague-Dawley (SD) rats in the neonatal stage were selected to establish memory impairment model by bacterial meningitis infection. Rats were randomly divided into experimental group (n=40) and control group (n=40). Rats in experimental group were injected with β-amyloid precursor protein 319-335 peptide APP17p into brain tissue to up-regulate the expression of NT-3, and the rats in control group didn't receive treatment. Behavioral changes of rats were observed in Morris water maze and passive avoidance experiment. Apoptosis of nerve cells was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method and Fluoro-Jade B method. NT-3 mRNA expression level was measured via reverse transcription polymerase chain reaction (RT-PCR). NT-3 expression level in experimental group was higher than that in control group (p<0.05). Apoptosis rate of nerve cells in experimental group was lower than that in control group, but the learning and memory ability of rats in experimental group was better than that in control group (p<0.05). Reduced NT-3 expression level may be correlated with the occurrence of meningitis because NT-3 can suppress nerve cell apoptosis and ameliorate learning and memory impairment to a certain extent to exert neuroprotective effects.

Smooth muscle brain-derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma.

Recent studies have demonstrated an effect of neurotrophins, particularly brain-derived neurotrophic factor (BDNF), on airway contractility [ via increased airway smooth muscle (ASM) intracellular calcium [Ca2+]i] and remodeling (ASM proliferation and extracellular matrix formation) in the context of airway disease. In the present study, we examined the role of BDNF in allergen-induced airway inflammation using 2 transgenic models: 1) tropomyosin-related kinase B (TrkB) conditional knockin (TrkBKI) mice allowing for inducible, reversible disruption of BDNF receptor kinase activity by administration of 1NMPP1, a PP1 derivative, and 2) smooth muscle-specific BDNF knockout (BDNFfl/fl/SMMHC11Cre/0) mice. Adult mice were intranasally challenged with PBS or mixed allergen ( Alternaria alternata, Aspergillus fumigatus, house dust mite, and ovalbumin) for 4 wk. Our data show that administration of 1NMPP1 in TrkBKI mice during the 4-wk allergen challenge blunted airway hyperresponsiveness (AHR) and reduced fibronectin mRNA expression in ASM layers but did not reduce inflammation per se. Smooth muscle-specific deletion of BDNF reduced AHR and blunted airway fibrosis but did not significantly alter airway inflammation. Together, our novel data indicate that TrkB signaling is a key modulator of AHR and that smooth muscle-derived BDNF mediates these effects during allergic airway inflammation.-Britt, R. D., Jr., Thompson, M. A., Wicher, S. A., Manlove, L. J., Roesler, A., Fang, Y.-H., Roos, C., Smith, L., Miller, J. D., Pabelick, C. M., Prakash, Y. S. Smooth muscle brain-derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma.

Glial-derived growth factor and pleiotrophin synergistically promote axonal regeneration in critical nerve injuries

The repair of nerve gap injuries longer than 3 cm is limited by the need to sacrifice donor tissue and the morbidity associated with the autograft gold standard, while decellularized grafts and biodegradable conduits are effective only in short nerve defects. The advantage of isogenic nerve implants seems to be the release of various growth factors by the denervated Schwann cells. We evaluated the effect of vascular endothelial growth factor, neurotrophins, and pleiotrophin (PTN) supplementation of multi-luminal conduits, in the repair of 3 and 4 cm nerve gaps in the rabbit peroneal nerve. In vitro screening revealed a synergistic regenerative effect of PTN with glial-derived neurotrophic factor (GDNF) in promoting sensory axon density, and motor axonal growth from spinal cord explants. In vivo, pleiotrophins were able to support nerve regrowth across a 3 cm gap. In the 4 cm lesions, PTN-GDNF had a modest effect in the number of axons distal to the implant, while increasing the mean axon diameter (1 ± 0.4; p ≤ 0.001) over PTN or GDNF alone (0.80 ± 0.2, 0.84 ± 0.5; respectively). Some regenerated axons reinnervated muscle targets as indicated by neuromuscular junction staining. However, many were wrapped in Remak bundles, suggesting a delay in axonal sorting, explaining the limited electrophysiological function of the reinnervated muscle, and the modest recovery in toe spreading in the PTN-GDNF repaired animals. These results support the use of synergistic neurotrophic/pleiotrophic growth factors in long gap repair and underscore the need for re-myelination strategies distal to the injury site. Statement of SignificanceNerve injuries due to trauma or tumor resection often result in long gaps that are challenging to repair. The best clinical option demands the use of autologous grafts that are associated with serious side effects. Bioengineered nerves are considered a good alternative, particularly if supplemented with growth factors, but current options do not match the regenerative capacity of autografts. This study revealed the synergistic effect of neurotrophins and pleiotrophins designed to achieve a broad cellular regenerative effect, and that GDNF-PTN are able to mediated axonal growth and partial functional recovery in a 4 cm nerve gap injury, albeit delays in remyelination. This report underscores the need for defining an optimal growth factor support for biosynthetic nerve implants.

Is there any effect of neurotrophin-3 on the pathogenesis of non-allergic nasal polyps?

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. 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. 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). Neurotrophin-3 may have a local effect in nasal polyps pathogenesis, without joining systemic circulation.