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 vari-ous 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 neu-roinflammation 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 in-tercellular 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 neurogen-esis 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.

Adult neurogenesis and regeneration in zebrafish brain: are the neurotrophins involved in?

Neurotrophins (NTs) are implicated in the maintenance and survival of the peripheral and central nervous systems and mediate several forms of synaptic plasticity. Members of the family include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3, and NT4. NTs were first identified as survival factors for developing neurons, but are pleiotropic molecules that can exert a variety of functions, including the regulation of neuronal differentiation, axonal and dendritic growth, and synaptic plasticity (Bothwell, 2014). NTs interact with two distinct types of receptors: the common p75 neurotrophin receptor, which belongs to the tumor necrosis factor receptor superfamily of death receptors and the Trk receptor tyrosine kinase family.

Updated overview on interplay between physical exercise,neurotrophins,and cognitive function in humans

The many important benefits of physical exercise also encompass maintenance or improvement of cognitive functions. Among the variousmechanisms underlying the association between physical exercise and brain health, recent evidence attests that neurotrophin receptor signalingmay have an important role, because the activation of this pathway leads to growth and differentiation of new neurons and synapses, supportsaxonal and dendritic growth, fosters synaptic plasticity, and preserves survival of existing neurons. In this review of published evidence, we highlightthat a positive relationship exists between physical exercise and circulating brain-derived neurotrophic factor levels and that the postexercisevariation of this molecule is associated with improvement of neurocognitive functioning. Less clear evidence has instead been published forother neurotrophins, such as nerve growth factor, neurotrophin-3, and neurotrophin-4. Overall, promotion of adequate volumes and intensities ofphysical exercise (i.e., approximately 3 months of moderate-intensity aerobic exercise, with 2—3 sessions/week lasting not less than 30 min)may hence be regarded as an inexpensive and safe strategy for boosting brain-derived neurotrophic factor release, thus preserving or restoringcognitive functions.

Neurotrophins and their receptors in satellite glial cells following nerve injury

Peripheral neuropathy is a condition where damage resulting from mechanical or pathological mechanisms is inflicted on nerves within the peripheral nervous system （PNS）. Physical injury is the most common cause and may result in nerves being partially or completely severed, crushed, compressed or stretched. Other causes include metabolic or endocrine disorders, with e.g.,

Embryonic Limb Buds Derived Neurotrophins on the Survival of Neurons and the Growth of Axons in Culture in Vitro

Bioactive proteins from SD rat limb buds were extracted and purified. Fractions of 22 ku, 34 ku and 95 ku were proved to have neurotrophic activity to neurons, and the combined activity of these three fractions was the highest. So they were combinedly added into the culture medium of sensor neurons in dorsal root ganglia and motor neurons of anterior spinal cord from 2-week-old embryonic rats, and PBS was added as control. Phase-contrast microscopic and electron microscopic observations, and true cholinesterase measurements were performed to evaluate the survival and changes in growth, function, and ultrastructure of these cultured neurons. In the experimental group, it was found that the AchE activity was higher (P<0. 01), ultrastructural changes in mitochondria,Gorgi's complex and other cell organs were milder than those in the control group. The results showed limb buds derived neurotrophins played an important role in maitaining the survival of the neurons and promoting the growth of axons. It was concluded that embryonic limb buds derived neurotrophins had high neurotrophic activities on neurons' survival and axon growth.

Correlation of the expression of neurotrophins family and its receptors with cell proliferation and invasion in ovarian cancer

Objective:To investigate the correlation among the expression of neurotrophins (NTs) family and its receptors with cell proliferation and invasion in ovarian cancer.Methods:Ninety patients with ovarian cancer who underwent surgical treatment in Guangyuan First People's Hospital between December 2015 and October 2017 were selected as ovarian cancer group, and 67 patients with ovarian chocolate cyst were selected as benign lesion group. The differences in the expression of NTs family and its receptors, proliferation genes and invasion genes in lesions were compared between the two groups, and Pearson test was used to further evaluate the correlation among the expression of NTs family and its receptors with cancer cell malignancy in ovarian cancer tissue.Results:NT-3 mRNA expression in ovarian cancer group was lower than that in benign lesion group whereas NT-5, TrkA, TrkB and TrkC mRNA expression were higher than those in benign lesion group;proliferation genes FUNDC1, GRP78, PTTG and SMG-1 mRNA expression were higher than those in benign lesion group whereas shSASH1 and ESRP1 mRNA expression were lower than those in benign lesion group;invasion genes Clusterin, EFEMP1, Twist and IFITM1 mRNA expression were higher than those in benign lesion group whereas DUSP10 mRNA expression was lower than that in benign lesion group. Pearson test showed that the NT-5, TrkA, TrkB AND TrkC mRNA expression in ovarian cancer were directly correlated with cancer cell proliferation and invasion activity.Conclusion: The expression levels of NTs family and its receptors are abnormal in ovarian cancer and the specific expression levels are directly correlated with the proliferation and invasion activity of cancer cells.

Neurotrophins differentially stimulate the growth of cochlear neurites on collagen surfaces and in gels

The electrodes of a cochlear implant are located far from the surviving neurons of the spiral ganglion, which results in decreased precision of neural activation compared to the normal ear. If the neurons could be induced to extend neurites toward the implant, it might be possible to stimulate more discrete subpopulations of neurons, and to increase the resolution of the device. However, a major barrier to neurite growth toward a cochlear implant is the fluid filling the scala tympani, which separates the neurons from the electrodes. The goal of this study was to evaluate the growth of cochlear neurites in three-dimensional extracellular matrix molecule gels, and to increase biocompatibility by using fibroblasts stably transfected to produce neurotrophin-3 and brain-derived neurotrophic factor. Spiral ganglion explants from neonatal rats were evaluated in cultures. They were exposed to soluble neurotrophins, cells transfected to secrete neurotrophins, and/or collagen gels. We found that cochlear neurites grew readily on collagen surfaces and in three-dimensional collagen gels. Co-culture with cells producing neurotrophin-3 resulted in increased numbers of neurites, and neurites that were longer than when explants were cultured with control fibroblasts stably transfected with green fluorescent protein. Brain-derived neurotrophic factor-producing cells resulted in a more dramatic increase in the number of neurites, but there was no significant effect on neurite length. It is suggested that extracellular matrix molecule gels and cells transfected to produce neurotrophins offer an opportunity to attract spiral ganglion neurites toward a cochlear implant.

Expression of Tyrosine-kinase Receptors and Neurotrophins in Human Neuroblastomas

OBJECTIVE The aim of this study was to investigate mRNA expression of tyrosine-kinase receptors （TRKs） and neurotrophins （NTs） in human neuroblastomas. METHODS Expression of TrkA, TrkB, TrkC and BDNF was quantitatively examined by reverse transcription-polymerase chain reaction （RT-PCR） in 27 cases of neuroblastomas. RESULTS The high and total rates of TrkA were expressed in significantly more tumors in a lower-stage group compared to a higher-stage group （P〈0.05） and the high level of TrkA expression was correlated positively with the 2-year cumulative-survival rate of the patients （P〈 0.01）. The high and total rates of TrkB were expressed in significantly more tumors in a higher-stage group compared to a lower-stage group （P〈0.05）. All 3 rates of BDNF expression between the 2 groups showed no statistical difference （P〉0.05）, but the co-expression ratio of TrkB and BDNF showed a remarkable significance in the higher-stage group more than in the lower-stage group （P〈0.05）. TrkC expression was usually accompanied by TrkA expression, but there was only a non-significant trend between TrkC expression and TrkA expression. CONCLUSION RT-PCR for mRNA expression of TRKs and NTs has important clinical significance relating to the tumor stage and outcome for patients with neuroblastomas.

Nanotechnology-based gene therapy as a credible tool in the treatment of Alzheimer’s disease

Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.

Neurotrophic fragments as therapeutic alternatives to ameliorate brain aging

Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes.During this physiological process,the brain is the most affected organ due to changes in its structural and chemical functions,such as changes in plasticity and decrease in the number,diameter,length,and branching of dendrites and dendritic spines.Likewise,it presents a great reduction in volume resulting from the contraction of the gray matter.Consequently,aging can affect not only cognitive functions,including learning and memory,but also the quality of life of older people.As a result of the phenomena,various molecules with notable neuroprotective capacity have been proposed,which provide a therapeutic alternative for people under conditions of aging or some neurodegenerative diseases.It is important to indicate that in recent years the use of molecules with neurotrophic activity has shown interesting results when evaluated in in vivo models.This review aims to describe the neurotrophic potential of molecules such as resveratrol(3,5,4′-trihydroxystilbene),neurotrophins(brain-derived neurotrophic factor),and neurotrophic-type compounds such as the terminal carboxyl domain of the heavy chain of tetanus toxin,cerebrolysin,neuropeptide-12,and rapamycin.Most of these molecules have been evaluated by our research group.Studies suggest that these molecules exert an important therapeutic potential,restoring brain function in aging conditions or models of neurodegenerative diseases.Hence,our interest is in describing the current scientific evidence that supports the therapeutic potential of these molecules with active neurotrophic.

Neurotrophic factor-based pharmacological approaches in neurological disorders

Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alzheimer’s disease,Parkinson’s disease,and ischemic stroke.The incidence of all these pathologies increases exponentially with age.Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies.Cognitive deficit and neurodegeneration,common features of aging-related pathologies,are related to the alteration of the activity and levels of neurotrophic factors,such as brain-derived neurotrophic factor,nerve growth factor,and glial cell-derived neurotrophic factor.For this reason,treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases.Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors,neurotrophins’binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies.Considering neurotrophins’crucial role in aging pathologies,here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.

Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway

Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury. In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3 K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3 K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3 K/AKT/mTOR pathway.

Cellular response toβ-amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics

β-Amyloid(Aβ)is a specific pathological hallmark of Alzheimer's disease(AD).Because of its neurotoxicity,AD patients exhibit multiple brain dysfunctions.Disease-modifying therapy(DMT)is the central concept in the development of AD thera-peutics today,and most DMT drugs that are currently in clinical trials are anti-Aβdrugs,such as aducanumab and lecanemab.Therefore,understanding Aβ's neurotoxic mechanism is crucial for Aβ-targeted drug development.Despite its total length of only a few dozen amino acids,Aβis incredibly diverse.In addition to the well-known Aβ_(1-42),N-terminally truncated,glutaminyl cyclase(QC)catalyzed,and pyroglutamate-modified Aβ(pEAβ)is also highly amyloidogenic and far more cytotoxic.The extracel-lular monomeric Aβ_(x-42)(x=1-11)initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor-coupled signal pathways.These signal cascades further influence many cel-lular metabolism-related processes,such as gene expression,cell cycle,and cell fate,and ultimately cause severe neural cell damage.However,endogenous cellular anti-Aβdefense processes always accompany the Aβ-induced microenvironment alterations.Aβ-cleaving endopeptidases,Aβ-degrading ubiquitin-proteasome system(UPS),and Aβ-engulfing glial cell immune responses are all essential self-defense mechanisms that we can leverage to develop new drugs.This review discusses some of the most recent advances in understanding Aβ-centric AD mechanisms and suggests prospects for promising anti-Aβstrategies.

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Lipofectamine ^(TM)2000介导pIRES2-EGFP-NT3转染新生小鼠离体耳蜗基底膜的实验研究

目的构建真核表达质粒载体pIRES2-EGFP-NT3,检测其在阳离子脂质体介导下对新生小鼠离体耳蜗基底膜的转染情况。方法构建含有目的基因NT3的真核表达质粒载体pIRES2-EGFP-NT3后,在阳离子脂质体LipofectamineTM2000介导下将其转染新生小鼠离体耳蜗基底膜培养组织,转染后24 h,通过Confocal显微镜观察小鼠离体耳蜗基底膜的转染情况和转染效率。结果成功构建了真核表达质粒载体pIRES2-EGFP-NT3,通过阳离子脂质体LipofectamineTM2000介导,该质粒在新生小鼠离体耳蜗基底膜转染的范围内转染进17个细胞,说明该质粒在阳离子脂质体介导下能转染新生小鼠离体耳蜗基底膜培养组织。结论含有目的基因NT3的真核表达质粒载体pIRES2-EGFP-NT3的成功构建,及其在阳离子脂质体介导下对新生小鼠离体耳蜗基底膜培养组织的有效转染,为研究NT3基因转染对正常及致聋小鼠耳蜗效应的实验奠定了基础。

Neurotrophin 3对本体感觉神经作用的研究进展

Neurotrophin 3(NT-3)是本体感觉神经存活和发挥生理功能所必需的营养因子。在胚胎期缺失NT-3,可直接导致本体感觉神经元凋亡,进而导致本体感受器(肌梭)不能分化发育。同时,NT-3在本体感觉神经投射和形成突触联系中起关键的诱导作用。成年后缺失NT-3,也同样可导致本体感觉神经功能下降。在病理状态下NT-3可以保护本体感觉神经,并促进其恢复正常生理功能。

Acute exercise is associated with specific executive functions in college students with ADHD:A preliminary study

Purpose： The relationship between acute exercise and executive functions in college students with attention deficit hyperactivity disorder （ADHD） has not been clearly established. The purpose of this preliminary study was to examine the difference in cognitive performance between college students with and without ADHD and to explore the effects of acute exercise on multiple aspects of executive functions and on serum brain derived neurotrophic factor （BDNF）. Methods： College students （normal： n = 10; ADHD： n = 10） performed the Stroop Test, Trail Making Test, and Digit Span Test prior to and after an acute exercise intervention. Blood samples were obtained prior to the pre-test cognitive test performance and then again after exercise and prior to the post-test cognitive test performance. Results： Students with ADHD exhibited impaired executive functions, particularly on inhibition. Additionally, while acute exercise improved all aspects of executive functions in those without ADHD, acute exercise only improved inhibitory performance for those with ADHD. Further, BDNF was not influenced by acute exercise regardless of the subjects＇ ADHD status. Conclusion： These results provide preliminary evidence for exercise as a potential adjunct treatment for benefitting inhibition in college students with ADHD.

The gut microbiome:implications for neurogenesis and neurological diseases

There is an increasing recognition of the strong links between the gut microbiome and the brain,and there is persuasive evidence that the gut microbiome plays a role in a variety of physiological processes in the central nervous system.This review summarizes findings that gut microbial composition alterations are linked to hippocampal neurogenesis,as well as the possible mechanisms of action;the existing literature suggests that microbiota influence neurogenic processes,which can result in neurological disorders.We consider this evidence from the perspectives of neuroinflammation,microbial-derived metabolites,neurotrophins,and neurotransmitters.Based on the existing research,we propose that the administration of probiotics can normalize the gut microbiome.This could therefore also represent a promising treatment strategy to counteract neurological impairment.

Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish

Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.

Emerging neuromodulatory molecules for the treatment of neurogenic erectile dysfunction caused by cavernous nerve injury

Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strategies for the cavernous nerves （CNs）, as therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function. Nitric oxide released from the axonal end plates of these nerves within the corpora cavernosa causes relaxation of smooth muscle, initiating the haemodynamic changes of penile erection as well as contributing to maintained tumescence; the loss of CN function is primarily responsible for the development of erectile dysfunction （ED） after pelvic surgery and serves as the primary target for potential neuroprotective or regenerative strategies. Evidence from pre-clinical studies for select neuromodulatory approaches is reviewed, including neurotrophins, glial cell line-derived neurotrophic factors （GDNF）, bone morphogenic proteins, immunophilin ligands, erythropoetin （EPO）, and stem cells.