Neuronal networks,especially those in the central nervous system(CNS),evolved to support extensive functional capabilities while ensuring stability.Several physiological"brakes"that maintain the stability of...Neuronal networks,especially those in the central nervous system(CNS),evolved to support extensive functional capabilities while ensuring stability.Several physiological"brakes"that maintain the stability of the neuronal networks in a healthy state quickly become a hinderance postinjury.These"brakes"include inhibition from the extracellular environment,intrinsic factors of neurons and the control of neuronal plasticity.There are distinct differences between the neuronal networks in the peripheral nervous system(PNS)and the CNS.Underpinning these differences is the trade-off between reduced functional capabilities with increased adaptability through the formation of new connections and new neurons.The PNS has"facilitators"that stimulate neuroregeneration and plasticity,while the CNS has"brakes"that limit them.By studying how these"facilitators"and"brakes"work and identifying the key processes and molecules involved,we can attempt to apply these theories to the neuronal networks of the CNS to increase its adaptability.The difference in adaptability between the CNS and PNS leads to a difference in neuroregenerative properties and plasticity.Plasticity ensures quick functional recovery of abilities in the short and medium term.Neuroregeneration involves synthesizing new neurons and connections,providing extra resources in the long term to replace those damaged by the injury,and achieving a lasting functional recovery.Therefore,by understanding the factors that affect neuroregeneration and plasticity,we can combine their advantages and develop rehabilitation techniques.Rehabilitation training methods,coordinated with pharmacological interventions and/or electrical stimulation,contributes to a precise,holistic treatment plan that achieves functional recovery from nervous system injuries.Furthermore,these techniques are not limited to limb movement,as other functions lost as a result of brain injury,such as speech,can also be recovered with an appropriate training program.展开更多
Acupuncture is potentially beneficial for post-stroke rehabilitation and is considered a promising preventive strategy for stroke.Electroacupuncture pretreatment or treatment after ischemic stroke by using appropriate...Acupuncture is potentially beneficial for post-stroke rehabilitation and is considered a promising preventive strategy for stroke.Electroacupuncture pretreatment or treatment after ischemic stroke by using appropriate electroacupuncture parameters generates neuroprotective and neuroregenerative effects that increase cerebral blood flow,regulate oxidative stress,attenuate glutamate excitotoxicity,maintain bloodbrain barrier integrity,inhibit apoptosis,increase growth factor production,and induce cerebral ischemic tolerance.展开更多
Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary fo...Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor(NSF) Attachment Protein Receptor(SNARE) proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration.展开更多
Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the und...Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.展开更多
The therapeutic potential of Annexin A1,an important member of the Annexin superfamily,has become evident in results of experiments with multiple human systems and animal models.The anti-inflammatory and pro-resolving...The therapeutic potential of Annexin A1,an important member of the Annexin superfamily,has become evident in results of experiments with multiple human systems and animal models.The anti-inflammatory and pro-resolving effects of Annexin A1 are characteristic of pathologies involving the nervous system.In this review,we initially describe the expression sites of Annexin A1,then outline the mechanisms by which Annexin A1 maintains the neurological homeostasis through either formyl peptide receptor 2 or other molecular approaches;and,finally,we discuss the neuroregenerative potential qualities of Annexin A1.The eye and the nervous system are anatomically and functionally connected,but the association between visual system pathogenesis,especially in the retina,and Annexin A1 alterations has not been well summarized.Therefore,we explain the beneficial effects of Annexin A1 for ocular diseases,especially for retinal diseases and glaucoma on the basis of published findings,and we explore present and future delivery strategies for Annexin A1 to the retina.展开更多
In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that hav...In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.展开更多
The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability ...The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3 D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation(cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this ‘proof-of-concept’ study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.展开更多
Parkinson’s disease is the second most common neurodegenerative disorder;it affects 1%of the population over the age of 65.The number of people with Parkinson’s disease is set to rapidly increase due to changing dem...Parkinson’s disease is the second most common neurodegenerative disorder;it affects 1%of the population over the age of 65.The number of people with Parkinson’s disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies.The pathological hallmarks of Parkinson’s disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum,and the aggregation ofα-synuclein;these result in a range of debilitating motor and non-motor symptoms.The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest.However,this strategy has had limited success to date.Clinical trials of two well-known neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have reported limited efficacy in Parkinson’s disease patients,despite these factors showing potent neurotrophic actions in animal studies.There is therefore a need to identify other neurotrophic factors that can protect againstα-synuclein-induced degeneration of dopaminergic neurons.The bone morphogenetic protein(BMP)family is the largest subgroup of the transforming growth factor-βsuperfamily of proteins.BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system.Importantly,many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons.Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra,and evidence for downregulation of BMP2 expression at distinct stages of Parkinson’s disease.We also discuss studies that explored the effects of BMP2 treatment,in in vitro and in vivo models of Parkinson’s disease.These studies found potent effects of BMP2 on dopaminergic neurites,which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson’s disease.Thus,the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway,in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson’s disease therapy.展开更多
Spinal cord injury(SCI) research is a very complex field lending to why reviews of SCI literatures can be beneficial to current and future researchers. This review focuses on recent articles regarding potential modali...Spinal cord injury(SCI) research is a very complex field lending to why reviews of SCI literatures can be beneficial to current and future researchers. This review focuses on recent articles regarding potential modalities for the treatment and management of SCI. The modalities were broken down into four categories: neuroprotectionpharmacologic, neuroprotection-non-pharmacologic, neuroregeneration-pharmacologic, neuroregeneration-non-pharmacologic. Peer-reviewed articles were found using Pub Med with search terms: "spinal cord injury", "spinal cord injury neuroregeneration", "olfactory ensheathing cells spinal cord injury", "rho-rock inhibitors spinal cord injury", "neural stem cell", "scaffold", "neural stem cell transplantation", "exosomes and SCI", "epidural stimulation SCI", "brain-computer interfaces and SCI". Most recent articles spanning two years were chosen for their relevance to the categories of SCI management and treatment. There has been a plethora of pre-clinical studies completed with their results being difficult to replicate in clinical studies. Therefore, scientists should focus on understanding and applying the results of previous research to develop more efficacious preclinical studies and clinical trials.展开更多
Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents a...Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.展开更多
As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further suppo...As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further supportive functions myelin provides to axons, as seen in demyelinating diseases such as multiple sclerosis(MS), leads to neurodegeneration and results in progressive disabilities. Multiple lines of evidence have demonstrated the increasing inability of oligodendrocyte precursor cells(OPCs) to replace lost oligodendrocytes(OLs) in order to restore lost myelin. Much research has been dedicated to reveal potential reasons for this regeneration deficit but despite promising approaches no remyelination-promoting drugs have successfully been developed yet. In addition to OPCs neural stem cells of the adult central nervous system also hold a high potential to generate myelinating OLs. There are at least two neural stem cell niches in the brain, the subventricular zone lining the lateral ventricles and the subgranular zone of the dentate gyrus, and an additional source of neural stem cells has been located in the central canal of the spinal cord. While a substantial body of literature has described their neurogenic capacity, still little is known about the oligodendrogenic potential of these cells, even if some animal studies have provided proof of their contribution to remyelination. In this review, we summarize and discuss these studies, taking into account the different niches, the heterogeneity within and between stem cell niches and present current strategies of how to promote stem cell-mediated myelin repair.展开更多
The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of dev...The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.展开更多
Biomaterials have increasingly become a focus of research on neuroprotection and neuroregeneration.Collagen,in terms of brain repair,presents many advantages such as being remarkably biocompatible,biodegradable,versat...Biomaterials have increasingly become a focus of research on neuroprotection and neuroregeneration.Collagen,in terms of brain repair,presents many advantages such as being remarkably biocompatible,biodegradable,versatile and non-toxic.Collagen can be used to form injectable scaffolds and micro/nano spheres in order to:(i) locally release therapeutic factors with the aim of protecting degenerating neurons in neurodegenerative conditions such as Alzheimer's or Parkinson's diseases,(ii) encapsulate stem cells for safe delivery,(iii) encapsulate genetically modified cells to provide a long term source of trophic factors,(iv) fill in the voids from injury to serve as a structural support and provide a permissive microenvironment to promote axonal growth.This mini-review summarizes different applications of collagen biomaterial for central nervous system protection and repair,as well as the future perspectives.Overall,collagen is a promising natural biomaterial with various applications which has the potential to progress the development of therapeutic strategies in central nervous system injuries and degeneration.展开更多
Spinal cord injury(SCI) is a highly debilitating neurological disease, which still lacks effective treatment strategies, causing significant financial burden and distress to the affected families. Nevertheless, nanote...Spinal cord injury(SCI) is a highly debilitating neurological disease, which still lacks effective treatment strategies, causing significant financial burden and distress to the affected families. Nevertheless, nanotechnology and regenerative medicine strategies holding promise for the development of novel therapies that would reach from bench to bedside to serve the SCI patients. There has already been significant progress in the field of cell-based therapies, with the clinical application for SCI, currently in phase II of the clinical trial. Stem cells(e.g., induced pluripotent stem cells, fetal stem cells, human embryonic stem cells, and olfactory ensheathing cells) are certainly not to be considered the panacea for neural repair but, especially when combined with rehabilitation or other combinatorial approaches using the help of nanotechnology, they seem to be the source of some of the most promising and clinical translatable cell-based therapies that could help solving impactful problems on neural repair.展开更多
Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)re...Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)repair.It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes,making development of CNS therapeutics challenging.Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society,it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels.Extracellular vesicles(EVs),also known as exosomes,when derived from mesenchymal stem cells,are one of the most promising approaches that have been attempted thus far,as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation.At the same time,advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur,as well as the release of biomolecules facilitating or inducing the reparative processes.This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels.The rationale behind this hypothesis is presented,analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain.This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur.Finally,the importance of including nonhuman primate models in the clinical translation pipeline,as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive,in vivo,quantifiable imagingbased biomarkers for CNS repair are discussed,aiming for more effective and safe clinical translation of such regenerative therapies to humans.展开更多
Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopa...Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH^(+))nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use(authorization No.162-15)on June 9,2019.展开更多
In the central nervous system,immunologic surveillance and response are carried out,in large part,by microglia.These resident macrophages derive from myeloid precursors in the embryonic yolk sac,migrating to the brain...In the central nervous system,immunologic surveillance and response are carried out,in large part,by microglia.These resident macrophages derive from myeloid precursors in the embryonic yolk sac,migrating to the brain and eventually populating local tissue prior to blood-brain barrier formation.Preserved for the duration of lifespan,microglia serve the host as more than just a central arm of innate immunity,also contributing significantly to the development and maintenance of neurons and neural networks,as well as neuroregeneration.The critical nature of these varied functions makes the characterization of key roles played by microglia in neurodegenerative disorders,especially Alzheimer’s disease,of paramount importance.While genetic models and rudimentary pharmacologic approaches for microglial manipulation have greatly improved our understanding of central nervous system health and disease,significant advances in the selective and near complete in vitro and in vivo depletion of microglia for neuroscience application continue to push the boundaries of research.Here we discuss the research efficacy and utility of various microglial depletion strategies,including the highly effective CSF1R inhibitor models,noteworthy insights into the relationship between microglia and neurodegeneration,and the potential for therapeutic repurposing of microglial depletion and repopulation.展开更多
Objective: Photobiomodulation (also known as Low Level Laser. LLLT or Cold Laser;Photo Medicine (PM)) has been a vital adjunct therapy in our clinical practice over 5 years, observations of improvement in cognition an...Objective: Photobiomodulation (also known as Low Level Laser. LLLT or Cold Laser;Photo Medicine (PM)) has been a vital adjunct therapy in our clinical practice over 5 years, observations of improvement in cognition and personality were noted in several patients. As a result, selected patients with Alzheimer’s Disease, vascular dementia, post-traumatic brain injury and other neuro-degenerative diseases were treated at clinical practices in Buffalo, New York;Sarasota, Florida;Lafayette, Indiana;Phoenix, Az., and Baton Rouge, La. Over 60 patients were treated with an average of 4 times over an 8-day period all reported/exhibited improvement in their condition, except that two men who were in their seventies were in robust health but had no short-term memory and no improvement was observed. However, Theralase has developed a more efficacious system which will be more efficacious, due to increased power for ATP activation. Method: Over 150 patients with the above conditions were treated in various areas (depending on diagnosis) including the prefrontal cortex, temporal lobe, Hippocampus, and Circle of Willis for duration of two and one-half minutes every 48 hours for 5 - 6 treatments. We utilized the Theralase multi-probe (905 nm/660 nm) at 60 miliwatts. It utilizes 5 - 905 nm near infra-red diodes and 4 infra-red 660 laser diodes with a peak power of 50,000 milliwatts at peak and pulse duration of 200 nanoseconds [1]. The PTSD patients were evaluated utilizing the co-occurring disorders program screening and assessment form. Conclusion: Dementia patients exhibited varying degrees of improvement in cognitive function and personality, leading to improved quality of life and decreased caregiver burden. PTSD patients’ improvement was objectively measured by formal neuropsychological testing utilizing the form. All PTSD patients scored no emotional problems after 3 - 5 treatments and all experienced overall sense of well-being. One experienced return of ability to smell he had not had for 5 years. Similar results were reported in a Japanese study where 15 patients were followed for a year. This non-invasive and non-systemic modality of therapy could play a key role in treating progressive neurodegenerative conditions, improving quality of life, and reducing health care costs.展开更多
文摘Neuronal networks,especially those in the central nervous system(CNS),evolved to support extensive functional capabilities while ensuring stability.Several physiological"brakes"that maintain the stability of the neuronal networks in a healthy state quickly become a hinderance postinjury.These"brakes"include inhibition from the extracellular environment,intrinsic factors of neurons and the control of neuronal plasticity.There are distinct differences between the neuronal networks in the peripheral nervous system(PNS)and the CNS.Underpinning these differences is the trade-off between reduced functional capabilities with increased adaptability through the formation of new connections and new neurons.The PNS has"facilitators"that stimulate neuroregeneration and plasticity,while the CNS has"brakes"that limit them.By studying how these"facilitators"and"brakes"work and identifying the key processes and molecules involved,we can attempt to apply these theories to the neuronal networks of the CNS to increase its adaptability.The difference in adaptability between the CNS and PNS leads to a difference in neuroregenerative properties and plasticity.Plasticity ensures quick functional recovery of abilities in the short and medium term.Neuroregeneration involves synthesizing new neurons and connections,providing extra resources in the long term to replace those damaged by the injury,and achieving a lasting functional recovery.Therefore,by understanding the factors that affect neuroregeneration and plasticity,we can combine their advantages and develop rehabilitation techniques.Rehabilitation training methods,coordinated with pharmacological interventions and/or electrical stimulation,contributes to a precise,holistic treatment plan that achieves functional recovery from nervous system injuries.Furthermore,these techniques are not limited to limb movement,as other functions lost as a result of brain injury,such as speech,can also be recovered with an appropriate training program.
基金supported under the Aim for the Top University Plan of the Ministry of Education,Taiwan,China
文摘Acupuncture is potentially beneficial for post-stroke rehabilitation and is considered a promising preventive strategy for stroke.Electroacupuncture pretreatment or treatment after ischemic stroke by using appropriate electroacupuncture parameters generates neuroprotective and neuroregenerative effects that increase cerebral blood flow,regulate oxidative stress,attenuate glutamate excitotoxicity,maintain bloodbrain barrier integrity,inhibit apoptosis,increase growth factor production,and induce cerebral ischemic tolerance.
基金supported by the Ramon y Cajal programme(RYC-2007-00417,RYC-2009-05510)grants from the Spanish MINECO(SAF2013-42445R and BFU2010-21507)CIBERNED
文摘Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor(NSF) Attachment Protein Receptor(SNARE) proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration.
基金funded by the Spanish Ministry of Economy and Competitiveness,No.PID(2019)-106498GB-100 (to MVS)by the Instituto de Salud CarlosⅢ,Fondo Europeo de Desarrollo Regional"Una manera de hacer Europa",No.PI19/00071 (to MAB)+2 种基金the RETICS subprograms of Spanish Networks OftoRed,Nos.RD16/0008/0026 (to DGB) and RD16/0008/0016 (to DGB)RICORS Terav,No.RD16/0011/0001 (to DGB)from Instituto de Salud CarlosⅢby the Fundacion Seneca,Agencia de Cienciay Tecnologia Región de Murcia,No.19881/GERM/15 (all to MVS)
文摘Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.
基金supported by the National Natural Science Foundation of China,Nos.31800868(to YZ),32271037(to XL)and 82271090(to HZ).
文摘The therapeutic potential of Annexin A1,an important member of the Annexin superfamily,has become evident in results of experiments with multiple human systems and animal models.The anti-inflammatory and pro-resolving effects of Annexin A1 are characteristic of pathologies involving the nervous system.In this review,we initially describe the expression sites of Annexin A1,then outline the mechanisms by which Annexin A1 maintains the neurological homeostasis through either formyl peptide receptor 2 or other molecular approaches;and,finally,we discuss the neuroregenerative potential qualities of Annexin A1.The eye and the nervous system are anatomically and functionally connected,but the association between visual system pathogenesis,especially in the retina,and Annexin A1 alterations has not been well summarized.Therefore,we explain the beneficial effects of Annexin A1 for ocular diseases,especially for retinal diseases and glaucoma on the basis of published findings,and we explore present and future delivery strategies for Annexin A1 to the retina.
基金supported by a grant from the Fundacao para a Ciencia e Tecnologia of the Ministerio da Educacao e Ciencia (2020.02006.CEECIND)iBiMED,University of Aveiro and the Fundacao para a Ciência e Tecnologia of the Ministerio da Educacao e Ciencia (to DT)。
文摘In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.
基金funded by a grant from the North Staffordshire Medical Institute,UK (to DMC and NT)。
文摘The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3 D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation(cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this ‘proof-of-concept’ study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.
基金supported by a RISAM PhD Scholarship from Cork Institute of Technology(R00094948)a research grant from Science Foundation Ireland(SFI)under the grant number 15/CDA/3498(to GWOK)
文摘Parkinson’s disease is the second most common neurodegenerative disorder;it affects 1%of the population over the age of 65.The number of people with Parkinson’s disease is set to rapidly increase due to changing demographics and there is an unmet clinical need for disease-modifying therapies.The pathological hallmarks of Parkinson’s disease are the progressive degeneration of dopaminergic neurons in the substantia nigra and their axons which project to the striatum,and the aggregation ofα-synuclein;these result in a range of debilitating motor and non-motor symptoms.The application of neurotrophic factors to protect and potentially regenerate the remaining dopaminergic neurons is a major area of research interest.However,this strategy has had limited success to date.Clinical trials of two well-known neurotrophic factors,glial cell line-derived neurotrophic factor and neurturin,have reported limited efficacy in Parkinson’s disease patients,despite these factors showing potent neurotrophic actions in animal studies.There is therefore a need to identify other neurotrophic factors that can protect againstα-synuclein-induced degeneration of dopaminergic neurons.The bone morphogenetic protein(BMP)family is the largest subgroup of the transforming growth factor-βsuperfamily of proteins.BMPs are naturally secreted proteins that play crucial roles throughout the developing nervous system.Importantly,many BMPs have been shown to be potent neurotrophic factors for dopaminergic neurons.Here we discuss recent work showing that transcripts for the BMP receptors and BMP2 are co-expressed with several key markers of dopaminergic neurons in the human substantia nigra,and evidence for downregulation of BMP2 expression at distinct stages of Parkinson’s disease.We also discuss studies that explored the effects of BMP2 treatment,in in vitro and in vivo models of Parkinson’s disease.These studies found potent effects of BMP2 on dopaminergic neurites,which is important given that axon degeneration is increasingly recognized as a key early event in Parkinson’s disease.Thus,the aim of this mini-review is to give an overview of the BMP family and the BMP-Smad signalling pathway,in addition to reviewing the available evidence demonstrating the potential of BMP2 for Parkinson’s disease therapy.
文摘Spinal cord injury(SCI) research is a very complex field lending to why reviews of SCI literatures can be beneficial to current and future researchers. This review focuses on recent articles regarding potential modalities for the treatment and management of SCI. The modalities were broken down into four categories: neuroprotectionpharmacologic, neuroprotection-non-pharmacologic, neuroregeneration-pharmacologic, neuroregeneration-non-pharmacologic. Peer-reviewed articles were found using Pub Med with search terms: "spinal cord injury", "spinal cord injury neuroregeneration", "olfactory ensheathing cells spinal cord injury", "rho-rock inhibitors spinal cord injury", "neural stem cell", "scaffold", "neural stem cell transplantation", "exosomes and SCI", "epidural stimulation SCI", "brain-computer interfaces and SCI". Most recent articles spanning two years were chosen for their relevance to the categories of SCI management and treatment. There has been a plethora of pre-clinical studies completed with their results being difficult to replicate in clinical studies. Therefore, scientists should focus on understanding and applying the results of previous research to develop more efficacious preclinical studies and clinical trials.
基金This work was supported by the Startup Grant for ZZ from the Department of Natural Sciences,University of Michigan-Dearborn and“CASL Faculty Summer Research Grant”for ZZ from Office of Research&Sponsored Programs,University of Michigan-Dearborn.
文摘Traumatic brain injury(TBI)is a major cause of mortality and morbidity in the pediatric population.With advances in medical care,the mortality rate of pediatric TBI has declined.However,more children and adolescents are living with TBI-related cognitive and emotional impairments,which negatively affects the quality of their life.Adult hippocampal neurogenesis plays an important role in cognition and mood regulation.Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases,including TBI.Promoting endogenous hippocampal neurogenesis after TBI merits significant attention.However,TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus,which results in aberrant migration and impaired dendrite development of adult-born neurons.Therefore,a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains.Secondary injuries,such as neuroinflammation and oxidative stress,exert a significant impact on hippocampal neurogenesis.Currently,a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries.In this review,we discuss the uniqueness of pediatric TBI,adult hippocampal neurogenesis after pediatric TBI,and current efforts that promote neuroprotection to the developing brains,which can be leveraged to facilitate neuroregeneration.
基金The German Academic Exchange Service (DAAD) supported RAsupported by grants to PK by the German Research Council (DFG+3 种基金 SPP1757/KU1934/2_1, KU1934/5-1)the Christiane and Claudia Hempel Foundation for clinical stem cell research and Young Gliasupported in part by the Walter and Ilse Rose Foundationthe James and Elisabeth Cloppenburg, Peek & Cloppenburg Düsseldorf Foundation
文摘As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further supportive functions myelin provides to axons, as seen in demyelinating diseases such as multiple sclerosis(MS), leads to neurodegeneration and results in progressive disabilities. Multiple lines of evidence have demonstrated the increasing inability of oligodendrocyte precursor cells(OPCs) to replace lost oligodendrocytes(OLs) in order to restore lost myelin. Much research has been dedicated to reveal potential reasons for this regeneration deficit but despite promising approaches no remyelination-promoting drugs have successfully been developed yet. In addition to OPCs neural stem cells of the adult central nervous system also hold a high potential to generate myelinating OLs. There are at least two neural stem cell niches in the brain, the subventricular zone lining the lateral ventricles and the subgranular zone of the dentate gyrus, and an additional source of neural stem cells has been located in the central canal of the spinal cord. While a substantial body of literature has described their neurogenic capacity, still little is known about the oligodendrogenic potential of these cells, even if some animal studies have provided proof of their contribution to remyelination. In this review, we summarize and discuss these studies, taking into account the different niches, the heterogeneity within and between stem cell niches and present current strategies of how to promote stem cell-mediated myelin repair.
基金supported by grants from the Italian Ministry of University and Research(MIUR)(SYSBIONET-Italian ROADMAP ESFRI Infrastructures to LA,AMC and MP IVASCOMAR-National Cluster to AMC)+5 种基金Netherlands Organization for Scientific Research(NWO)in the integrated program of WOTRO [W01.65.324.00/project 4] Science for Global DevelopmentSynpol:EU-FP7 [KBBE.2012.3.4-02#311815]Corbel:EU-H2020 [NFRADEV-4-2014-2015#654248]Epipredict:EU-H2020 MSCA-ITN-2014-ETN:Marie Sk?odowska-Curie Innovative Training Networks(ITN-ETN)[#642691]BBSRC China [BB/J020060/1] to HVWCorbel:EU-H2020 [PID 2354] to HVW and AMC
文摘The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.
基金supported by The Brain Mat Train project,which is funded by the European Union Horizon 2020 Programme(H2020-MSCA-ITN-2015)under the Marie Sklodowska-Curie Initial Training Network and Grant Agreement No.676408
文摘Biomaterials have increasingly become a focus of research on neuroprotection and neuroregeneration.Collagen,in terms of brain repair,presents many advantages such as being remarkably biocompatible,biodegradable,versatile and non-toxic.Collagen can be used to form injectable scaffolds and micro/nano spheres in order to:(i) locally release therapeutic factors with the aim of protecting degenerating neurons in neurodegenerative conditions such as Alzheimer's or Parkinson's diseases,(ii) encapsulate stem cells for safe delivery,(iii) encapsulate genetically modified cells to provide a long term source of trophic factors,(iv) fill in the voids from injury to serve as a structural support and provide a permissive microenvironment to promote axonal growth.This mini-review summarizes different applications of collagen biomaterial for central nervous system protection and repair,as well as the future perspectives.Overall,collagen is a promising natural biomaterial with various applications which has the potential to progress the development of therapeutic strategies in central nervous system injuries and degeneration.
文摘Spinal cord injury(SCI) is a highly debilitating neurological disease, which still lacks effective treatment strategies, causing significant financial burden and distress to the affected families. Nevertheless, nanotechnology and regenerative medicine strategies holding promise for the development of novel therapies that would reach from bench to bedside to serve the SCI patients. There has already been significant progress in the field of cell-based therapies, with the clinical application for SCI, currently in phase II of the clinical trial. Stem cells(e.g., induced pluripotent stem cells, fetal stem cells, human embryonic stem cells, and olfactory ensheathing cells) are certainly not to be considered the panacea for neural repair but, especially when combined with rehabilitation or other combinatorial approaches using the help of nanotechnology, they seem to be the source of some of the most promising and clinical translatable cell-based therapies that could help solving impactful problems on neural repair.
基金This work was supported by the National Center for Complementary and Integrative Health(NCCIH),No.R21AT008865(to NM)the National Institute of Aging(NIA)/National Institute of Mental Health(NIMH),No.R01AG042512(to NM).
文摘Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)repair.It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes,making development of CNS therapeutics challenging.Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society,it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels.Extracellular vesicles(EVs),also known as exosomes,when derived from mesenchymal stem cells,are one of the most promising approaches that have been attempted thus far,as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation.At the same time,advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur,as well as the release of biomolecules facilitating or inducing the reparative processes.This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels.The rationale behind this hypothesis is presented,analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain.This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur.Finally,the importance of including nonhuman primate models in the clinical translation pipeline,as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive,in vivo,quantifiable imagingbased biomarkers for CNS repair are discussed,aiming for more effective and safe clinical translation of such regenerative therapies to humans.
基金supported by the Consejo Nacional de Ciencia Tecnología(Conacyt)de México(Grant#254686,to DMF)。
文摘Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDNF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDNF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDNF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDNF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDNF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH^(+))nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDNF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDNF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of Centro de Investigación y de Estudios Avanzados approved our experimental procedures for animal use(authorization No.162-15)on June 9,2019.
基金This work was supported by DePaul University grant URC450622(to EC).
文摘In the central nervous system,immunologic surveillance and response are carried out,in large part,by microglia.These resident macrophages derive from myeloid precursors in the embryonic yolk sac,migrating to the brain and eventually populating local tissue prior to blood-brain barrier formation.Preserved for the duration of lifespan,microglia serve the host as more than just a central arm of innate immunity,also contributing significantly to the development and maintenance of neurons and neural networks,as well as neuroregeneration.The critical nature of these varied functions makes the characterization of key roles played by microglia in neurodegenerative disorders,especially Alzheimer’s disease,of paramount importance.While genetic models and rudimentary pharmacologic approaches for microglial manipulation have greatly improved our understanding of central nervous system health and disease,significant advances in the selective and near complete in vitro and in vivo depletion of microglia for neuroscience application continue to push the boundaries of research.Here we discuss the research efficacy and utility of various microglial depletion strategies,including the highly effective CSF1R inhibitor models,noteworthy insights into the relationship between microglia and neurodegeneration,and the potential for therapeutic repurposing of microglial depletion and repopulation.
文摘Objective: Photobiomodulation (also known as Low Level Laser. LLLT or Cold Laser;Photo Medicine (PM)) has been a vital adjunct therapy in our clinical practice over 5 years, observations of improvement in cognition and personality were noted in several patients. As a result, selected patients with Alzheimer’s Disease, vascular dementia, post-traumatic brain injury and other neuro-degenerative diseases were treated at clinical practices in Buffalo, New York;Sarasota, Florida;Lafayette, Indiana;Phoenix, Az., and Baton Rouge, La. Over 60 patients were treated with an average of 4 times over an 8-day period all reported/exhibited improvement in their condition, except that two men who were in their seventies were in robust health but had no short-term memory and no improvement was observed. However, Theralase has developed a more efficacious system which will be more efficacious, due to increased power for ATP activation. Method: Over 150 patients with the above conditions were treated in various areas (depending on diagnosis) including the prefrontal cortex, temporal lobe, Hippocampus, and Circle of Willis for duration of two and one-half minutes every 48 hours for 5 - 6 treatments. We utilized the Theralase multi-probe (905 nm/660 nm) at 60 miliwatts. It utilizes 5 - 905 nm near infra-red diodes and 4 infra-red 660 laser diodes with a peak power of 50,000 milliwatts at peak and pulse duration of 200 nanoseconds [1]. The PTSD patients were evaluated utilizing the co-occurring disorders program screening and assessment form. Conclusion: Dementia patients exhibited varying degrees of improvement in cognitive function and personality, leading to improved quality of life and decreased caregiver burden. PTSD patients’ improvement was objectively measured by formal neuropsychological testing utilizing the form. All PTSD patients scored no emotional problems after 3 - 5 treatments and all experienced overall sense of well-being. One experienced return of ability to smell he had not had for 5 years. Similar results were reported in a Japanese study where 15 patients were followed for a year. This non-invasive and non-systemic modality of therapy could play a key role in treating progressive neurodegenerative conditions, improving quality of life, and reducing health care costs.
