Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)iso...Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.展开更多
Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injur...Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injury remain limited.Recently,extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain injury.Extracellular vesicles are small membrane-bound vesicles that are naturally released by cells,including those in the brain,and can be engineered to contain therapeutic cargo,such as anti-inflammatory molecules,growth factors,and microRNAs.When administered intravenously,extra cellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury,where they can be taken up by recipient cells and modulate the inflammatory response,promote neuroregeneration,and improve functional outcomes.In preclinical studies,extracellular vesicle-based therapies have shown promising results in promoting recove ry after traumatic brain injury,including reducing neuronal damage,improving cognitive function,and enhancing motor recovery.While further research is needed to establish the safety and efficacy of extra cellular vesicle-based therapies in humans,extra cellular vesicles represent a promising novel approach for the treatment of traumatic brain injury.In this review,we summarize mesenchymal ste m/stromal cell-de rived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brainderived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.展开更多
Stroke, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage, is the leading cause of long-term disability and death worldwide. Animal models have greatly contributed to our understanding...Stroke, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage, is the leading cause of long-term disability and death worldwide. Animal models have greatly contributed to our understanding of the risk factors and the pathophysiology of stroke, as well as the development of therapeutic strategies for its treatment. Further development and investigation of experimental models, however, are needed to elucidate the pathogenesis of stroke and to enhance and expand novel therapeutic targets. In this article, we provide an overview of the characteristics of commonly-used animal models of stroke and focus on the inflammatory responses to cerebral stroke, which may provide insights into a framework for developing effective therapies for stroke in humans.展开更多
Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor co...Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.展开更多
Traumatic brain injury is an important global public health problem.Traumatic brain injury not only causes neural cell death,but also induces dendritic spine degeneration.Spared neurons from cell death in the injured ...Traumatic brain injury is an important global public health problem.Traumatic brain injury not only causes neural cell death,but also induces dendritic spine degeneration.Spared neurons from cell death in the injured brain may exhibit dendrite damage,dendritic spine degeneration,mature spine loss,synapse loss,and impairment of activity.Dendritic degeneration and synapse loss may significantly contribute to functional impairments and neurological disorders following traumatic brain injury.Normal function of the nervous system depends on maintenance of the functionally intact synaptic connections between the presynaptic and postsynaptic spines from neurons and their target cells.During synaptic plasticity,the numbers and shapes of dendritic spines undergo dynamic reorganization.Enlargement of spine heads and the formation and stabilization of new spines are associated with long-term potentiation,while spine shrinkage and retraction are associated with long-term depression.Consolidation of memory is associated with remodeling and growth of preexisting synapses and the formation of new synapses.To date,there is no effective treatment to prevent dendritic degeneration and synapse loss.This review outlines the current data related to treatments targeting dendritic spines that propose to enhance spine remodeling and improve functional recovery after traumatic brain injury.The mechanisms underlying proposed beneficial effects of therapy targeting dendritic spines remain elusive,possibly including blocking activation of Cofilin induced by beta amyloid,Ras activation,and inhibition of GSK-3 signaling pathway.Further understanding of the molecular and cellular mechanisms underlying synaptic degeneration/loss following traumatic brain injury will advance the understanding of the pathophysiology induced by traumatic brain injury and may lead to the development of novel treatments for traumatic brain injury.展开更多
Objectives: The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH). Methods: Primary ICH was...Objectives: The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH). Methods: Primary ICH was induced in 27 male Wistar rats by stereotactic injection of100mL of autologous blood into the striatum. Rats were divided into three groups (n = 9/group): 1) oral treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin, or 3) phosphate buffered saline daily starting 24-hours post-ICH and continuing daily for the next 3 days. On the fourth day, the animals underwent magnetic resonance imaging (MRI) for measurements of T1sat (a marker for BBB integrity), T2 (edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed and immunohistology or Western blotting was performed. Results: MRI data for animals receiving simvastatin treatment showed significantly reduced BBB dysfunction and improved CBF in the ICH rim compared to controls (P 0.05) 4 days after ICH. Simvastatin also significantly reduced edema (T2) in the rim at 4 days after ICH (P 0.05). Both statin-treated groups demonstrated increased occludin and endothelial barrier antigen levels within the vessel walls, indicating better preservation of BBB function (P 0.05) and increased number of blood vessels (P 0.05). Conclusions: Simvastatin treatment administered acutely after ICH protects BBB integrity as measured by MRI and correlative immunohistochemistry. There was also evidence of improved CBF and reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend by MRI measurement.展开更多
Stroke is a leading cause of death and disability in adults worldwide. For decades, the primary approach and goal of therapy for stroke has focused on neuroprotection, namely treating the injured tissue, with interven...Stroke is a leading cause of death and disability in adults worldwide. For decades, the primary approach and goal of therapy for stroke has focused on neuroprotection, namely treating the injured tissue, with interventions designed to reduce the volume of cerebral infarction. Enormous effort in the laboratory has been devoted to the development of neuroprotective agents in an attempt to salvage ischemic neurons in the brain from irreversible injury; however, all these efforts have failed to demonstrate efficacy in clinical trials of stroke. In order to treat stroke, we have to re-con- ceptualize and redefine our therapeutic targets. Acute neu- roprotective treatments for stroke fight a temporal battle of salvaging cerebral tissue before the onset of death, as well as a physiological impediment of delivery of therapy to tissue which has inadequate blood flow.展开更多
Traumatic brain injury（TBI） is one of the major causes of death and disability worldwide.No effective treatment has been identified from clinical trials.Compelling evidence exists that treatment with mesenchymal ste...Traumatic brain injury（TBI） is one of the major causes of death and disability worldwide.No effective treatment has been identified from clinical trials.Compelling evidence exists that treatment with mesenchymal stem cells（MSCs） exerts a substantial therapeutic effect after experimental brain injury.In addition to their soluble factors,therapeutic effects of MSCs may be attributed to their generation and release of exosomes.Exosomes are endosomal origin small-membrane nano-sized vesicles generated by almost all cell types.Exosomes play a pivotal role in intercellular communication.Intravenous delivery of MSC-derived exosomes improves functional recovery and promotes neuroplasticity in rats after TBI.Therapeutic effects of exosomes derive from the exosome content,especially micro RNAs（mi RNAs）.mi RNAs are small non-coding regulatory RNAs and play an important role in posttranscriptional regulation of genes.Compared with their parent cells,exosomes are more stable and can cross the blood-brain barrier.They have reduced the safety risks inherent in administering viable cells such as the risk of occlusion in microvasculature or unregulated growth of transplanted cells.Developing a cell-free exosome-based therapy may open up a novel approach to enhancing multifaceted aspects of neuroplasticity and to amplifying neurological recovery,potentially for a variety of neural injuries and neurodegenerative diseases.This review discusses the most recent knowledge of exosome therapies for TBI,their associated challenges and opportunities.展开更多
Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neurop...Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neuropathy,展开更多
Microvascular dysfunction has been implicated in many diseases such as stroke and diabetes.In addition to the microvascular endothelial cell(EC),the pericyte,a perivascular cell that adheres to the abluminal side of t...Microvascular dysfunction has been implicated in many diseases such as stroke and diabetes.In addition to the microvascular endothelial cell(EC),the pericyte,a perivascular cell that adheres to the abluminal side of the EC may also be important to ensure proper microvascular function.As a prominent perivascular cell,the pericyte has garnered increasing attention for its multiple functional aspects,especially the pericyte of central nervous system(Yemisci et al.,2009;Armulik et al.,2010;Gaceb et al.,2018).展开更多
Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective e...Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective effect. The present study extends our previous investigation and tests the effect of acute high-dose (within 24 hours) statin therapy on experimental ICH. Material and Methods: Fifty-six male wistar rats were subjected to ICHby stereotactic injection of 100 μl of autologous blood into the striatum. Rats were divided randomly into seven groups: saline control group (n = 8);10, 20 and 40 mg/kg simvastatin-treated groups (n = 8);and 10, 20 and 40 mg/kg atorvastatin-treated groups (n = 8). Simvastatin or atorvastatin were administered orally at 3 and 24 hours after ICH. Neurological functional outcome was evaluated using behavioral tests (mNSS and corner turn test) at multiple time points afterICH. Animals were sacrificed at 28 days after treatment, and histological studies were completed. Results: Acute treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg, but not at 40 mg/kg, significantly enhanced recovery of neurological function starting from 2 weeks post-ICH and persisting for up to 4 weeks postICH. In addition, at doses of 10 mg/kg and 20 mg/kg, histological evaluations revealed that simvastatin or atorvastatin reduced tissue loss, increased cell proliferation in the subventricular zone and enhanced vascular density and synaptogenesis in the hematoma boundary zone when compared to salinetreated rats. Conclusions: Treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg significantly improves neurological recovery after administration during the first 24 hours after ICH. Decreased tissue loss, increased cell proliferation and vascularity likely contribute to improved functional recovery in rats treated with statins after ICH.展开更多
Ischemic stroke is a cerebrovasculardisease with a high risk of mortality andlong-lasting neurological disabilities.Medical advances have resulted in adeclining trend in stroke incidence anddeaths in the United States...Ischemic stroke is a cerebrovasculardisease with a high risk of mortality andlong-lasting neurological disabilities.Medical advances have resulted in adeclining trend in stroke incidence anddeaths in the United States. However,increasing age and risk factors such asdiabetes have contributed to an increasedlifetime risk of stroke.展开更多
Traumatic brain injury （TBI）： Despite improved supportive and rehabilitative care of TBI patients, TBI remains a leading cause of death and disability worldwide. To date, no effective pharmacological treatments are...Traumatic brain injury （TBI）： Despite improved supportive and rehabilitative care of TBI patients, TBI remains a leading cause of death and disability worldwide. To date, no effective pharmacological treatments are available for TBI. The mechanisms underlying brain damage and repair following TBI are complex and not completely understood. Coagulopathy after TBI is frequent and an independent prognostic factor for unfavorable outcome and prognosis （Stein and Smith, 2004）. It may be amenable to treatment, and effective management of coagulopathy may protect from secondary injury and poor outcomes. Although the main challenge for TBI management is to address the risk of hypocoagulopathy with prolonged bleeding and progression of hemorrhagic lesions, the risk of hypercoagulopathy with an increased microthrombosis formation warrants investigation to reduce neurological deficits after TBI.展开更多
Previous studies have demonstrated that statins improve neurological outcome and promote neuro-vascular recovery after ICH. This study is designed to examine whether simvastatin and atorvastatin affect levels of growt...Previous studies have demonstrated that statins improve neurological outcome and promote neuro-vascular recovery after ICH. This study is designed to examine whether simvastatin and atorvastatin affect levels of growth factors and activate the Akt signaling pathway during the recovery phase after intracerebral hemorrhage (ICH) in rats. Sixty (60) male Wistar rats were subjected to ICH by stereotactic injecttion of 100 μL of autologous blood into the striatum and were treated with or without simvastatin or atorvastatin. Neurological functional outcome was evaluated by behavioral tests (mNSS and corner turn test) at different time points after ICH. Brain extracts were utilized for Enzyme-linked immunosorbent assay (ELISA) analyses to measure vascular endothelial growth factor (VEGF);brain-derived neurotrophin factor (BDNF) expression, and nerve growth factor (NGF). Western blot was used to measure the changes in the Akt-mediated signaling pathway. Both the simvastatin and atorvastatin-treated animals had significant neurological improvement at 2 weeks post-ICH. Simvastatin and atorvastatin treatment increased the expression of BDNF, VEGF and NGF in both low- and high-dose groups at 7 days after ICH (p < 0.05). Phosphorylation of Akt, glycogen synthase kinase-3β (GSK-3β), and cAMP response element-binding proteins (CREB) were also increased at 7 days after statin treatment. These results suggest that the therapeutic effects of statins after experimental ICH may be mediated by the transient induction of BDNF, VEGF and NGF expression and the activation of the Akt-mediated signaling pathway.展开更多
Adopted by the 2nd IANR Annual Conference General Assembly,Beijing,China,April 2009 and amended by the:8th IANR Annual Conference General Assembly,Tehran,Iran,April 201514th IANR Annual Conference,Xi'an,China,Marc...Adopted by the 2nd IANR Annual Conference General Assembly,Beijing,China,April 2009 and amended by the:8th IANR Annual Conference General Assembly,Tehran,Iran,April 201514th IANR Annual Conference,Xi'an,China,March 20231.With the rapid advancement of basic and clinical research in neurorestoration,Neurorestoratology has become a distinct medical discipline based on both the neurorestorative potential findings and neurorestorable theory of the central nervous system(CNS).Several relevant academic organizations,institutions,clinical centers and departments have been established worldwide,and many guidelines and expert consensus documents have been released for the purpose of promoting CNS restoration.The International Association of Neurorestoratology(IANR)is one of the most important academic platforms for this discipline.展开更多
COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020.Facing this dangerous situation,many colleagues in Neurorestoratology did their best to avoid infection if themselves and their pa...COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020.Facing this dangerous situation,many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients,and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology.Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases,neurorestorative mechanisms and clinical therapeutic achievements.Therapeutic progress during this year included advances in cell therapies,neurostimulation/neuromodulation,brain-computer interface(BCI),and pharmaceutical neurorestorative therapies,which improved neurological functions and quality of life for patients.Four clinical guidelines or standards of Neurorestoratology were published in 2020.Milestone examples include:1)a multicenter randomized,double-blind,placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements;2)patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis;3)a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential(SSVEP)-based BCI to achieve accurate and speedy computer input;4)a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions.We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.展开更多
Traumatic brain injury （TBI） remains a major cause of death and disability worldwide, Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer＇s disease,...Traumatic brain injury （TBI） remains a major cause of death and disability worldwide, Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer＇s disease, Parkinson＇s disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and promote functional recovery after TBI.展开更多
基金supported by the NIH grants,R01 NS111801(to ZGZ)American Heart Association 16SDG29860003(to YZ)。
文摘Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.
基金supported by Notional Institutes of Health Grant,No.1R01NS100710-01A1(to YX)。
文摘Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injury remain limited.Recently,extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain injury.Extracellular vesicles are small membrane-bound vesicles that are naturally released by cells,including those in the brain,and can be engineered to contain therapeutic cargo,such as anti-inflammatory molecules,growth factors,and microRNAs.When administered intravenously,extra cellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury,where they can be taken up by recipient cells and modulate the inflammatory response,promote neuroregeneration,and improve functional outcomes.In preclinical studies,extracellular vesicle-based therapies have shown promising results in promoting recove ry after traumatic brain injury,including reducing neuronal damage,improving cognitive function,and enhancing motor recovery.While further research is needed to establish the safety and efficacy of extra cellular vesicle-based therapies in humans,extra cellular vesicles represent a promising novel approach for the treatment of traumatic brain injury.In this review,we summarize mesenchymal ste m/stromal cell-de rived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brainderived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.
基金supported by grants from National Institute on Aging (R01 AG031811, R01 AG037506)National Institute of Neurological Disorders and Stroke (R01 NS083078-01A1, R41 NS080329-01A1)+1 种基金American Heart Association grant (14GRNT20460026)the National Natural Science Foundation of China (81300993, 81571145)
文摘Stroke, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage, is the leading cause of long-term disability and death worldwide. Animal models have greatly contributed to our understanding of the risk factors and the pathophysiology of stroke, as well as the development of therapeutic strategies for its treatment. Further development and investigation of experimental models, however, are needed to elucidate the pathogenesis of stroke and to enhance and expand novel therapeutic targets. In this article, we provide an overview of the characteristics of commonly-used animal models of stroke and focus on the inflammatory responses to cerebral stroke, which may provide insights into a framework for developing effective therapies for stroke in humans.
文摘Stroke remains the leading cause of long-term disability.Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex.As the only direct descending motor pathway,the corticospinal tract(CST)is the primary pathway to innervate spinal motor neurons,and thus,forms the neuroanatomical basis to control the peripheral muscles for voluntary movements.Here,we review evidence from both experimental animals and stroke patients,regarding CST axonal damage,functional contribution of CST axonal integrity and remodeling to neurological recovery,and therapeutic approaches aimed to enhance CST axonal remodeling after stroke.The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation,which will significantly impact the current clinical needs of subacute and chronic stroke treatment.
文摘Traumatic brain injury is an important global public health problem.Traumatic brain injury not only causes neural cell death,but also induces dendritic spine degeneration.Spared neurons from cell death in the injured brain may exhibit dendrite damage,dendritic spine degeneration,mature spine loss,synapse loss,and impairment of activity.Dendritic degeneration and synapse loss may significantly contribute to functional impairments and neurological disorders following traumatic brain injury.Normal function of the nervous system depends on maintenance of the functionally intact synaptic connections between the presynaptic and postsynaptic spines from neurons and their target cells.During synaptic plasticity,the numbers and shapes of dendritic spines undergo dynamic reorganization.Enlargement of spine heads and the formation and stabilization of new spines are associated with long-term potentiation,while spine shrinkage and retraction are associated with long-term depression.Consolidation of memory is associated with remodeling and growth of preexisting synapses and the formation of new synapses.To date,there is no effective treatment to prevent dendritic degeneration and synapse loss.This review outlines the current data related to treatments targeting dendritic spines that propose to enhance spine remodeling and improve functional recovery after traumatic brain injury.The mechanisms underlying proposed beneficial effects of therapy targeting dendritic spines remain elusive,possibly including blocking activation of Cofilin induced by beta amyloid,Ras activation,and inhibition of GSK-3 signaling pathway.Further understanding of the molecular and cellular mechanisms underlying synaptic degeneration/loss following traumatic brain injury will advance the understanding of the pathophysiology induced by traumatic brain injury and may lead to the development of novel treatments for traumatic brain injury.
文摘Objectives: The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH). Methods: Primary ICH was induced in 27 male Wistar rats by stereotactic injection of100mL of autologous blood into the striatum. Rats were divided into three groups (n = 9/group): 1) oral treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin, or 3) phosphate buffered saline daily starting 24-hours post-ICH and continuing daily for the next 3 days. On the fourth day, the animals underwent magnetic resonance imaging (MRI) for measurements of T1sat (a marker for BBB integrity), T2 (edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed and immunohistology or Western blotting was performed. Results: MRI data for animals receiving simvastatin treatment showed significantly reduced BBB dysfunction and improved CBF in the ICH rim compared to controls (P 0.05) 4 days after ICH. Simvastatin also significantly reduced edema (T2) in the rim at 4 days after ICH (P 0.05). Both statin-treated groups demonstrated increased occludin and endothelial barrier antigen levels within the vessel walls, indicating better preservation of BBB function (P 0.05) and increased number of blood vessels (P 0.05). Conclusions: Simvastatin treatment administered acutely after ICH protects BBB integrity as measured by MRI and correlative immunohistochemistry. There was also evidence of improved CBF and reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend by MRI measurement.
基金supported by National Institute of Neurological Disorders and Stroke(NINDS)of the National Institutes of Health under award number R01NS066041(ZL),R01NS081189(HX) and R01AG037506(MC)
文摘Stroke is a leading cause of death and disability in adults worldwide. For decades, the primary approach and goal of therapy for stroke has focused on neuroprotection, namely treating the injured tissue, with interventions designed to reduce the volume of cerebral infarction. Enormous effort in the laboratory has been devoted to the development of neuroprotective agents in an attempt to salvage ischemic neurons in the brain from irreversible injury; however, all these efforts have failed to demonstrate efficacy in clinical trials of stroke. In order to treat stroke, we have to re-con- ceptualize and redefine our therapeutic targets. Acute neu- roprotective treatments for stroke fight a temporal battle of salvaging cerebral tissue before the onset of death, as well as a physiological impediment of delivery of therapy to tissue which has inadequate blood flow.
基金supported by National Institute of Neurological Disorders and Stroke(NINDS)of the National Institutes of Health under award number R01 NS088656 to MC
文摘Traumatic brain injury（TBI） is one of the major causes of death and disability worldwide.No effective treatment has been identified from clinical trials.Compelling evidence exists that treatment with mesenchymal stem cells（MSCs） exerts a substantial therapeutic effect after experimental brain injury.In addition to their soluble factors,therapeutic effects of MSCs may be attributed to their generation and release of exosomes.Exosomes are endosomal origin small-membrane nano-sized vesicles generated by almost all cell types.Exosomes play a pivotal role in intercellular communication.Intravenous delivery of MSC-derived exosomes improves functional recovery and promotes neuroplasticity in rats after TBI.Therapeutic effects of exosomes derive from the exosome content,especially micro RNAs（mi RNAs）.mi RNAs are small non-coding regulatory RNAs and play an important role in posttranscriptional regulation of genes.Compared with their parent cells,exosomes are more stable and can cross the blood-brain barrier.They have reduced the safety risks inherent in administering viable cells such as the risk of occlusion in microvasculature or unregulated growth of transplanted cells.Developing a cell-free exosome-based therapy may open up a novel approach to enhancing multifaceted aspects of neuroplasticity and to amplifying neurological recovery,potentially for a variety of neural injuries and neurodegenerative diseases.This review discusses the most recent knowledge of exosome therapies for TBI,their associated challenges and opportunities.
基金supported by NINDS grants RO1 NS075084(LW)NIDDK RO1 DK097519(LW)
文摘Diabetes mellitus affects an estimated 422 million people worldwide.Peripheral neuropathy is one of the most common and disabling complications of diabetes.There is currently no effective treatment for diabetic neuropathy,
基金This work was supported by the National Heart,Lung,and Blood Institute R01HL143432(to JC).
文摘Microvascular dysfunction has been implicated in many diseases such as stroke and diabetes.In addition to the microvascular endothelial cell(EC),the pericyte,a perivascular cell that adheres to the abluminal side of the EC may also be important to ensure proper microvascular function.As a prominent perivascular cell,the pericyte has garnered increasing attention for its multiple functional aspects,especially the pericyte of central nervous system(Yemisci et al.,2009;Armulik et al.,2010;Gaceb et al.,2018).
文摘Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective effect. The present study extends our previous investigation and tests the effect of acute high-dose (within 24 hours) statin therapy on experimental ICH. Material and Methods: Fifty-six male wistar rats were subjected to ICHby stereotactic injection of 100 μl of autologous blood into the striatum. Rats were divided randomly into seven groups: saline control group (n = 8);10, 20 and 40 mg/kg simvastatin-treated groups (n = 8);and 10, 20 and 40 mg/kg atorvastatin-treated groups (n = 8). Simvastatin or atorvastatin were administered orally at 3 and 24 hours after ICH. Neurological functional outcome was evaluated using behavioral tests (mNSS and corner turn test) at multiple time points afterICH. Animals were sacrificed at 28 days after treatment, and histological studies were completed. Results: Acute treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg, but not at 40 mg/kg, significantly enhanced recovery of neurological function starting from 2 weeks post-ICH and persisting for up to 4 weeks postICH. In addition, at doses of 10 mg/kg and 20 mg/kg, histological evaluations revealed that simvastatin or atorvastatin reduced tissue loss, increased cell proliferation in the subventricular zone and enhanced vascular density and synaptogenesis in the hematoma boundary zone when compared to salinetreated rats. Conclusions: Treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg significantly improves neurological recovery after administration during the first 24 hours after ICH. Decreased tissue loss, increased cell proliferation and vascularity likely contribute to improved functional recovery in rats treated with statins after ICH.
文摘Ischemic stroke is a cerebrovasculardisease with a high risk of mortality andlong-lasting neurological disabilities.Medical advances have resulted in adeclining trend in stroke incidence anddeaths in the United States. However,increasing age and risk factors such asdiabetes have contributed to an increasedlifetime risk of stroke.
文摘Traumatic brain injury （TBI）： Despite improved supportive and rehabilitative care of TBI patients, TBI remains a leading cause of death and disability worldwide. To date, no effective pharmacological treatments are available for TBI. The mechanisms underlying brain damage and repair following TBI are complex and not completely understood. Coagulopathy after TBI is frequent and an independent prognostic factor for unfavorable outcome and prognosis （Stein and Smith, 2004）. It may be amenable to treatment, and effective management of coagulopathy may protect from secondary injury and poor outcomes. Although the main challenge for TBI management is to address the risk of hypocoagulopathy with prolonged bleeding and progression of hemorrhagic lesions, the risk of hypercoagulopathy with an increased microthrombosis formation warrants investigation to reduce neurological deficits after TBI.
文摘Previous studies have demonstrated that statins improve neurological outcome and promote neuro-vascular recovery after ICH. This study is designed to examine whether simvastatin and atorvastatin affect levels of growth factors and activate the Akt signaling pathway during the recovery phase after intracerebral hemorrhage (ICH) in rats. Sixty (60) male Wistar rats were subjected to ICH by stereotactic injecttion of 100 μL of autologous blood into the striatum and were treated with or without simvastatin or atorvastatin. Neurological functional outcome was evaluated by behavioral tests (mNSS and corner turn test) at different time points after ICH. Brain extracts were utilized for Enzyme-linked immunosorbent assay (ELISA) analyses to measure vascular endothelial growth factor (VEGF);brain-derived neurotrophin factor (BDNF) expression, and nerve growth factor (NGF). Western blot was used to measure the changes in the Akt-mediated signaling pathway. Both the simvastatin and atorvastatin-treated animals had significant neurological improvement at 2 weeks post-ICH. Simvastatin and atorvastatin treatment increased the expression of BDNF, VEGF and NGF in both low- and high-dose groups at 7 days after ICH (p < 0.05). Phosphorylation of Akt, glycogen synthase kinase-3β (GSK-3β), and cAMP response element-binding proteins (CREB) were also increased at 7 days after statin treatment. These results suggest that the therapeutic effects of statins after experimental ICH may be mediated by the transient induction of BDNF, VEGF and NGF expression and the activation of the Akt-mediated signaling pathway.
文摘Adopted by the 2nd IANR Annual Conference General Assembly,Beijing,China,April 2009 and amended by the:8th IANR Annual Conference General Assembly,Tehran,Iran,April 201514th IANR Annual Conference,Xi'an,China,March 20231.With the rapid advancement of basic and clinical research in neurorestoration,Neurorestoratology has become a distinct medical discipline based on both the neurorestorative potential findings and neurorestorable theory of the central nervous system(CNS).Several relevant academic organizations,institutions,clinical centers and departments have been established worldwide,and many guidelines and expert consensus documents have been released for the purpose of promoting CNS restoration.The International Association of Neurorestoratology(IANR)is one of the most important academic platforms for this discipline.
文摘COVID-19 has been an emerging and rapidly evolving risk to people of the world in 2020.Facing this dangerous situation,many colleagues in Neurorestoratology did their best to avoid infection if themselves and their patients,and continued their work in the research areas described in the 2020 Yearbook of Neurorestoratology.Neurorestorative achievements and progress during 2020 includes recent findings on the pathogenesis of neurological diseases,neurorestorative mechanisms and clinical therapeutic achievements.Therapeutic progress during this year included advances in cell therapies,neurostimulation/neuromodulation,brain-computer interface(BCI),and pharmaceutical neurorestorative therapies,which improved neurological functions and quality of life for patients.Four clinical guidelines or standards of Neurorestoratology were published in 2020.Milestone examples include:1)a multicenter randomized,double-blind,placebo-controlled study of olfactory ensheathing cell treatment of chronic stroke showed functional improvements;2)patients after transhumeral amputation experienced increased sensory acuity and had improved effectiveness in work and other activities of daily life using a prosthesis;3)a patient with amyotrophic lateral sclerosis used a steady-state visual evoked potential(SSVEP)-based BCI to achieve accurate and speedy computer input;4)a patient with complete chronic spinal cord injury recovered both motor function and touch sensation with a BCI and restored ability to detect objects by touch and several sensorimotor functions.We hope these achievements motivate and encourage other scientists and physicians to increase neurorestorative research and its therapeutic applications.
文摘Traumatic brain injury （TBI） remains a major cause of death and disability worldwide, Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer＇s disease, Parkinson＇s disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and promote functional recovery after TBI.
