Target of research in subarachnoid hemorrhage（SAH）：The outcome of aneurysmal SAH remains poor despite advances in the diagnosis and treatment.Although many factors related to patients,aneurysms,and institutions,as ...Target of research in subarachnoid hemorrhage（SAH）：The outcome of aneurysmal SAH remains poor despite advances in the diagnosis and treatment.Although many factors related to patients,aneurysms,and institutions,as well as physiological parameters and medical complications were reported as prognostic factors,展开更多
Hypobaric hypoxia(HH)exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases.Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using...Hypobaric hypoxia(HH)exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases.Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans,thus hindering the development of disease treatment.Here,we report that cynomolgus monkeys(Macaca fascicularis)exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior.Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways,such as the vitamin D receptor(VDR)signaling pathway,in co-regulating HH-induced inflammation processes.We also observed profound transcriptomic alterations in brains after exposure to acute HH,including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes,which likely underlie the pathological effects of HH-induced brain injury.Administration of progesterone(PROG)and steroid neuroprotectant 5α-androst-3β,5,6β-triol(TRIOL)significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH.Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways,with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity.Thus,this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.展开更多
Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest...Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest challenge for medical staff;however,there are currently few effective therapeutic targets for secondary damage.Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system.Homer signaling can exert either positive or negative effects during such insults,depending on the specific subtype of Homer protein.Homer 1b/c couples with other proteins to form postsynaptic densities,which form the basis of synaptic transmission,while Homer 1a expression can be induced by harmful external factors.Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells,mediated or affected by extracellular or intracellular signaling or cytoskeletal processes.This review summarizes the structural features,related signaling pathways,and diverse roles of Homer proteins in physiological and pathological processes.Upregulating Homer 1a or downregulating Homer 1b/c may play a neuroprotective role in secondary brain injuries.Homer also plays an important role in the formation of photoreceptor synapses.These findings confirm the neuroprotective effects of Homer,and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.展开更多
Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, T...Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor（NF）-κΒ signaling among TLR4 signaling pathways as to the development of early brain injury（EBI） such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κΒ and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.展开更多
There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone（SVZ）. However, a comprehensive understanding of SVZ cell responses to brain injuri...There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone（SVZ）. However, a comprehensive understanding of SVZ cell responses to brain injuries has been hindered by the lack of sensitive approaches to study the cellular composition of this niche. Here we review progress being made in deciphering the cells of the SVZ gleaned from the use of a recently designed flow cytometry panel that allows SVZ cells to be parsed into multiple subsets of progenitors as well as putative stem cells. We review how this approach has begun to unmask both the heterogeneity of SVZ cells as well as the dynamic shifts in cell populations with neonatal and pediatric brain injuries. We also discuss how flow cytometric analyses also have begun to reveal how specific cytokines, such as Leukemia inhibitory factor are coordinating SVZ responses to injury.展开更多
Introduction: Traumatic Brain Injury (TBI) is a major public health problem causing significant morbidity and mortality in young adults. This study aimed to describe the epidemiological, diagnostic, therapeutic, and e...Introduction: Traumatic Brain Injury (TBI) is a major public health problem causing significant morbidity and mortality in young adults. This study aimed to describe the epidemiological, diagnostic, therapeutic, and evolutionary aspects of TBI. Materials and Methods: This was a prospective, descriptive study conducted from 1 April 2022 to 31 March 2023 on patients admitted to and treated for cranioencephalic trauma in the General Surgery department of Kara Regional Hospital. Results: Eighty-three (83) patients with cranioencephalic trauma were managed out of 773 patients admitted to the department during the study period. The mean age was 34 ± 14.98 years and the sex ratio was 3.6 in favour of men. Motorbike taxi drivers were the social group most affected (n = 33, 40%). The causes of trauma were dominated by public road accidents (n = 80;96%). TBI was mild (n = 40;48%), moderate (n = 35;42%) and severe (n = 8;10%). Cerebral CT scans were performed in 19 patients (23%). Cerebral contusion (n = 4) was the most frequent cerebral lesion. Six patients (7%) with severe head injuries were transferred to Kara University Hospital. Six deaths (7%) occurred in patients with severe head injuries. The main sequelae were intermittent headaches in all patients reviewed, and memory problems (6%). Conclusion: Traumatic brain injuries are common at Kara Regional Hospital. Severe cranial trauma is less frequent but leads to death because of financial difficulties and limited technical facilities.展开更多
Introduction: Traumatic brain injury (TBI) in children is a common cause of emergency department admission to our institution. TBI constitutes a real public health problem in developed countries and marked increase in...Introduction: Traumatic brain injury (TBI) in children is a common cause of emergency department admission to our institution. TBI constitutes a real public health problem in developed countries and marked increase in underdeveloped countries. The aim of this study was to evaluate the results of neurosurgical treatment of TBI in children at the neurosurgery department of Yopougon Teaching Hospital, while underlining the difficulties of the adequate management of this affection in Abidjan. Patients and Methods: It was a retrospective, descriptive monocentric study performed in the neurosurgery department, of Yopougon Teaching Hospital-Abidjan (Ivory Coast) from January 2000 to December 2017. We included all patients less than 16 years old admitted to the emergency department and all admitted in neurosurgery department for a TBI with a cerebral tomodensitometry and/or a magnetic resonance imaging having undergone a neurosurgical treatment. Results: During the study period 2825 cases of TBI in children aged less than 16 years old admitted to pediatric emergencies of our institution;among them 1020 (36%) presented clinical abnormalities and/or imaging. 292 (10.34%) children were hospitalized in neurosurgery department. 108 (36.9%) had surgical treatment. The mean age of patients was 7.8 ± 0.80 years with a male predominance (64%). Of the 108 children who had been operated on, 41 had acute extra-dural hematoma evacuation, 22 had a cranio-cerebral wound healing, 36 had a lift from a fracture depressing the skull and 9 had an acute subdural hematoma evacuation with a decompressive flap. The mean delay between diagnosis and surgical care was 104 ± 67.25 hours. The postoperative evolution at the last follow-up was favorable in 96 (88.8%) children with sequelae in 12 children (6 language disorders, 2 epileptic seizures and 4 motor deficits). The postoperative mortality rate was 11.2%. Conclusion: Ivory Coast Health System does not provide optimal care management of patients with TBI. There is an emerging imperative to develop an insurance system for the management of TBI.展开更多
Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microgl...Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.展开更多
Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the curr...Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the current understanding of the bidirectional relationship between blood-brain barrier disruption and neuroinflammation in traumatic brain injury,along with emerging combination therapeutic strategies.Literature review indicates that blood-brain barrier disruption and neuroinflammatory responses are key pathological features following traumatic brain injury.In the acute phase after traumatic brain injury,the pathological characteristics include primary blood-brain barrier disruption and the activation of inflammatory cascades.In the subacute phase,the pathological features are characterized by repair mechanisms and inflammatory modulation.In the chronic phase,the pathological features show persistent low-grade inflammation and incomplete recovery of the blood-brain barrier.Various physiological changes,such as structural alterations of the blood-brain barrier,inflammatory cascades,and extracellular matrix remodeling,interact with each other and are influenced by genetic,age,sex,and environmental factors.The dynamic balance between blood-brain barrier permeability and neuroinflammation is regulated by hormones,particularly sex hormones and stress-related hormones.Additionally,the role of gastrointestinal hormones is receiving increasing attention.Current treatment strategies for traumatic brain injury include various methods such as conventional drug combinations,multimodality neuromonitoring,hyperbaric oxygen therapy,and non-invasive brain stimulation.Artificial intelligence also shows potential in treatment decision-making and personalized therapy.Emerging sequential combination strategies and precision medicine approaches can help improve treatment outcomes;however,challenges remain,such as inadequate research on the mechanisms of the chronic phase traumatic brain injury and difficulties with technology integration.Future research on traumatic brain injury should focus on personalized treatment strategies,the standardization of techniques,costeffectiveness evaluations,and addressing the needs of patients with comorbidities.A multidisciplinary approach should be used to enhance treatment and improve patient outcomes.展开更多
Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated...Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).展开更多
Despite growing treatments for traumatic brain injury,there is still no ideal strategy for efficiently mitigating these processes.Ultrashort wave therapy,a type of physical factor therapy,has been widely used in vario...Despite growing treatments for traumatic brain injury,there is still no ideal strategy for efficiently mitigating these processes.Ultrashort wave therapy,a type of physical factor therapy,has been widely used in various clinical treatments.However,its effects on traumatic brain injury and the underlying mechanisms are not well understood.In this study,we demonstrate that ultrashort wave treatment can significantly promote injury repair and alleviate emotional and cognitive disorders.Our data showed that ultrashort wave reduced the levels of pro-inflammatory factors and inhibited neuroinflammation.In vitro experiments showed that ultrashort wave inhibited activation of C8-D1A astrocytes and BV2 microglia.Furthermore,traumatic brain injury induced the expression of Piezo1,while ultrashort wave effectively suppressed this high expression.Administration of Yoda1,a Piezo1 agonist,to traumatic brain injury mice reversed the beneficial effects of ultrashort wave.Consistently,Yoda1 also reversed the inhibitory effect of ultrashort wave on activation of C8-D1A astrocytes.These findings indicate that ultrashort wave is an ideal therapeutic strategy for traumatic brain injury,which works by inhibiting Piezo1,reducing neuroinflammation,and promoting nerve repair after traumatic brain injury.展开更多
Traumatic brain injury causes permanent cell death and can lead to long-term cognitive dysfunction,with no available treatments to repair the damaged brain tissue.Methods to track and understand traumatic brain injury...Traumatic brain injury causes permanent cell death and can lead to long-term cognitive dysfunction,with no available treatments to repair the damaged brain tissue.Methods to track and understand traumatic brain injury in humans are severely limited by the inaccessibility of living brain tissue,creating a need for in vitro model systems to study cellular mechanisms of degeneration and regeneration following injury.Here we describe methods to establish a 3D human brain tissue model,consisting of a silk-collagen composite scaffold seeded with human neurons,astrocytes,and microglia,to study neuro-regeneration after traumatic brain injury.Step-by-step fabrication,injury,and analytical assessments of the 3D“triculture”system are described.Using this tissue model system,we demonstrate that glial cells promote regeneration of neuronal networks within the injury site over several weeks post-injury.Further,we found that regenerating networks in the 3D triculture tissues did not secrete early markers of neurodegenerative disease,but displayed signs of excitatory/inhibitory imbalance,suggesting that pro-regenerative treatments for traumatic brain injury in the future may need to direct cell differentiation to promote proper function.The mechanical stability of this model system enables physiologically relevant impact injury and long-term culture capability,while its modular design enables modification of cell contents,extracellular matrix composition,and scaffold properties.This adaptability could allow the integration of patient-derived cells and genetic modifications to bridge research and clinical applications focused on personalized targeted therapies.This in vitro system provides a valuable platform for accelerating therapeutic advancements in traumatic brain injury and neurodegenerative disorders,ultimately improving patient outcomes.展开更多
BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in m...BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).展开更多
The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiqui...The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.展开更多
Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonst...Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions.In this study,we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model.This approach converted reactive astrocytes into neurons,increased neuronal density,protected endogenous neurons,decreased microglial activation,reduced peripheral CD8+T cell infiltration,and diminished angiogenesis in the injured area,leading to a significant reduction in lesion volume.Additionally,we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing,which showed an upregulation of neurogenesis-related genes and a downregulation of immune response-related and angiogenesis-related genes.Furthermore,our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model.In summary,this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiation-induced brain injury and hemorrhagic stroke,and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury.展开更多
Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functio...Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functional recovery after brain injury.Neuromodulation technologies represent one of the fastest-growing fields in medicine.These techniques utilize electricity,magnetism,sound,and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury.Therefore,this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury.Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury.However,studies report negative findings,potentially due to variations in stimulation protocols,differences in observation periods,and the severity of functional impairments among participants across different clinical trials.Additionally,we observed that different neuromodulation techniques share remarkably similar mechanisms,including promoting neuroplasticity,enhancing neurotrophic factor release,improving cerebral blood flow,suppressing neuroinflammation,and providing neuroprotection.Finally,considering the advantages and disadvantages of various neuromodulation techniques,we propose that future development should focus on closed-loop neural circuit stimulation,personalized treatment,interdisciplinary collaboration,and precision stimulation.展开更多
Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century.However,the inaccessibility and complexity of the human brain have always represented a challeng...Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century.However,the inaccessibility and complexity of the human brain have always represented a challenge in understanding the pathophysiology of the central nervous system.Brain organoids are self-assembled threedimensional aggregates derived from pluripotent stem cells with cell types and structures similar to the embryonic human brain,giving them potential for investigating the atypical cellular,molecular,and genetic characteristics characteristic of central nervous system disorders.Brain organoids also provide a platform for drug screening and serve as a potential source for transplantation therapy for brain injuries.However,the broad application of brain organoids is hampered by several limitations,such as the lack of high-fidelity cell types,insufficient maturation,and considerable heterogeneity,undermining their reliability in specific applications.This review summarizes brain organoid evolution,discusses recent technological and methodological innovations,and reviews their applications in drug screening,transplantation therapy,and disease modeling,as well as clinical research progress.Additionally,we emphasize the limitations of current brain organoid research and explore the potential for advancing the technology to enhance its applicability.展开更多
BACKGROUND:To investigate the mechanism underlying the basal forebrain-DMN/solv cholinergic projection-induced attenuation of brain injury after cardiopulmonary resuscitation(CPR).METHODS:Forty-six male Sprague-Dawley...BACKGROUND:To investigate the mechanism underlying the basal forebrain-DMN/solv cholinergic projection-induced attenuation of brain injury after cardiopulmonary resuscitation(CPR).METHODS:Forty-six male Sprague-Dawley rats were randomly divided into five groups:the sham group(n=6),the return of spontaneous circulation(ROSC) group(n=10),the optogenetic activation(CHAT-Light-CHR2) group(n=10),the optogenetic inhibition(CHAT-Light-NpHR) group(n=10),and the optogenetic activation combined with left cervical vagotomy(CHAT-Light-CHR2 + Lc VGX) group(n=10).Excitatory(CHR2) or inhibitory(NpHR) optogenetic viruses were injected into the basal forebrain(BF) of rats,followed by the implantation of ceramic ferrules.After three weeks of viral expression,the sham group received tracheotomy and catheterization only,the ROSC group underwent tracheotomy,asphyxial cardiac arrest,and CPR,and the CHR2 and NpHR groups received post-ROSC optogenetic activation or inhibition,respectively.The CHAT-Light-CHR2 + LcVGX group was pretreated with left cervical vagotomy followed by post-ROSC activation.Post-ROSC assessments included neurofunctional deficit score(NDS),histopathology(HE/Nissl/TUNEL staining and CD11b microglial activation) in the hippocampal CA1/prefrontal cortex,serum cytokines(IL-1β,IL-6 and TNF-α),and whole-brain immunofluorescence(c-Fos/CHAT) for neuronal activation mapping.RESULTS:Compared with the rats of sham group,rats of the ROSC group presented reduced NDS,neuronal loss,increased apoptosis,elevated CD11b expression,and increased cytokine levels.CHAT-CHR2 activation improved NDS,reduced neuronal loss and apoptosis,and decreased CD11b expression and TNF-α levels.CHAT-NpHR inhibition caused no improvement in NDS but exacerbated neuronal loss and CD11b expression elevation.CHAT-CHR2+LcVGX reversed these protective effects.Whole-brain immunofluorescence staining revealed that optogenetic activation of cholinergic neurons in the BF of the CHAT-Light-CHR2 group excited neurons in the DMN/solv region,which were identified as dopaminergic neurons.CONCLUSION:Cholinergic projections from the basal forebrain-DMN/solv may alleviate systemic and neuroinflammatory responses through the cholinergic anti-inflammatory pathway and mitigate brain injury following CPR.展开更多
Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of kn...Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.展开更多
The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury.This review provides a comprehensive overview of ErbB receptors and their ligands,highlighting canonical...The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury.This review provides a comprehensive overview of ErbB receptors and their ligands,highlighting canonical and non-canonical signaling mechanisms relevant to brain damage.We explore how ErbB signaling is dynamically regulated following injury and how it orchestrates processes such as neuroinflammation,gliosis,and neural repair.Special attention is given to its interplay with other critical pathways,including Notch signaling,and its roles within adult neurogenic niches,where it modulates neural stem cell behavior in response to damage.Based on accumulating preclinical evidence,we propose two therapeutic strategies for targeting ErbB signaling in brain injury:(1)dampening neuroinflammation through ErbB inhibition and(2)promoting neuroprotection and neurogenesis via neuregulin-1-mediated activation.The first strategy is supported by studies,which demonstrate that inhibition of ErbB1 limits neuroinflammation and supports neural repair in preclinical models.The latter strategy is supported by emerging studies demonstrating the significant potential of novel protein kinase C activating diterpenes in modulating ErbB signaling pathways through the regulation of neuregulin-1 release.Diterpenes,by influencing the ErbB pathway,may uniquely bridge the gap between neuroprotection and regeneration.Their potential to modulate inflammation and promote pro-regenerative cellular environments positions them as promising tools in the development of targeted therapies.By dissecting these mechanisms,we aim to shed light on the translational potential of ErbB-targeted therapies and their capacity to enhance endogenous repair processes in the injured brain.展开更多
基金supported by a Grant-in-Aid for Scientific Research from Mie Medical Research Foundation to HS
文摘Target of research in subarachnoid hemorrhage（SAH）：The outcome of aneurysmal SAH remains poor despite advances in the diagnosis and treatment.Although many factors related to patients,aneurysms,and institutions,as well as physiological parameters and medical complications were reported as prognostic factors,
基金supported by the National Natural Science Foundation of China(81773711)to W.Y.Strategic Priority Research Program of the Chinese Academy of Sciences(XDB13000000)+6 种基金Lundbeck Foundation Grant(R190-2014-2827)Carlsberg Foundation Grant(CF16-0663)to G.J.Z.Science and Technology Program of Guangzhou,China(201704020103)to W.Y.Introduction of Innovative R&D Team Program of Guangdong Province(2013Y104)Leading Talent Project in Science and Technology of Guangzhou Development District(2019-L002)National Major Scientific and Technological Special Project for“Significant New Drugs Development”(2016ZX09101026)to S.Z.L.Key Projects of the Military Science and Technology PLA(AWS14C007 and AWS16J023)to Y.Q.G
文摘Hypobaric hypoxia(HH)exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases.Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans,thus hindering the development of disease treatment.Here,we report that cynomolgus monkeys(Macaca fascicularis)exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior.Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways,such as the vitamin D receptor(VDR)signaling pathway,in co-regulating HH-induced inflammation processes.We also observed profound transcriptomic alterations in brains after exposure to acute HH,including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes,which likely underlie the pathological effects of HH-induced brain injury.Administration of progesterone(PROG)and steroid neuroprotectant 5α-androst-3β,5,6β-triol(TRIOL)significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH.Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways,with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity.Thus,this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.
基金supported by the National Natural Science Foundation of China,Nos.81600738(to FF),81771239(to ZF),81801300(to NS)。
文摘Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage.Secondary damage presents the greatest challenge for medical staff;however,there are currently few effective therapeutic targets for secondary damage.Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system.Homer signaling can exert either positive or negative effects during such insults,depending on the specific subtype of Homer protein.Homer 1b/c couples with other proteins to form postsynaptic densities,which form the basis of synaptic transmission,while Homer 1a expression can be induced by harmful external factors.Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells,mediated or affected by extracellular or intracellular signaling or cytoskeletal processes.This review summarizes the structural features,related signaling pathways,and diverse roles of Homer proteins in physiological and pathological processes.Upregulating Homer 1a or downregulating Homer 1b/c may play a neuroprotective role in secondary brain injuries.Homer also plays an important role in the formation of photoreceptor synapses.These findings confirm the neuroprotective effects of Homer,and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.
基金supported by a Grant-in-Aid for Scientific Research from Mie Medical Research Foundation to Dr.Suzuki
文摘Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor（NF）-κΒ signaling among TLR4 signaling pathways as to the development of early brain injury（EBI） such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κΒ and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.
文摘There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone（SVZ）. However, a comprehensive understanding of SVZ cell responses to brain injuries has been hindered by the lack of sensitive approaches to study the cellular composition of this niche. Here we review progress being made in deciphering the cells of the SVZ gleaned from the use of a recently designed flow cytometry panel that allows SVZ cells to be parsed into multiple subsets of progenitors as well as putative stem cells. We review how this approach has begun to unmask both the heterogeneity of SVZ cells as well as the dynamic shifts in cell populations with neonatal and pediatric brain injuries. We also discuss how flow cytometric analyses also have begun to reveal how specific cytokines, such as Leukemia inhibitory factor are coordinating SVZ responses to injury.
文摘Introduction: Traumatic Brain Injury (TBI) is a major public health problem causing significant morbidity and mortality in young adults. This study aimed to describe the epidemiological, diagnostic, therapeutic, and evolutionary aspects of TBI. Materials and Methods: This was a prospective, descriptive study conducted from 1 April 2022 to 31 March 2023 on patients admitted to and treated for cranioencephalic trauma in the General Surgery department of Kara Regional Hospital. Results: Eighty-three (83) patients with cranioencephalic trauma were managed out of 773 patients admitted to the department during the study period. The mean age was 34 ± 14.98 years and the sex ratio was 3.6 in favour of men. Motorbike taxi drivers were the social group most affected (n = 33, 40%). The causes of trauma were dominated by public road accidents (n = 80;96%). TBI was mild (n = 40;48%), moderate (n = 35;42%) and severe (n = 8;10%). Cerebral CT scans were performed in 19 patients (23%). Cerebral contusion (n = 4) was the most frequent cerebral lesion. Six patients (7%) with severe head injuries were transferred to Kara University Hospital. Six deaths (7%) occurred in patients with severe head injuries. The main sequelae were intermittent headaches in all patients reviewed, and memory problems (6%). Conclusion: Traumatic brain injuries are common at Kara Regional Hospital. Severe cranial trauma is less frequent but leads to death because of financial difficulties and limited technical facilities.
文摘Introduction: Traumatic brain injury (TBI) in children is a common cause of emergency department admission to our institution. TBI constitutes a real public health problem in developed countries and marked increase in underdeveloped countries. The aim of this study was to evaluate the results of neurosurgical treatment of TBI in children at the neurosurgery department of Yopougon Teaching Hospital, while underlining the difficulties of the adequate management of this affection in Abidjan. Patients and Methods: It was a retrospective, descriptive monocentric study performed in the neurosurgery department, of Yopougon Teaching Hospital-Abidjan (Ivory Coast) from January 2000 to December 2017. We included all patients less than 16 years old admitted to the emergency department and all admitted in neurosurgery department for a TBI with a cerebral tomodensitometry and/or a magnetic resonance imaging having undergone a neurosurgical treatment. Results: During the study period 2825 cases of TBI in children aged less than 16 years old admitted to pediatric emergencies of our institution;among them 1020 (36%) presented clinical abnormalities and/or imaging. 292 (10.34%) children were hospitalized in neurosurgery department. 108 (36.9%) had surgical treatment. The mean age of patients was 7.8 ± 0.80 years with a male predominance (64%). Of the 108 children who had been operated on, 41 had acute extra-dural hematoma evacuation, 22 had a cranio-cerebral wound healing, 36 had a lift from a fracture depressing the skull and 9 had an acute subdural hematoma evacuation with a decompressive flap. The mean delay between diagnosis and surgical care was 104 ± 67.25 hours. The postoperative evolution at the last follow-up was favorable in 96 (88.8%) children with sequelae in 12 children (6 language disorders, 2 epileptic seizures and 4 motor deficits). The postoperative mortality rate was 11.2%. Conclusion: Ivory Coast Health System does not provide optimal care management of patients with TBI. There is an emerging imperative to develop an insurance system for the management of TBI.
基金supported by the Natural Science Foundation of Yunnan Province,No.202401AS070086(to ZW)the National Key Research and Development Program of China,No.2018YFA0801403(to ZW)+1 种基金Yunnan Science and Technology Talent and Platform Plan,No.202105AC160041(to ZW)the Natural Science Foundation of China,No.31960120(to ZW)。
文摘Traumatic brain injury can be categorized into primary and secondary injuries.Secondary injuries are the main cause of disability following traumatic brain injury,which involves a complex multicellular cascade.Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury.In this article,we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury.We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia.We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia,such as the Toll-like receptor 4/nuclear factor-kappa B,mitogen-activated protein kinase,Janus kinase/signal transducer and activator of transcription,phosphoinositide 3-kinase/protein kinase B,Notch,and high mobility group box 1 pathways,can alleviate the inflammatory response triggered by microglia in traumatic brain injury,thereby exerting neuroprotective effects.We also reviewed the strategies developed on the basis of these pathways,such as drug and cell replacement therapies.Drugs that modulate inflammatory factors,such as rosuvastatin,have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury.Mesenchymal stem cells possess anti-inflammatory properties,and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury.Additionally,advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials,genetic engineering,and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models.However,numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed.In the future,new technologies,such as single-cell RNA sequencing and transcriptome analysis,can facilitate further experimental studies.Moreover,research involving non-human primates can help translate these treatment strategies to clinical practice.
基金supported by Open Scientific Research Program of Military Logistics,No.BLB20J009(to YZhao).
文摘Blood-brain barrier disruption and the neuroinflammatory response are significant pathological features that critically influence disease progression and treatment outcomes.This review systematically analyzes the current understanding of the bidirectional relationship between blood-brain barrier disruption and neuroinflammation in traumatic brain injury,along with emerging combination therapeutic strategies.Literature review indicates that blood-brain barrier disruption and neuroinflammatory responses are key pathological features following traumatic brain injury.In the acute phase after traumatic brain injury,the pathological characteristics include primary blood-brain barrier disruption and the activation of inflammatory cascades.In the subacute phase,the pathological features are characterized by repair mechanisms and inflammatory modulation.In the chronic phase,the pathological features show persistent low-grade inflammation and incomplete recovery of the blood-brain barrier.Various physiological changes,such as structural alterations of the blood-brain barrier,inflammatory cascades,and extracellular matrix remodeling,interact with each other and are influenced by genetic,age,sex,and environmental factors.The dynamic balance between blood-brain barrier permeability and neuroinflammation is regulated by hormones,particularly sex hormones and stress-related hormones.Additionally,the role of gastrointestinal hormones is receiving increasing attention.Current treatment strategies for traumatic brain injury include various methods such as conventional drug combinations,multimodality neuromonitoring,hyperbaric oxygen therapy,and non-invasive brain stimulation.Artificial intelligence also shows potential in treatment decision-making and personalized therapy.Emerging sequential combination strategies and precision medicine approaches can help improve treatment outcomes;however,challenges remain,such as inadequate research on the mechanisms of the chronic phase traumatic brain injury and difficulties with technology integration.Future research on traumatic brain injury should focus on personalized treatment strategies,the standardization of techniques,costeffectiveness evaluations,and addressing the needs of patients with comorbidities.A multidisciplinary approach should be used to enhance treatment and improve patient outcomes.
文摘Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).
基金supported by grants from Beijing Natural Science Foundation,No.7242278National Natural Science Foundation of China,No.32471422(both to XJ).
文摘Despite growing treatments for traumatic brain injury,there is still no ideal strategy for efficiently mitigating these processes.Ultrashort wave therapy,a type of physical factor therapy,has been widely used in various clinical treatments.However,its effects on traumatic brain injury and the underlying mechanisms are not well understood.In this study,we demonstrate that ultrashort wave treatment can significantly promote injury repair and alleviate emotional and cognitive disorders.Our data showed that ultrashort wave reduced the levels of pro-inflammatory factors and inhibited neuroinflammation.In vitro experiments showed that ultrashort wave inhibited activation of C8-D1A astrocytes and BV2 microglia.Furthermore,traumatic brain injury induced the expression of Piezo1,while ultrashort wave effectively suppressed this high expression.Administration of Yoda1,a Piezo1 agonist,to traumatic brain injury mice reversed the beneficial effects of ultrashort wave.Consistently,Yoda1 also reversed the inhibitory effect of ultrashort wave on activation of C8-D1A astrocytes.These findings indicate that ultrashort wave is an ideal therapeutic strategy for traumatic brain injury,which works by inhibiting Piezo1,reducing neuroinflammation,and promoting nerve repair after traumatic brain injury.
基金supported by funding from the U.S.Department of Defense,Nos.W911NF-23-1-0276,W81XWH2211065the NIH,No.P41EB027062(all to DLK).
文摘Traumatic brain injury causes permanent cell death and can lead to long-term cognitive dysfunction,with no available treatments to repair the damaged brain tissue.Methods to track and understand traumatic brain injury in humans are severely limited by the inaccessibility of living brain tissue,creating a need for in vitro model systems to study cellular mechanisms of degeneration and regeneration following injury.Here we describe methods to establish a 3D human brain tissue model,consisting of a silk-collagen composite scaffold seeded with human neurons,astrocytes,and microglia,to study neuro-regeneration after traumatic brain injury.Step-by-step fabrication,injury,and analytical assessments of the 3D“triculture”system are described.Using this tissue model system,we demonstrate that glial cells promote regeneration of neuronal networks within the injury site over several weeks post-injury.Further,we found that regenerating networks in the 3D triculture tissues did not secrete early markers of neurodegenerative disease,but displayed signs of excitatory/inhibitory imbalance,suggesting that pro-regenerative treatments for traumatic brain injury in the future may need to direct cell differentiation to promote proper function.The mechanical stability of this model system enables physiologically relevant impact injury and long-term culture capability,while its modular design enables modification of cell contents,extracellular matrix composition,and scaffold properties.This adaptability could allow the integration of patient-derived cells and genetic modifications to bridge research and clinical applications focused on personalized targeted therapies.This in vitro system provides a valuable platform for accelerating therapeutic advancements in traumatic brain injury and neurodegenerative disorders,ultimately improving patient outcomes.
基金supported by the award W81XWH1910309 (to HF) from the Department of Defensethe award R01-AG075092-01 (to HF)+2 种基金the award RF1AG063521 from the National Institute of Aging at the National Institutes of Healththe Neurological Research Institute Seed grant (to HF) from The Ohio State Universitythe Summer Undergraduate Research Fellowship (to NS) from The Ohio State University Chronic Brain Injury Discovery Theme
文摘BCL2-associated anthanogene 3 facilitates the clearance of tau protein aggregates:BCL2-associated anthanogene 3(BAG3)is a ubiquitously expressed and highly conserved multi-functional co-chaperone protein involved in many biological processes that supports cellular homeostasis,including the inhibition of apoptosis by preventing mitochondrial BAX localization(Lin et al.,2022)and the promotion of the degradation of hyperphosphorylated tau aggregates by its interactions with SQSTM1(p62)(Hamano and Mutoh,2022).
基金supported by grants from the Major Projects of Health Science Research Foundation for Middle-Aged and Young Scientist of Fujian Province,China,No.2022ZQNZD01010010the National Natural Science Foundation of China,No.82371390Fujian Province Scientific Foundation,No.2023J01725(all to XC).
文摘The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury.The post-transcriptional modification of N^(6)-methyladenosine is ubiquitous in the immune response of the central nervous system.The fat mass and obesity-related protein catalyzes the demethylation of N^(6)-methyladenosine modifications on mRNA and is widely expressed in various tissues,participating in the regulation of multiple diseases’biological processes.However,the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear.In this study,we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model.After fat mass and obesity interference,BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b^(+)/CD86^(+)cells and the secretion of pro-inflammatory cytokines.Fat mass and obesity-mediated N^(6)-methyladenosine demethylation accelerated the degradation of ADAM17 mRNA,while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA.Therefore,down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia.These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N^(6)-methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.
基金the National Natural Science Foundation of China,Nos.81925031(to YT)82330099(to YT)+7 种基金82404189(to KZ)the Key-Area Research and Development Program of Guangdong Province,No.2023B0303040003(to YT)STI 2030-Major Projects,No.2022ZD0211603(to YT)Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology,No.202206060002(to GC and YS)Science and Technology Project of Guangdong Province,No.2018B030332001(to GC)Guangdong Provincial Pearl River Project,No.2021ZT09Y552(to GC)the Guangdong Basic and Applied Basic Research Foundation,No.2022A1515110189(to KZ)Sun Yat-sen Pilot Scientific Research Fund,No.YXQH202427(to KZ).
文摘Radiation-induced brain injury remains one of the most severe complications of radiotherapy for head and neck tumors,with limited options for prevention and treatment.In situ neural regeneration technology has demonstrated promising therapeutic effects in various neurodegenerative and neurotrauma conditions.In this study,we overexpressed the neural transcription factor NeuroD1 using in situ neural regeneration technology in a radiation-induced brain injury mouse model.This approach converted reactive astrocytes into neurons,increased neuronal density,protected endogenous neurons,decreased microglial activation,reduced peripheral CD8+T cell infiltration,and diminished angiogenesis in the injured area,leading to a significant reduction in lesion volume.Additionally,we explored the potential mechanisms of NeuroD1 in situ neural regeneration technology through bulk RNA sequencing,which showed an upregulation of neurogenesis-related genes and a downregulation of immune response-related and angiogenesis-related genes.Furthermore,our findings suggested that NeuroD1 in situ neural regeneration technology converted reactive astrocytes into neurons and reduced microglial activation in a thalamic hemorrhagic stroke mouse model.In summary,this study supports NeuroD1 in situ neural regeneration technology as a potential therapeutic approach for treating radiation-induced brain injury and hemorrhagic stroke,and offers new insights into the therapeutic role of NeuroD1 in delayed brain injury.
基金supported by the National Natural Science Foundation of China,No.82371399(to YY)the Natural Science Foundation of Jiangsu Province,No.BK20221206(to YY)+1 种基金the Young Elite Scientists Sponsorship Program of Jiangsu Province,No.TJ-2022-028(to YY)the Scientific Research Program of Wuxi Health Commission,No.Z202302(to LY)。
文摘Spontaneous recovery frequently proves maladaptive or insufficient because the plasticity of the injured adult mammalian central nervous system is limited.This limited plasticity serves as a primary barrier to functional recovery after brain injury.Neuromodulation technologies represent one of the fastest-growing fields in medicine.These techniques utilize electricity,magnetism,sound,and light to restore or optimize brain functions by promoting reorganization or long-term changes that support functional recovery in patients with brain injury.Therefore,this review aims to provide a comprehensive overview of the effects and underlying mechanisms of neuromodulation technologies in supporting motor function recovery after brain injury.Many of these technologies are widely used in clinical practice and show significant improvements in motor function across various types of brain injury.However,studies report negative findings,potentially due to variations in stimulation protocols,differences in observation periods,and the severity of functional impairments among participants across different clinical trials.Additionally,we observed that different neuromodulation techniques share remarkably similar mechanisms,including promoting neuroplasticity,enhancing neurotrophic factor release,improving cerebral blood flow,suppressing neuroinflammation,and providing neuroprotection.Finally,considering the advantages and disadvantages of various neuromodulation techniques,we propose that future development should focus on closed-loop neural circuit stimulation,personalized treatment,interdisciplinary collaboration,and precision stimulation.
基金supported by Guizhou Provincial Higher Education Science and Technological Innovation Team,No.[2023]072 (to LX)Graduate Education and Teaching Innovation Program of Zunyi Medical University,No.ZYK262 (to QW)the Guizhou Graduate Research Fund,No.2024YJSKYJJ333 (to QW)
文摘Investigating the mechanisms underlying central nervous system disorders is a major scientific issue in the 21st century.However,the inaccessibility and complexity of the human brain have always represented a challenge in understanding the pathophysiology of the central nervous system.Brain organoids are self-assembled threedimensional aggregates derived from pluripotent stem cells with cell types and structures similar to the embryonic human brain,giving them potential for investigating the atypical cellular,molecular,and genetic characteristics characteristic of central nervous system disorders.Brain organoids also provide a platform for drug screening and serve as a potential source for transplantation therapy for brain injuries.However,the broad application of brain organoids is hampered by several limitations,such as the lack of high-fidelity cell types,insufficient maturation,and considerable heterogeneity,undermining their reliability in specific applications.This review summarizes brain organoid evolution,discusses recent technological and methodological innovations,and reviews their applications in drug screening,transplantation therapy,and disease modeling,as well as clinical research progress.Additionally,we emphasize the limitations of current brain organoid research and explore the potential for advancing the technology to enhance its applicability.
基金supported by grants from the Medical and Health Research Project of Zhejiang Province (No.2023KY1167)the Key Discipline Group of Trauma Treatment in Huzhou City (No.XKQ-HT-202103C)Young Talent Program of Huzhou Central Hospital (No.2020YC15)。
文摘BACKGROUND:To investigate the mechanism underlying the basal forebrain-DMN/solv cholinergic projection-induced attenuation of brain injury after cardiopulmonary resuscitation(CPR).METHODS:Forty-six male Sprague-Dawley rats were randomly divided into five groups:the sham group(n=6),the return of spontaneous circulation(ROSC) group(n=10),the optogenetic activation(CHAT-Light-CHR2) group(n=10),the optogenetic inhibition(CHAT-Light-NpHR) group(n=10),and the optogenetic activation combined with left cervical vagotomy(CHAT-Light-CHR2 + Lc VGX) group(n=10).Excitatory(CHR2) or inhibitory(NpHR) optogenetic viruses were injected into the basal forebrain(BF) of rats,followed by the implantation of ceramic ferrules.After three weeks of viral expression,the sham group received tracheotomy and catheterization only,the ROSC group underwent tracheotomy,asphyxial cardiac arrest,and CPR,and the CHR2 and NpHR groups received post-ROSC optogenetic activation or inhibition,respectively.The CHAT-Light-CHR2 + LcVGX group was pretreated with left cervical vagotomy followed by post-ROSC activation.Post-ROSC assessments included neurofunctional deficit score(NDS),histopathology(HE/Nissl/TUNEL staining and CD11b microglial activation) in the hippocampal CA1/prefrontal cortex,serum cytokines(IL-1β,IL-6 and TNF-α),and whole-brain immunofluorescence(c-Fos/CHAT) for neuronal activation mapping.RESULTS:Compared with the rats of sham group,rats of the ROSC group presented reduced NDS,neuronal loss,increased apoptosis,elevated CD11b expression,and increased cytokine levels.CHAT-CHR2 activation improved NDS,reduced neuronal loss and apoptosis,and decreased CD11b expression and TNF-α levels.CHAT-NpHR inhibition caused no improvement in NDS but exacerbated neuronal loss and CD11b expression elevation.CHAT-CHR2+LcVGX reversed these protective effects.Whole-brain immunofluorescence staining revealed that optogenetic activation of cholinergic neurons in the BF of the CHAT-Light-CHR2 group excited neurons in the DMN/solv region,which were identified as dopaminergic neurons.CONCLUSION:Cholinergic projections from the basal forebrain-DMN/solv may alleviate systemic and neuroinflammatory responses through the cholinergic anti-inflammatory pathway and mitigate brain injury following CPR.
基金funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation):project ID 431549029-SFB 1451the Marga-und-Walter-Boll-Stiftung(#210-10-15)(to MAR)a stipend from the'Gerok Program'(Faculty of Medicine,University of Cologne,Germany)。
文摘Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions.Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities,a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed.Thus,we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment,with a particular emphasis on traumatic brain injury and stroke.Due to the lack of translational models in most noninvasive brain stimulation techniques proposed,we found this review to the most relevant techniques used in humans,i.e.,transcranial magnetic stimulation and transcranial direct current stimulation.We searched the literature in Pub Med,encompassing the MEDLINE and PMC databases,for studies published between January 1,2020 and September 30,2024.Thirty-five studies were eligible.Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury,with emerging mechanistic evidence.Overall,we identified neuronal,inflammatory,microvascular,and apoptotic pathways highlighted in the literature.This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.
基金supported by the I+D+i(PID2022-142418OB-C21)grant funded by MICIU/AEI/10.13039/501100011033 and by ERDF/UE.
文摘The ErbB signaling network has recently emerged as a key modulator of central nervous system responses to injury.This review provides a comprehensive overview of ErbB receptors and their ligands,highlighting canonical and non-canonical signaling mechanisms relevant to brain damage.We explore how ErbB signaling is dynamically regulated following injury and how it orchestrates processes such as neuroinflammation,gliosis,and neural repair.Special attention is given to its interplay with other critical pathways,including Notch signaling,and its roles within adult neurogenic niches,where it modulates neural stem cell behavior in response to damage.Based on accumulating preclinical evidence,we propose two therapeutic strategies for targeting ErbB signaling in brain injury:(1)dampening neuroinflammation through ErbB inhibition and(2)promoting neuroprotection and neurogenesis via neuregulin-1-mediated activation.The first strategy is supported by studies,which demonstrate that inhibition of ErbB1 limits neuroinflammation and supports neural repair in preclinical models.The latter strategy is supported by emerging studies demonstrating the significant potential of novel protein kinase C activating diterpenes in modulating ErbB signaling pathways through the regulation of neuregulin-1 release.Diterpenes,by influencing the ErbB pathway,may uniquely bridge the gap between neuroprotection and regeneration.Their potential to modulate inflammation and promote pro-regenerative cellular environments positions them as promising tools in the development of targeted therapies.By dissecting these mechanisms,we aim to shed light on the translational potential of ErbB-targeted therapies and their capacity to enhance endogenous repair processes in the injured brain.
