Neural Regeneration Research最新文献

{"title":"Targeting the brain's glymphatic pathway: A novel therapeutic approach for cerebral small vessel disease.","authors":"Yuhui Ma, Yan Han","doi":"10.4103/NRR.NRR-D-24-00821","DOIUrl":"10.4103/NRR.NRR-D-24-00821","url":null,"abstract":"<p><p>Cerebral small vessel disease encompasses a group of neurological disorders characterized by injury to small blood vessels, often leading to stroke and dementia. Due to its diverse etiologies and complex pathological mechanisms, preventing and treating cerebral small vessel vasculopathy is challenging. Recent studies have shown that the glymphatic system plays a crucial role in interstitial solute clearance and the maintenance of brain homeostasis. Increasing evidence also suggests that dysfunction in glymphatic clearance is a key factor in the progression of cerebral small vessel disease. This review begins with a comprehensive introduction to the structure, function, and driving factors of the glymphatic system, highlighting its essential role in brain waste clearance. Afterwards, cerebral small vessel disease was reviewed from the perspective of the glymphatic system, after which the mechanisms underlying their correlation were summarized. Glymphatic dysfunction may lead to the accumulation of metabolic waste in the brain, thereby exacerbating the pathological processes associated with cerebral small vessel disease. The review also discussed the direct evidence of glymphatic dysfunction in patients and animal models exhibiting two subtypes of cerebral small vessel disease: arteriolosclerosis-related cerebral small vessel disease and amyloid-related cerebral small vessel disease. Diffusion tensor image analysis along the perivascular space is an important non-invasive tool for assessing the clearance function of the glymphatic system. However, the effectiveness of its parameters needs to be enhanced. Among various nervous system diseases, including cerebral small vessel disease, glymphatic failure may be a common final pathway toward dementia. Overall, this review summarizes prevention and treatment strategies that target glymphatic drainage and will offer valuable insight for developing novel treatments for cerebral small vessel disease.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"433-442"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142838368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces.","authors":"Junichi Yuasa-Kawada, Mariko Kinoshita-Kawada, Masaki Hiramoto, Satoru Yamagishi, Takayasu Mishima, Shin'ichiro Yasunaga, Yoshio Tsuboi, Nobutaka Hattori, Jane Y Wu","doi":"10.4103/NRR.NRR-D-24-01330","DOIUrl":"10.4103/NRR.NRR-D-24-01330","url":null,"abstract":"<p><p>The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual's susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"612-635"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human stem cell-based cell replacement therapy for Parkinson's disease: Enhancing the survival of postmitotic dopamine neuron grafts.","authors":"Tae Wan Kim","doi":"10.4103/NRR.NRR-D-24-01394","DOIUrl":"10.4103/NRR.NRR-D-24-01394","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":"21 2","pages":"689-690"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tryptophan metabolism and ischemic stroke: An intricate balance.","authors":"Chongjie Yao, Dong Xie, Yuchen Zhang, Yuanhao Shen, Pingping Sun, Zhao Ma, Jin Li, Jiming Tao, Min Fang","doi":"10.4103/NRR.NRR-D-24-00777","DOIUrl":"10.4103/NRR.NRR-D-24-00777","url":null,"abstract":"<p><p>Ischemic stroke, which is characterized by hypoxia and ischemia, triggers a cascade of injury responses, including neurotoxicity, inflammation, oxidative stress, disruption of the blood-brain barrier, and neuronal death. In this context, tryptophan metabolites and enzymes, which are synthesized through the kynurenine and 5-hydroxytryptamine pathways, play dual roles. The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke. Neuroprotective metabolites, such as kynurenic acid, exert their effects through various mechanisms, including competitive blockade of N-methyl-D-aspartate receptors, modulation of α7 nicotinic acetylcholine receptors, and scavenging of reactive oxygen species. In contrast, neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins, induce neurotoxicity mediated by reactive oxygen species, and disrupt mitochondrial function. Additionally, the enzymes involved in tryptophan metabolism play major roles in these processes. Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis. Consequently, the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke. Stroke treatment aims to restore the balance of various metabolite levels; however, precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke. Therefore, this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":"21 2","pages":"466-477"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tropism-shifted AAV-PHP.eB-mediated bFGF gene therapy promotes varied neurorestoration after ischemic stroke in mice.","authors":"Rubing Shi, Jing Ye, Ze Liu, Cheng Wang, Shengju Wu, Hui Shen, Qian Suo, Wanlu Li, Xiaosong He, Zhijun Zhang, Yaohui Tang, Guo-Yuan Yang, Yongting Wang","doi":"10.4103/NRR.NRR-D-23-01802","DOIUrl":"10.4103/NRR.NRR-D-23-01802","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202602000-00040/figure1/v/2025-05-05T160104Z/r/image-tiff AAV-PHP.eB is an artificial adeno-associated virus (AAV) that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically. While AAV-PHP.eB has been used in various disease models, its cellular tropism in cerebrovascular diseases remains unclear. In the present study, we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor ( bFGF ) gene therapy. Mice were injected intravenously with AAV-PHP.eB either 14 days prior to (pre-stroke) or 1 day following (post-stroke) transient middle cerebral artery occlusion. Notably, we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen (mNG). This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A (Ly6A). Furthermore, AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke. Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"704-714"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optogenetic approaches for neural tissue regeneration: A review of basic optogenetic principles and target cells for therapy.","authors":"Davletshin Eldar, Sufianov Albert, Ageeva Tatyana, Sufianova Galina, Rizvanov Albert, Mukhamedshina Yana","doi":"10.4103/NRR.NRR-D-24-00685","DOIUrl":"10.4103/NRR.NRR-D-24-00685","url":null,"abstract":"<p><p>Optogenetics has revolutionized the field of neuroscience by enabling precise control of neural activity through light-sensitive proteins known as opsins. This review article discusses the fundamental principles of optogenetics, including the activation of both excitatory and inhibitory opsins, as well as the development of optogenetic models that utilize recombinant viral vectors. A considerable portion of the article addresses the limitations of optogenetic tools and explores strategies to overcome these challenges. These strategies include the use of adeno-associated viruses, cell-specific promoters, modified opsins, and methodologies such as bioluminescent optogenetics. The application of viral recombinant vectors, particularly adeno-associated viruses, is emerging as a promising avenue for clinical use in delivering opsins to target cells. This trend indicates the potential for creating tools that offer greater flexibility and accuracy in opsin delivery. The adaptations of these viral vectors provide advantages in optogenetic studies by allowing for the restricted expression of opsins through cell-specific promoters and various viral serotypes. The article also examines different cellular targets for optogenetics, including neurons, astrocytes, microglia, and Schwann cells. Utilizing specific promoters for opsin expression in these cells is essential for achieving precise and efficient stimulation. Research has demonstrated that optogenetic stimulation of both neurons and glial cells-particularly the distinct phenotypes of microglia, astrocytes, and Schwann cells-can have therapeutic effects in neurological diseases. Glial cells are increasingly recognized as important targets for the treatment of these disorders. Furthermore, the article emphasizes the emerging field of bioluminescent optogenetics, which combines optogenetic principles with bioluminescent proteins to visualize and manipulate neural activity in real time. By integrating molecular genetics techniques with bioluminescence, researchers have developed methods to monitor neuronal activity efficiently and less invasively, enhancing our understanding of central nervous system function and the mechanisms of plasticity in neurological disorders beyond traditional neurobiological methods. Evidence has shown that optogenetic modulation can enhance motor axon regeneration, achieve complete sensory reinnervation, and accelerate the recovery of neuromuscular function. This approach also induces complex patterns of coordinated motor neuron activity and promotes neural reorganization. Optogenetic approaches hold immense potential for therapeutic interventions in the central nervous system. They enable precise control of neural circuits and may offer new treatments for neurological disorders, particularly spinal cord injuries, peripheral nerve injuries, and other neurodegenerative diseases.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"521-533"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress granules: Guardians of cellular health and triggers of disease.","authors":"Meghal Desai, Keya Gulati, Manasi Agrawal, Shruti Ghumra, Pabitra K Sahoo","doi":"10.4103/NRR.NRR-D-24-01196","DOIUrl":"10.4103/NRR.NRR-D-24-01196","url":null,"abstract":"<p><p>Stress granules are membraneless organelles that serve as a protective cellular response to external stressors by sequestering non-translating messenger RNAs (mRNAs) and regulating protein synthesis. Stress granules formation mechanism is conserved across species, from yeast to mammals, and they play a critical role in minimizing cellular damage during stress. Composed of heterogeneous ribonucleoprotein complexes, stress granules are enriched not only in mRNAs but also in noncoding RNAs and various proteins, including translation initiation factors and RNA-binding proteins. Genetic mutations affecting stress granule assembly and disassembly can lead to abnormal stress granule accumulation, contributing to the progression of several diseases. Recent research indicates that stress granule dynamics are pivotal in determining their physiological and pathological functions, with acute stress granule formation offering protection and chronic stress granule accumulation being detrimental. This review focuses on the multifaceted roles of stress granules under diverse physiological conditions, such as regulation of mRNA transport, mRNA translation, apoptosis, germ cell development, phase separation processes that govern stress granule formation, and their emerging implications in pathophysiological scenarios, such as viral infections, cancer, neurodevelopmental disorders, neurodegeneration, and neuronal trauma.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"588-597"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-brain barrier disruption and neuroinflammation in the hippocampus of a cardiac arrest porcine model: Single-cell RNA sequencing analysis.","authors":"Tangxing Jiang, Yaning Li, Hehui Liu, Yijun Sun, Huidan Zhang, Qirui Zhang, Shuyao Tang, Xu Niu, Han Du, Yinxia Yu, Hongwei Yue, Yunyun Guo, Yuguo Chen, Feng Xu","doi":"10.4103/NRR.NRR-D-24-01269","DOIUrl":"10.4103/NRR.NRR-D-24-01269","url":null,"abstract":"<p><p>JOURNAL/nrgr/04.03/01300535-202602000-00043/figure1/v/2025-05-05T160104Z/r/image-tiff Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality. Despite advancements in resuscitation science, our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies. Previous studies primarily focused on neuronal death, potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury. To address these gaps, we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations, altered cell communication networks, and novel molecular mechanisms involved in post-cardiac arrest brain injury. In this study, we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation, and from sham control pigs. Sequencing results revealed changes in the proportions of different cell types, suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils. These results were validated through western blotting, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence staining. We also identified and validated a unique subcluster of activated microglia with high expression of S100A8, which increased over time following cardiac arrest. This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins. Additionally, we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes. Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin, driving pro-inflammatory microglial polarization. Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus, offering potential novel targets for neuroprotection and repair following cardiac arrest.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"742-755"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measuring glymphatic function: Assessing the toolkit.","authors":"Koushikk Ayyappan, Lucas Unger, Philip Kitchen, Roslyn M Bill, Mootaz M Salman","doi":"10.4103/NRR.NRR-D-24-01013","DOIUrl":"10.4103/NRR.NRR-D-24-01013","url":null,"abstract":"<p><p>Glymphatic flow has been proposed to clear brain waste while we sleep. Cerebrospinal fluid moves from periarterial to perivenous spaces through the parenchyma, with subsequent cerebrospinal fluid drainage to dural lymphatics. Glymphatic disruption is associated with neurological conditions such as Alzheimer's disease and traumatic brain injury. Therefore, investigating its structure and function may improve understanding of pathophysiology. The recent controversy on whether glymphatic flow increases or decreases during sleep demonstrates that the glymphatic hypothesis remains contentious. However, discrepancies between different studies could be due to limitations of the specific techniques used and confounding factors. Here, we review the methods used to study glymphatic function and provide a toolkit from which researchers can choose. We conclude that tracer analysis has been useful, ex vivo techniques are unreliable, and in vivo imaging is still limited. Finally, we explore the potential for future methods and highlight the need for in vitro models, such as microfluidic devices, which may address technique limitations and enable progression of the field.</p>","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"534-541"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FIREproof: Intricacies of microglial biology.","authors":"Wei Cao","doi":"10.4103/NRR.NRR-D-24-01198","DOIUrl":"10.4103/NRR.NRR-D-24-01198","url":null,"abstract":"","PeriodicalId":19113,"journal":{"name":"Neural Regeneration Research","volume":" ","pages":"663-664"},"PeriodicalIF":5.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}