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Metabolic reprogramming: a new option for the treatment of spinal cord injury

Neural Regeneration Research 2025年第4期20卷 1042-1057页

作者： Jiangjie Chen Jinyang Chen Chao Yu Kaishun Xia Biao Yang Ronghao Wang Yi Li Kesi Shi Yuang Zhang Haibin Xu Xuesong Zhang Jingkai Wang Qixin Chen Chengzhen Liang Department of Orthopedics The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouZhejiang ProvinceChina Orthopedics Research institute of Zhejiang University Zhejiang UniversityHangzhouZhejiang ProvinceChina Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang province HangzhouZhejiang ProvinceChina Clinical Research Center of Motor System Disease of Zhejiang province HangzhouZhejiang ProvinceChina Qiandongnan Prefecture People’s Hospital KailiGuizhou ProvinceChina Department of Orthopedics Fourth Medical CenterChinese PLA General HospitalBeijingChina

Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they *** the ongoing development of various therapies for spinal cord injuries,their effectiveness remains ***,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic *** this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic *** spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic ***,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial *** metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of *** rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell *** available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord *** further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.

关键词： axons glycolysis metabolic reprogramming metabolism mitochondria neural regeneration neuroprotection oxidative phosphorylation spinal cord injury therapy

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Repetitive transcranial magnetic stimulation in Alzheimer’s disease:effects on neural and synaptic rehabilitation

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Neural Regeneration Research 2025年第2期20卷 326-342页

作者： Yi Ji Chaoyi Yang Xuerui Pang Yibing Yan Yue Wu Zhi Geng Wenjie Hu Panpan Hu Xingqi Wu Kai Wang Department of Neurology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhui ProvinceChina Anhui province Key Laboratory of Cognition and Neuropsychiatric Disorders HefeiAnhui ProvinceChina Collaborative Innovation Center of Neuropsychiatric Disorders and Mental Health HefeiAnhui ProvinceChina institute of Artificial Intelligence Hefei Comprehensive National Science CenterHefeiAnhui ProvinceChina Department of Psychology and Sleep Medicine The Second Affiliated Hospital of Anhui Medical UniversityHefeiAnhui ProvinceChina

Alzheimer’s disease is a neurodegenerative disease resulting from deficits in synaptic transmission and *** Alzheimer’s disease brain tends to be hyperexcitable and hypersynchronized,thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life,leaving patients *** transcranial magnetic stimulation is a cost-effective,neuro-modulatory technique used for multiple neurological *** the past two decades,it has been widely used to predict cognitive decline;identify pathophysiological markers;promote neuroplasticity;and assess brain excitability,plasticity,and *** has also been applied to patients with dementia,because it can yield facilitatory effects on cognition and promote brain recovery after a neurological ***,its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of *** study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment,evaluate its effects on synaptic plasticity,and identify the associated *** review essentially focuses on changes in the pathology,amyloidogenesis,and clearance pathways,given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer’s *** mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription,which are closely related to the neural regeneration process,are also ***,we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation,with the aim to highlight future directions for better clinical translations.

关键词： Alzheimer’s disease amyloid deposition apoptotic mechanisms biomarker neural regeneration neurodegeneration repetitive transcranial magnetic stimulation synaptic plasticity

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Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases

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Neural Regeneration Research 2025年第3期20卷 763-778页

作者： Minghuang Gao Xinyue Wang Shijie Su Weicheng Feng Yaona Lai Kongli Huang Dandan Cao Qi Wang Science and Technology Innovation Center Guangzhou University of Chinese MedicineGuangzhouGuangdong ProvinceChina institute of Clinical Pharmacology Guangzhou University of Chinese MedicineGuangzhouGuangdong ProvinceChina The Sixth Affiliated Hospital Sun Yat-sen UniversityGuangzhouGuangdong ProvinceChina

Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.

关键词： central nervous system meningeal lymphatic vessels immunity myeloid cells lymphatic cells neurodegenerative disease

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Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

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Neural Regeneration Research 2025年第1期20卷 159-173页

作者： Man Han Deyang Zeng Wei Tan Xingxing Chen Shuyuan Bai Qiong Wu Yushan Chen Zhen Wei Yufei Mei Yan Zeng Brain Science and Advanced Technology institute Wuhan University of Science and TechnologyWuhanHubei ProvinceChina Geriatric Hospital Affiliated to Wuhan University of Science and Technology WuhanHubei ProvinceChina School of Public Health Wuhan University of Science and TechnologyWuhanHubei ProvinceChina

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral *** studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region–specific,particularly involving the corticolimbic system,including the ventral tegmental area,nucleus accumbens,prefrontal cortex,amygdala,and *** how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress *** this review,we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of *** focused on associated molecular pathways and neural circuits,with special attention to the brain-derived neurotrophic factor–tropomyosin receptor kinase B signaling pathway and the ventral tegmental area–nucleus accumbens dopamine *** determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature,severity,and duration of stress,especially in the above-mentioned brain regions of the corticolimbic ***,BDNF might be a biological indicator regulating stress-related processes in various brain regions.

关键词： amygdala chronic mild stress chronic social defeat stress corticolimbic system depression hippocampus medial prefrontal cortex nucleus accumbens social stress models ventral tegmental area

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Postnatal development of rat retina:a continuous observation and comparison between the organotypic retinal explant model and in vivo development

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Neural Regeneration Research 2025年第3期20卷 900-912页

作者： Baoqi Hu Rui Wang Hanyue Zhang Xiou Wang Sijia Zhou Bo Ma Yan Luan Xin Wang Xinlin Chen Zhichao Zhang Qianyan Kang Department of Ophthalmology The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anShaanxi ProvinceChina Department of Ophthalmology The First Affiliated Hospital of Northwest UniversityXi’anShaanxi ProvinceChina institute of Neurobiology Xi’an Jiaotong University Health Science CenterXi’anShaanxi ProvinceChina

The organotypic retinal explant culture has been established for more than a decade and offers a range of unique advantages compared with in vivo experiments and cell ***,the lack of systematic and continuous comparison between in vivo retinal development and the organotypic retinal explant culture makes this model controversial in postnatal retinal development ***,we aimed to verify the feasibility of using this model for postnatal retinal development studies by comparing it with the in vivo *** this study,we showed that postnatal retinal explants undergo normal development,and exhibit a consistent structure and timeline with retinas in ***,we used SOX2 and PAX6 immunostaining to identify retinal progenitor *** then examined cell proliferation and migration by immunostaining with Ki-67 and doublecortin,***-67-and doublecortin-positive cells decreased in both in vivo and explants during postnatal retinogenesis,and exhibited a high degree of similarity in abundance and distribution between ***,we used Ceh-10 homeodomain-containing homolog,glutamate-ammonia ligase(glutamine synthetase),neuronal nuclei,and ionized calcium-binding adapter molecule 1 immunostaining to examine the emergence of bipolar cells,Müller glia,mature neurons,and microglia,*** timing and spatial patterns of the emergence of these cell types were remarkably consistent between in vivo and explant *** study showed that the organotypic retinal explant culture model had a high degree of consistency with the progression of in vivo early postnatal retina *** findings confirm the accuracy and credibility of this model and support its use for long-term,systematic,and continuous observation.

关键词： bipolar cells differentiation in vivo microglia Müller glia organotypic retinal explant culture postnatal retina development proliferation retinal progenitor cells

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Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming

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Neural Regeneration Research 2025年第4期20卷 1178-1191页

作者： Wanxian Luo Chuanhui Xu Linxi Li Yunxiang Ji Yezhong Wang Yingjia Li Yongyi Ye Department of Medicine Ultrasonics Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina institute of Neuroscience Department of NeurosurgeryThe Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong ProvinceChina

Microglia,the primary immune cells within the brain,have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system,including Parkinson’s *** perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity,but also exhibit remarkable anti-inflammatory ***,the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly *** this study,we developed perfluoropentane-based oxygen-loaded nanodroplets(PFP-OLNDs)and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo,and suppressed microglial activation in a mouse model of Parkinson’s *** suppression led to a reduction in the inflammatory response,oxidative stress,and cell migration capacity in ***,the neurotoxic effects were mitigated,which alleviated neuronal ***,ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic *** further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1α***,our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

关键词： metabolic reprogramming microglia microglial migration nanotherapy neurodegenerative diseases neuroinflammation oxygen-loaded nanodroplets Parkinson’s disease perfluoropentane ultra-performance liquid chromatography–mass spectrometry

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Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stress–induced anxiety-like behavior

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Neural Regeneration Research 2025年第6期20卷 1721-1734页

作者： Xirong Xu Shoumin Xuan Shuai Chen Dan Liu Qian Xiao Jie Tu Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases Shenzhen-Hong Kong Institute of Brain ScienceShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina CAS Key Laboratory of Brain Connectome and Manipulation Brain Cognition and Brain Disease Institute(BCBDI)Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina Guangdong Provincial Key Laboratory of Brain Connectome and Behavior the Brain Cognition and Brain Disease Institute(BCBDI)Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina University of Chinese of Academy of Sciences BeijingChina Faculty of Life and Health Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong ProvinceChina

The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with ***, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal *** knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was ob

关键词： anxiety astrocytes basolateral amygdala behavior dihydrokainic acid excitatory amino acid transporter 2 fiber photometry glutamate LDN-212320 transporter

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CNKSR2 interactome analysis indicates its association with the centrosome/microtubule system

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Neural Regeneration Research 2025年第8期20卷 2420-2432页

作者： Lin Yin Yalan Xu Jie Mu Yu Leng Lei Ma Yu Zheng Ruizhi Li Yin Wang Peifeng Li Hai Zhu Dong Wang Jing Li institute for Translational Medicine The Affiliated Hospital of Qingdao UniversityMedical CollegeQingdao UniversityQingdaoShandong ProvinceChina School of Basic Medicine Qingdao UniversityQingdaoShandong ProvinceChina College of Life Sciences and School of PharmacyMedical CollegeQingdao UniversityQingdaoShandong ProvinceChina Department of Urology Qingdao Municipal Hospital Affiliated to Qingdao UniversityQingdaoShandong ProvinceChina

The protein connector enhancer of kinase suppressor of Ras 2(CNKSR2),present in both the postsynaptic density and cytoplasm of neurons,is a scaffolding protein with several protein-binding *** of the CNKSR2 gene have been implicated in neurodevelopmental disorders,particularly intellectual disability,although the precise mechanism involved has not yet been fully *** has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane,thereby influencing synaptic signaling and the morphogenesis of dendritic ***,the function of CNKSR2 in the cytoplasm remains to be *** this study,we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of *** a combination of bioinformatic analysis and cytological experiments,we found that the CNKSR2 interactors were significantly enriched in the proteome of the *** also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker *** colocalization analysis confirmed the centrosomal localization of *** we downregulated CNKSR2 expression in mouse neuroblastoma cells(Neuro 2A),we observed significant changes in the expression of numerous centrosomal *** manipulation also affected centrosome-related functions,including cell size and shape,cell proliferation,and ***,we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum *** findings establish a connection between CNKSR2 and the centrosome,and offer new insights into the underlying mechanisms of neurodevelopmental disorders.

关键词： autism spectrum disorder centrosome CNKSR2 intellectual disability interactome mass spectrometry microtubule neurodevelopmental disease protein complexes protein-protein interactions

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Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis

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Neural Regeneration Research 2025年第9期20卷 2556-2570页

作者： Yongting Lv Hongfu Li Department of Neurology Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina Department of Medical Genetics and Center for Rare disease Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina Nanhu Brain-Computer Interface institute HangzhouZhejiang Province

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely *** principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial *** biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even *** these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and *** light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and ***,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal *** fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration *** DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related *** is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease *** the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable *** review summarizes the lat

关键词： amyotrophic lateral sclerosis biomarker blood biomarkers diagnosis glial fibrillary acidic protein neurofilament light chain prognosis TAR DNA-binding protein 43

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Dip2a regulates stress susceptibility in the basolateral amygdala

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Neural Regeneration Research 2025年第6期20卷 1735-1748页

作者： Jing Li Zixuan He Weitai Chai Meng Tian Huali Yu Xiaoxiao He Xiaojuan Zhu Key Laboratory of Molecular Epigenetics Ministry of Education Institute of Genetics and CytologyNortheast Normal UniversityChangchunJilin ProvinceChina

Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.

关键词： 5-hydroxytryptamine acute restraint stress basolateral amygdala CaMKII neurons DIP2A metabolomics neurotransmitters principal component analysis stress susceptibility tryptophan

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