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15 June 2025, Volume 20 Issue 6 Previous Issue   

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Single-cell and spatial omics: exploring hypothalamic heterogeneity Muhammad Junaid, Eun Jeong Lee, Su Bin Lim 2025, 20 (6):  1525-1540.  doi: 10.4103/NRR.NRR-D-24-00231 Abstract ( 78 )   PDF (4842KB) ( 122 )   Save Elucidating the complex dynamic cellular organization in the hypothalamus is critical for understanding its role in coordinating fundamental body functions. Over the past decade, single-cell and spatial omics technologies have significantly evolved, overcoming initial technical challenges in capturing and analyzing individual cells. These high-throughput omics technologies now offer a remarkable opportunity to comprehend the complex spatiotemporal patterns of transcriptional diversity and cell-type characteristics across the entire hypothalamus. Current single-cell and single-nucleus RNA sequencing methods comprehensively quantify gene expression by exploring distinct phenotypes across various subregions of the hypothalamus. However, single-cell/single-nucleus RNA sequencing requires isolating the cell/nuclei from the tissue, potentially resulting in the loss of spatial information concerning neuronal networks. Spatial transcriptomics methods, by bypassing the cell dissociation, can elucidate the intricate spatial organization of neural networks through their imaging and sequencing technologies. In this review, we highlight the applicative value of single-cell and spatial transcriptomics in exploring the complex molecular-genetic diversity of hypothalamic cell types, driven by recent high-throughput achievements. Related Articles | Metrics

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Peripheral mitochondrial DNA as a neuroinflammatorybiomarker for major depressive disorder Jinmei Ye, Cong Duan, Jiaxin Han, Jinrong Chen , Ning Sun, Yuan Li, Tifei Yuan, Daihui Peng 2025, 20 (6):  1541-1554.  doi: 10.4103/NRR.NRR-D-23-01878 Abstract ( 101 )   PDF (2361KB) ( 95 )   Save In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder. Related Articles | Metrics

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Therapeutic potential of exercise-hormone irisin in Alzheimer’s disease Eunhee Kim, Rudolph E. Tanzi, Se Hoon Choi 2025, 20 (6):  1555-1564.  doi: 10.4103/NRR.NRR-D-24-00098 Abstract ( 74 )   PDF (1047KB) ( 76 )   Save Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer’s disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer’s disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer’s disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloidβ-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5’s protective roles and mechanisms against Alzheimer’s disease. Related Articles | Metrics

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Neurogenesis dynamics in the olfactory bulb: deciphering circuitry organization, function, and adaptive plasticity Moawiah M. Naffaa 2025, 20 (6):  1565-1581.  doi: 10.4103/NRR.NRR-D-24-00312 Abstract ( 96 )   PDF (1253KB) ( 68 )   Save Adult neurogenesis persists after birth in the subventricular zone, with new neurons migrating to the granule cell layer and glomerular layers of the olfactory bulb, where they integrate into existing circuitry as inhibitory interneurons. The generation of these new neurons in the olfactory bulb supports both structural and functional plasticity, aiding in circuit remodeling triggered by memory and learning processes. However, the presence of these neurons, coupled with the cellular diversity within the olfactory bulb, presents an ongoing challenge in understanding its network organization and function. Moreover, the continuous integration of new neurons in the olfactory bulb plays a pivotal role in regulating olfactory information processing. This adaptive process responds to changes in epithelial composition and contributes to the formation of olfactory memories by modulating cellular connectivity within the olfactory bulb and interacting intricately with higher-order brain regions. The role of adult neurogenesis in olfactory bulb functions remains a topic of debate. Nevertheless, the functionality of the olfactory bulb is intricately linked to the organization of granule cells around mitral and tufted cells. This organizational pattern significantly impacts output, network behavior, and synaptic plasticity, which are crucial for olfactory perception and memory. Additionally, this organization is further shaped by axon terminals originating from cortical and subcortical regions. Despite the crucial role of olfactory bulb in brain functions and behaviors related to olfaction, these complex and highly interconnected processes have not been comprehensively studied as a whole. Therefore, this manuscript aims to discuss our current understanding and explore how neural plasticity and olfactory neurogenesis contribute to enhancing the adaptability of the olfactory system. These mechanisms are thought to support olfactory learning and memory, potentially through increased complexity and restructuring of neural network structures, as well as the addition of new granule granule cells that aid in olfactory adaptation. Additionally, the manuscript underscores the importance of employing precise methodologies to elucidate the specific roles of adult neurogenesis amidst conflicting data and varying experimental paradigms. Understanding these processes is essential for gaining insights into the complexities of olfactory function and behavior. Related Articles | Metrics

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The complex roles of m6A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases Yanxi Li, Jing Xue, Yuejia Ma, Ke Ye, Xue Zhao, Fangliang Ge, Feifei Zheng, Lulu Liu, Xu Gao, Dayong Wang, Qing Xia 2025, 20 (6):  1582-1598.  doi: 10.4103/NRR.NRR-D-23-01872 Abstract ( 91 )   PDF (5272KB) ( 121 )   Save N6-methyladenosine (m6 A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m6 A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m6 A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m6 A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m6 A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m6 A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m6 A levels across different models of neurodegenerative disease, particularly Alzheimer’s disease and Parkinson’s disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m6 A levels observed in Parkinson’s disease models exposed to manganese compared to normal Parkinson’s disease models further underscore the complexity of m6 A’s role in neurodegenerative processes. The roles of m6 A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m6 A and its varying effects on distinct brain regions and in different environments Related Articles | Metrics

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Potential role of tanycyte-derived neurogenesis in Alzheimer’s disease Guibo Qi, Han Tang, Jianian Hu, Siying Kang, Song Qin 2025, 20 (6):  1599-1612.  doi: 10.4103/NRR.NRR-D-23-01865 Abstract ( 93 )   PDF (5172KB) ( 85 )   Save Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. The precise coordination of the gene networks controlling neurogenesis in naive and mature tanycytes is essential for maintaining homeostasis in adulthood. However, our understanding of the molecular mechanisms and signaling pathways that govern the proliferation and differentiation of tanycytes into neurons remains limited. This article aims to review the recent advancements in research into the mechanisms and functions of tanycyte-derived neurogenesis. Studies employing lineage-tracing techniques have revealed that the neurogenesis specifically originating from tanycytes in the hypothalamus has a compensatory role in neuronal loss and helps maintain energy homeostasis during metabolic diseases. Intriguingly, metabolic disorders are considered early biomarkers of Alzheimer’s disease. Furthermore, the neurogenic potential of tanycytes and the state of newborn neurons derived from tanycytes heavily depend on the maintenance of mild microenvironments, which may be disrupted in Alzheimer’s disease due to the impaired blood–brain barrier function. However, the specific alterations and regulatory mechanisms governing tanycyte-derived neurogenesis in Alzheimer’s disease remain unclear. Accumulating evidence suggests that tanycyte-derived neurogenesis might be impaired in Alzheimer’s disease, exacerbating neurodegeneration. Confirming this hypothesis, however, poses a challenge because of the lack of long-term tracing and nucleus-specific analyses of newborn neurons in the hypothalamus of patients with Alzheimer’s disease. Further research into the molecular mechanisms underlying tanycyte-derived neurogenesis holds promise for identifying small molecules capable of restoring tanycyte proliferation in neurodegenerative diseases. This line of investigation could provide valuable insights into potential therapeutic strategies for Alzheimer’s disease and related conditions. Related Articles | Metrics

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The potential mechanism and clinical application value of remote ischemic conditioning in stroke Yajun Zhu, Xiaoguo Li, Xingwei Lei, Liuyang Tang, Daochen Wen, Bo Zeng, Xiaofeng Zhang, Zichao Huang, Zongduo Guo 2025, 20 (6):  1613-1627.  doi: 10.4103/NRR.NRR-D-23-01800 Abstract ( 83 )   PDF (3201KB) ( 81 )   Save Some studies have confirmed the neuroprotective effect of remote ischemic conditioning against stroke. Although numerous animal researches have shown that the neuroprotective effect of remote ischemic conditioning may be related to neuroinflammation, cellular immunity, apoptosis, and autophagy, the exact underlying molecular mechanisms are unclear. This review summarizes the current status of different types of remote ischemic conditioning methods in animal and clinical studies and analyzes their commonalities and differences in neuroprotective mechanisms and signaling pathways. Remote ischemic conditioning has emerged as a potential therapeutic approach for improving stroke-induced brain injury owing to its simplicity, non-invasiveness, safety, and patient tolerability. Different forms of remote ischemic conditioning exhibit distinct intervention patterns, timing, and application range. Mechanistically, remote ischemic conditioning can exert neuroprotective effects by activating the Notch1/phosphatidylinositol 3-kinase/ Akt signaling pathway, improving cerebral perfusion, suppressing neuroinflammation, inhibiting cell apoptosis, activating autophagy, and promoting neural regeneration. While remote ischemic conditioning has shown potential in improving stroke outcomes, its full clinical translation has not yet been achieved. Related Articles | Metrics

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Role of the globus pallidus in motor and non-motor symptoms of Parkinson’s disease Yimiao Jiang, Zengxin Qi, Huixian Zhu , Kangli Shen, Ruiqi Liu, Chenxin Fang, Weiwei Lou , Yifan Jiang, Wangrui Yuan, Xin Cao, Liang Chen, Qianxing Zhuang 2025, 20 (6):  1628-1643.  doi: 10.4103/NRR.NRR-D-23-01660 Abstract ( 108 )   PDF (3973KB) ( 86 )   Save The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson’s disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson’s disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson’s disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore, bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson’s disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson’s disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson’s disease, particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremordominant and non-tremor-dominant Parkinson’s disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity, and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson’s disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation. Related Articles | Metrics

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Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease Gabriela Seplovich , Yazan Bouchi , Juan Pablo de Rivero Vaccari ,  Jennifer C. Munoz Pareja , Andrew Reisner, Laura Blackwell , Yehia Mechref, Kevin K. Wang, J. Adrian Tyndall, Binu Tharakan, Firas Kobeissy 2025, 20 (6):  1644-1664.  doi: 10.4103/NRR.NRR-D-24-00107 Abstract ( 75 )   PDF (24285KB) ( 19 )   Save Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer’s disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline. Related Articles | Metrics

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Nanoparticles for the treatment of spinal cord injury Qiwei Yang, Di Lu, Jiuping Wu, Fuming Liang, Huayi Wang, Junjie Yang, Ganggang Zhang, Chen Wang, Yanlian Yang, Ling Zhu, Xinzhi Sun 2025, 20 (6):  1665-1680.  doi: 10.4103/NRR.NRR-D-23-01848 Abstract ( 107 )   PDF (5625KB) ( 65 )   Save Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development. Related Articles | Metrics

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MicroRNAs as potential diagnostic biomarkers for bipolar disorder Bridget Martinez, Philip V. Peplow 2025, 20 (6):  1681-1695.  doi: 10.4103/NRR.NRR-D-23-01588 Abstract ( 54 )   PDF (711KB) ( 71 )   Save Abnormal expression of microRNAs is connected to brain development and disease and could provide novel biomarkers for the diagnosis and prognosis of bipolar disorder. We performed a PubMed search for microRNA biomarkers in bipolar disorder and found 18 original research articles on studies performed with human patients and published from January 2011 to June 2023. These studies included microRNA profiling in bloodand brain-based materials. From the studies that had validated the preliminary findings, potential candidate biomarkers for bipolar disorder in adults could be miR-140-3p, -30d5p, -330-5p, -378a-5p, -21-3p, -330-3p, -345-5p in whole blood, miR-19b-3p, -1180-3p, -125a-5p, let-7e-5p in blood plasma, and miR-7-5p, -23b-5p, -142-3p, -221-5p, -370-3p in the blood serum. Two of the studies had investigated the changes in microRNA expression of patients with bipolar disorder receiving treatment. One showed a significant increase in plasma miR-134 compared to baseline after 4 weeks of treatment which included typical antipsychotics, atypical antipsychotics, and benzodiazepines. The other study had assessed the effects of prescribed medications which included neurotransmitter receptorsite binders (drug class B) and sedatives, hypnotics, anticonvulsants, and analgesics (drug class C) on microRNA results. The combined effects of the two drug classes increased the significance of the results for miR-219 and -29c with miR-30e-3p and -526b* acquiring significance. MicroRNAs were tested to see if they could serve as biomarkers of bipolar disorder at different clinical states of mania, depression, and euthymia. One study showed that upregulation in whole blood of miR-9-5p, -29a-3p, -106a-5p, -106b-5p, -107, -125a-3p, -125b-5p and of miR-107, -125a-3p occurred in manic and euthymic patients compared to controls, respectively, and that upregulation of miR-106a-5p, -107 was found for manic compared to euthymic patients. In two other studies using blood plasma, downregulation of miR-134 was observed in manic patients compared to controls, and dysregulation of miR-134, -152, -607, -633, -652, -155 occurred in euthymic patients compared to controls. Finally, microRNAs such as miR-34a, -34b, -34c, -137, and -140-3p, -21-3p, -30d-5p, -330-5p, -378a-5p, -134, -19b-3p were shown to have diagnostic potential in distinguishing bipolar disorder patients from schizophrenia or major depressive disorder patients, respectively. Further studies are warranted with adolescents and young adults having bipolar disorder and consideration should be given to using animal models of the disorder to investigate the effects of suppressing or overexpressing specific microRNAs. Related Articles | Metrics

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Dendritic spine degeneration: a primary mechanism in the aging process Gonzalo Flores, Leonardo Aguilar-Hernández, Fernado García-Dolores, Humberto Nicolini, Andrea Judith Vázquez-Hernández, Hiram Tendilla-Beltrán 2025, 20 (6):  1696-1698.  doi: 10.4103/NRR.NRR-D-24-00311 Abstract ( 58 )   PDF (3074KB) ( 26 )   Save Recent reports suggest that aging is not solely a physiological process in living beings; instead, it should be considered a pathological process or disease (Amorim et al., 2022). Consequently, this process involves a wide range of factors, spanning from genetic to environmental factors, and even includes the gut microbiome (GM) (Mayer et al., 2022). All these processes coincide at some point in the inflammatory process, oxidative stress, and apoptosis, at different degrees in various organs and systems that constitute a living organism (Mayer et al., 2022; AguilarHernández et al., 2023). However, one of the most studied organs in the aging process is the brain, due to the cognitive deficits observed in aging animals, including humans (Aguilar-Hernández et al., 2023). Moreover, with aging, a set of both metabolic and cardiovascular diseases manifests, among which are diabetes mellitus and high blood pressure. With the progression of both aging and these diseases, cognitive deficits have been demonstrated in both human and animal models (Flores-Gómez et al., 2019; Flores et al., 2020). These cognitive deficits can vary depending on the degree of affectation to interneuronal communication, specifically at the level of dendritic spines (Aguilar-Hernández et al., 2023). A recent study conducted by our research team has revealed that aging results in a decline in dendritic spine density and a reconfiguration of dendritic spine shapes in corticolimbic areas in rodents, such as the prefrontal cortex (PFC). The PFC plays a crucial role in cognitive functions like attention, decision-making, and control over reward and motivation (Reyes-Lizaola et al., 2024). While there is extensive data on the decrease in dendritic spine density due to aging in humans (AguilarHernández et al., 2023), the impact of aging on the structural neuroplasticity of dendritic spines remains unexplored, to the best of our knowledge. Related Articles | Metrics

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New insights on the role of chondroitin sulfate proteoglycans in neural stem cell–mediated repair in spinal cord injury Seyed Mojtaba Hosseini, Soheila Karimi-Abdolrezaee 2025, 20 (6):  1699-1700.  doi: 10.4103/NRR.NRR-D-24-00378 Abstract ( 70 )   PDF (1702KB) ( 30 )   Save Extensive neurodegeneration is a hallmark of traumatic spinal cord injury (SCI) that underlies permanent sensorimotor and autonomic impairments (Alizadeh et al., 2019). Following the primary impact, the spinal cord undergoes a cascade of secondary injury mechanisms that are driven by disruption of the blood–spinal cord barrier, vascular injury, glial reactivity, neuroinflammation, oxidative stress, lipid peroxidation, and glutamate excitotoxicity that culminate in neuronal and oligodendroglial cell death, demyelination, and axonal damage (Alizadeh et al., 2019). To achieve a meaningful functional recovery after SCI, regeneration of new neurons and oligodendrocytes and their successful growth and integration within the neural network are critical steps for reconstructing the damaged spinal cord tissue (Fischer et al., 2020). Related Articles | Metrics

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Phosphodiesterase 9 localization in cytoplasm and nucleus: the gateway to selective targeting in neuroprotection? Giovanni Ribaudo, Matteo Giannangeli, Margrate Anyanwu, Alessandra Gianoncelli 2025, 20 (6):  1701-1702.  doi: 10.4103/NRR.NRR-D-24-00373 Abstract ( 48 )   PDF (586KB) ( 34 )   Save T h e u m b re l l a t e r m “ n e u ro d e g e n e ra t i v e disorders” (NDDs) refers to several conditions characterized by a progressive loss of structure and function of cells belonging to the nervous system. Such diseases affect more than 50 million people worldwide. Neurodegenerative disorders are characterized by sundry factors and pathophysiological mechanisms that are challenging to be fully profiled. Many of these rely on cell signaling pathways to preserve homeostasis, involving second messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine 3′,5′-monophosphate (cGMP). Their ability to control the duration and amplitude of the signaling cascade is given by the presence of several common and uncommon effectors. Protein kinases A and G (PKA and PKG), phosphodiesterases (PDEs), and scaffold proteins are among them. Related Articles | Metrics

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Single-cell pan-omics, environmental neurology, and artificial intelligence: the time for holistic brain health research Paolo Abondio , Francesco Bruno 2025, 20 (6):  1703-1704.  doi: 10.4103/NRR.NRR-D-24-00324 Abstract ( 61 )   PDF (474KB) ( 25 )   Save The brain, with its trillions of neural connections, d i ffe re n t c e l l u l a r t y p e s , a n d m o l e c u l a r complexities, presents a formidable challenge for researchers aiming to comprehend the multifaceted nature of neural health. As traditional methods have provided valuable insights, emerging technologies offer unprecedented o p p o r t u n i t i e s to d e l v e d e e p e r i nt o t h e underpinnings of brain function. In the everevolving landscape of neuroscience, the quest to unravel the mysteries of the human brain is bound to take a leap forward thanks to new technological improvements and bold interpretative frameworks. Indeed, as our understanding of the intricacies of the human brain advances, so does the need for comprehensive and integrative approaches to studying brain health in a synergistic manner, bridging the gap between biology (e.g., molecular pathways), interactions (e.g., environmental influences), and advanced computational analyses (e.g., explainable artificial intelligence). Brain health, therefore, is not just about understanding brain function in and of itself; it is about comprehending its complex relational networks with the surrounding environment (represented by physiological, psychological, or external stimuli) and putting this information at the service of personalized well-being through precision medicine. Related Articles | Metrics

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Aging-induced memory loss due to decreased N1-acetyl-5- methoxykynuramine, a melatonin metabolite, in the hippocampus: a potential prophylactic agent for dementia Kazuki Watanabe, Atsuhiko Hattori 2025, 20 (6):  1705-1706.  doi: 10.4103/NRR.NRR-D-24-00379 Abstract ( 82 )   PDF (618KB) ( 27 )   Save Melatonin (N-acetyl-5-methoxytryptamine) is known as the hormone of darkness because it is synthesized at night and involved in regulating the circadian clock. The hormone is primarily synthesized by the vertebrate pineal gland, but is ubiquitous among invertebrates, unicellular organisms, plants, and even cyanobacteria (Hattori and Suzuki, 2024). Melatonin is well-conserved evolutionarily and possesses several physiological functions, such as immune response, bone and glucose metabolism, and memory formation besides regulating the circadian rhythm. In mammals, G-protein–linked melatonin membrane receptors are present in the brain, retina, spleen, spinal cord, intestine, kidney, prostate, ovary, skin, muscle, and liver. Nuclear receptors are also present in many mammalian tissues, implying the widespread physiological actions of melatonin via receptors. Moreover, melatonin has established functions as an endogenous free radical scavenger and as a broad-spectrum antioxidant (Galano and Reiter, 2018). Altogether, these findings demonstrate that melatonin has diverse physiological functions, which are thought to be supported by evolutionary relationships. Furthermore, melatonin metabolites have been observed to have several functions similar to those of melatonin. Melatonin metabolites, including 3-hydroxymelatonin, 2-hydroxymelatonin, N1- acetyl-N2-formyl-5-methoxykynuramine (AFMK), or N1-acetyl-5-methoxykynuramine (AMK), have been detected among species. In this perspective, we introduce the function of melatonin metabolites, notably focusing on the memory formation–related function of AMK. Related Articles | Metrics

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Unlocking hypoglycemia–associated brain microvascular dysfunction: critical insights from proteomic analysis Siva S.V.P. Sakamuri , Anil Sakamuri 2025, 20 (6):  1707-1708.  doi: 10.4103/NRR.NRR-D-24-00217 Abstract ( 52 )   PDF (664KB) ( 31 )   Save Hypoglycemia – a critical complication linked to worsened brain function in diabetic subjects: Hypoglycemia is characterized by a decline in circulatory glucose levels below standard physiological thresholds. Mild hypoglycemia, classified as level 1 hypoglycemia, is defined by blood glucose levels below 70 mg/dL and can be effectively addressed through carbohydrate intake. Severe hypoglycemia, denoted by blood glucose levels less than 54 mg/dL, poses a life-threatening risk if left untreated. Individuals with type 1 and type 2 diabetes undergoing insulin treatment are particularly susceptible to hypoglycemia due to impaired counterregulatory mechanisms. According to International Hypoglycemia Study Group, nearly 40% of type 1 diabetic individuals and 20% of type 2 diabetic individuals with a history of insulin treatment exceeding five years may develop severe hypoglycemia as a complication. Notably, recurrent occurrences of mild hypoglycemia are more prevalent in diabetic subjects compared to instances of severe hypoglycemia (Brazeau et al., 2022). Related Articles | Metrics

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Emerging insights into the function of very long chain fatty acids at cerebellar synapses Martin-Paul Agbaga , Mohiuddin Ahmad 2025, 20 (6):  1709-1710.  doi: 10.4103/NRR.NRR-D-24-00436 Abstract ( 50 )   PDF (871KB) ( 19 )   Save Very long chain-saturated and -polyunsaturated fatty acids (VLC-SFA and VLC-PUFA, respectively) are a functionally important class of fatty acids containing 28 carbons or more in their acyl chain. They are synthesized by the elongation of very long fatty acids-4 (ELOVL4) enzyme, expressed mainly in the brain, retina, skin, testes, and meibomian gland, where these fatty acids are found (Agbaga et al., 2008). Further, these organs exhibit tissuespecific VLC-PUFA and VLC-SFA biosynthesis and incorporation into complex lipids for specific functions. In the brain, skin, and Meibomian glands, the ELOVL4 mainly makes VLC-SFA, which are incorporated into complex sphingolipids. In the retina, the ELOVL4 makes VLC-PUFA that are incorporated into phosphatidylcholine, that are critical for visual function, while in testes and sperm, the VLC-PUFA are incorporated into sphingolipids that are critical for fertility (Yeboah et al., 2021). Related Articles | Metrics

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Sleep as a window to understand and regulate Alzheimer’s disease: emerging roles of thalamic reticular nucleus Haoqi Sun, Shiqian Shen, Robert J. Thomas, M. Brandon Westover, Can Zhang 2025, 20 (6):  1711-1712.  doi: 10.4103/NRR.NRR-D-24-00351 Abstract ( 96 )   PDF (494KB) ( 87 )   Save Introduction: Alzheimer ’s disease (AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β (Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism, showing slowed clinical decline (van Dyck et al., 2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches (Zhang, 2023). As a complex disease, AD neuropathology and risk are heterogeneous and regulated by aging, genetics, and sex, in combination with other risk-modifying factors. Among the risk factors of AD, sleep disturbance is an important factor that may occur early in AD and last throughout the disease. Related Articles | Metrics

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Decline and fall of aging astrocytes: the human perspective Alexei Verkhratsky , Alexey Semyanov 2025, 20 (6):  1713-1714.  doi: 10.4103/NRR.NRR-D-24-00418 Abstract ( 53 )   PDF (1107KB) ( 36 )   Save “Last scene of all that ends this strange, eventful history, is second childishness and mere oblivion. I am sans teeth, sans eyes, sans taste, sans everything.” William Shakespeare ‘As You Like It’ Act 2, Sc. 7, l. 139 Aging of the human brain is characterized by a progressive decline of its functional capacity; this decline however varies widely, and cognitive longevity differs substantially between individuals. Aging is associated with an increased prevalence of neurodegenerative diseases ultimately causing dementia; again the cognitive outcome of agedependent neurodegenerative diseases is widely different and is not directly correlated with the pathological damage to the nervous tissue. This disparity between age-dependent deterioration of the brain and cognitive presentation is defined by the individual properties of every given individual generally referred to as cognitive reserve (Stern and Barulli, 2019). The cognitive reserve is the function of the life-long interaction of the organism and its brain with the exposome, the latter being a cumulative effect of all environmental challenges and intrinsic responses (adaptations and learning) that occur during the life span. The brain, because of its remarkable plasticity, is significantly modified during life; learning affects active milieu of the brain (Semyanov and Verkhratsky, 2021) thus defining its resilience (or vulnerability) to aging and age-associated brain disorders. Related Articles | Metrics

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Harnessing therapeutic potential of induced pluripotent stem cell– derived endothelial cells for remyelination in the central nervous system Dan Ma , Nona Pop 2025, 20 (6):  1715-1716.  doi: 10.4103/NRR.NRR-D-24-00209 Abstract ( 47 )   PDF (1180KB) ( 16 )   Save Myelin is the protective sheath surrounding nerve fibers, and its damage (demyelination) occurs in many central nervous system (CNS) diseases, including multiple sclerosis (MS), traumatic injury, neurodegenerative diseases such as Alzheimer’s disease, and mental disorders such as schizophrenia (Barateiro et al., 2016). Repair of damaged myelin sheaths (remyelination) often fails in MS, leading to neuronal loss and irreversible functional deficits. Remyelination involves the activation and recruitment of adult oligodendrocyte progenitor cells (OPCs), the residential stem cells in CNS, which eventually differentiate into new mature oligodendrocytes and form new myelin sheaths on demyelinated axons. Promoting remyelination emerges as a potentially effective clinical intervention for a broad range of demyelinating diseases such as progressive MS (Franklin and Ffrench-Constant, 2017). Currently, there is no treatment directly promoting remyelination in the clinic. Related Articles | Metrics

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Insights from an academic endeavor into central nervous system drug discovery Lieve van Veggel, An M. Voets, Tim Vanmierlo, Rudy Schreiber 2025, 20 (6):  1717-1718.  doi: 10.4103/NRR.NRR-D-24-00340 Abstract ( 46 )   PDF (653KB) ( 19 )   Save Historically, “big pharma” did most central nervous system drug discovery R&D in-house. Yet, in modern times their “management reductionism” resulted in disappointing pipelines and pharma resided to (late) development, regulatory approval, and marketing (Thong, 2015). This had significant consequences for financing and executing research, resulting in a larger role for funding by governments and patient-organizations and a shift of research to academia (Mazzucato, 2013). Factors that make academia an attractive partner in drug discovery include: (1) their excellence in science; a sine qua non for successful drug discovery; (2) availability of open resources and incubators; (3) increasing interest in translational research, and (4) new educational programs to train drug researchers (Verkman, 2004; ShamasDin and Schimmer, 2015; Schreiber et al., 2021). But drug discovery at academia remains a tall order and we will describe the lessons learned from an ambitious project on multiple sclerosis (MS). Our lab has extensive experience in the MS field and a strong valorization mind-set (Schepers et al., 2023; Tiane et al., 2023). It is crucial to keep searching for novel targets to treat MS, especially progressive MS and myelin repair, for which no cure nor appropriate treatment is currently on the market (Hauser and Cree, 2020). We investigated a novel molecular target: the excitatory amino acid transporter 3 (EAAT3). Related Articles | Metrics

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Remaking a connection: molecular players involved in post-injury synapse formation Diogo Tomé, Ramiro D. Almeida 2025, 20 (6):  1719-1720.  doi: 10.4103/NRR.NRR-D-24-00265 Abstract ( 90 )   PDF (720KB) ( 21 )   Save Functional recovery from central nervous system (CNS) trauma depends not only on axon regeneration or compensatory sprouting of uninjured fibers but also on the ability of newly grown axons to establish functional synapses with appropriate targets. Although several studies have successfully promoted long-distance axonal regeneration in distinct CNS injury models, none of them have resulted in a viable therapeutic approach for patient recovery. A possible reason may be the lack of new synaptogenesis for reestablishing the circuitry lost after injury. Herein, we discuss how our understanding of the mechanisms that instruct synapse formation in the injured nervous system may contribute to the design of new strategies to promote functional restoration in traumatic CNS disorders. Related Articles | Metrics

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Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stress– induced anxiety-like behavior Xirong Xu, Shoumin Xuan, Shuai Chen, Dan Liu, Qian Xiao, Jie Tu 2025, 20 (6):  1721-1734.  doi: 10.4103/NRR.NRR-D-23-01411 Abstract ( 142 )   PDF (4996KB) ( 61 )   Save 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 emotions. Specifically, 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 2 agonists 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 mice. After 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 obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.  Related Articles | Metrics

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Dip2a regulates stress susceptibility in the basolateral amygdala Jing Li, Zixuan He, Weitai Chai, Meng Tian, Huali Yu, Xiaoxiao He, Xiaojuan Zhu 2025, 20 (6):  1735-1748.  doi: 10.4103/NRR.NRR-D-23-01871 Abstract ( 78 )   PDF (5409KB) ( 57 )   Save 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. Related Articles | Metrics

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Enhancing m6 A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury Tian Qin, Yuxin Jin, Yiming Qin, Feifei Yuan, Hongbin Lu, Jianzhong Hu, Yong Cao, Chengjun Li 2025, 20 (6):  1749-1763.  doi: 10.4103/NRR.NRR-D-23-01477 Abstract ( 133 )   PDF (11455KB) ( 30 )   Save Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6 -methyladenosine (m6 A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m6 A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein (METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m6 A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m6 A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m6 A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury. Related Articles | Metrics

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Peripheral blood RNA biomarkers can predict lesion severity in degenerative cervical myelopathy Zhenzhong Zheng, Jialin Chen, Jinghong Xu, Bin Jiang, Lei Li, Yawei Li, Yuliang Dai, Bing Wang 2025, 20 (6):  1764-1775.  doi: 10.4103/NRR.NRR-D-23-01069 Abstract ( 92 )   PDF (3372KB) ( 74 )   Save Degenerative cervical myelopathy is a common cause of spinal cord injury, with longer symptom duration and higher myelopathy severity indicating a worse prognosis. While numerous studies have investigated serological biomarkers for acute spinal cord injury, few studies have explored such biomarkers for diagnosing degenerative cervical myelopathy. This study involved 30 patients with degenerative cervical myelopathy (51.3 ± 7.3 years old, 12 women and 18 men), seven healthy controls (25.7 ± 1.7 years old, one woman and six men), and nine patients with cervical spondylotic radiculopathy (51.9 ± 8.6 years old, three women and six men). Analysis of blood samples from the three groups showed clear differences in transcriptomic characteristics. Enrichment analysis identified 128 differentially expressed genes that were enriched in patients with neurological disabilities. Using least absolute shrinkage and selection operator analysis, we constructed a five-gene model (TBCD, TPM2, PNKD, EIF4G2, and AP5Z1) to diagnose degenerative cervical myelopathy with an accuracy of 93.5%. One-gene models (TCAP and SDHA) identified mild and severe degenerative cervical myelopathy with accuracies of 83.3% and 76.7%, respectively. Signatures of two immune cell types (memory B cells and memory-activated CD4+ T cells) predicted levels of lesions in degenerative cervical myelopathy with 80% accuracy. Our results suggest that peripheral blood RNA biomarkers could be used to predict lesion severity in degenerative cervical myelopathy. Related Articles | Metrics

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Hydrogen sulfide reduces oxidative stress in Huntington’s disease via Nrf2 Zige Jiang, Dexiang Liu, Tingting Li , Chengcheng Gai , Danqing Xin , Yijing Zhao , Yan Song , Yahong Cheng, Tong Li, Zhen Wang 2025, 20 (6):  1776-1788.  doi: 10.4103/NRR.NRR-D-23-01051 Abstract ( 65 )   PDF (49699KB) ( 7 )   Save The pathophysiology of Huntington’s disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington’s disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington’s disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS (a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2 inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington’s disease by activating nuclear factor erythroid 2-related factor 2, suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington’s disease.  Related Articles | Metrics

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Silk-based nerve guidance conduits with macroscopic holes modulate the vascularization of regenerating rat sciatic nerve Carina Hromada, Patrick Heimel, Markus Kerbl, László Gál , Sylvia Nürnberger, Barbara Schaedl, James Ferguson , Nicole Swiadek, Xavier Monforte, Johannes C. Heinzel, Antal Nógrádi , Andreas H. Teuschl-Woller, David Hercher 2025, 20 (6):  1789-1800.  doi: 10.4103/NRR.NRR-D-23-01518 Abstract ( 60 )   PDF (10705KB) ( 2 )   Save Peripheral nerve injuries induce a severe motor and sensory deficit. Since the availability of autologous nerve transplants for nerve repair is very limited, alternative treatment strategies are sought, including the use of tubular nerve guidance conduits (tNGCs). However, the use of tNGCs results in poor functional recovery and central necrosis of the regenerating tissue, which limits their application to short nerve lesion defects (typically shorter than 3 cm). Given the importance of vascularization in nerve regeneration, we hypothesized that enabling the growth of blood vessels from the surrounding tissue into the regenerating nerve within the tNGC would help eliminate necrotic processes and lead to improved regeneration. In this study, we reported the application of macroscopic holes into the tubular walls of silk-based tNGCs and compared the various features of these improved silk+ tNGCs with the tubes without holes (silk– tNGCs) and autologous nerve transplants in an 8-mm sciatic nerve defect in rats. Using a combination of micro-computed tomography and histological analyses, we were able to prove that the use of silk+ tNGCs induced the growth of blood vessels from the adjacent tissue to the intraluminal neovascular formation. A significantly higher number of blood vessels in the silk+ group was found compared with autologous nerve transplants and silk– , accompanied by improved axon regeneration at the distal coaptation point compared with the silk– tNGCs at 7 weeks postoperatively. In the 15-mm (critical size) sciatic nerve defect model, we again observed a distinct ingrowth of blood vessels through the tubular walls of silk+ tNGCs, but without improved functional recovery at 12 weeks postoperatively. Our data proves that macroporous tNGCs increase the vascular supply of regenerating nerves and facilitate improved axonal regeneration in a short-defect model but not in a critical-size defect model. This study suggests that further optimization of the macroscopic holes silk+ tNGC approach containing macroscopic holes might result in improved grafting technology suitable for future clinical use. Related Articles | Metrics

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Characteristic changes in astrocyte properties during astrocyte-to-neuron conversion induced by NeuroD1/ Ascl1/Dlx2 Qing He , Zhen Wang , Yuchen Wang, Mengjie Zhu, Zhile Liang, Kanghong Zhang, Yuge Xu, Gong Chen 2025, 20 (6):  1801-1815.  doi: 10.4103/NRR.NRR-D-23-01897 Abstract ( 205 )   PDF (53669KB) ( 111 )   Save Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore, we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4 (astrocyte endfeet signal), CX43 (gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain. Related Articles | Metrics

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Mechanism by which Rab5 promotes regeneration and functional recovery of zebrafish Mauthner axons Jiantao Cui , Yueru Shen , Zheng Song, Dinggang Fan, Bing Hu 2025, 20 (6):  1816-1824.  doi: 10.4103/NRR.NRR-D-23-00529 Abstract ( 97 )   PDF (11593KB) ( 25 )   Save Rab5 is a GTPase protein that is involved in intracellular membrane trafficking. It functions by binding to various effector proteins and regulating cellular responses, including the formation of transport vesicles and their fusion with the cellular membrane. Rab5 has been reported to play an important role in the development of the zebrafish embryo; however, its role in axonal regeneration in the central nervous system remains unclear. In this study, we established a zebrafish Mauthner cell model of axonal injury using single-cell electroporation and two-photon axotomy techniques. We found that overexpression of Rab5 in single Mauthner cells promoted marked axonal regeneration and increased the number of intra-axonal transport vesicles. In contrast, treatment of zebrafish larvae with the Rab kinase inhibitor CID-1067700 markedly inhibited axonal regeneration in Mauthner cells. We also found that Rab5 activated phosphatidylinositol 3-kinase (PI3K) during axonal repair of Mauthner cells and promoted the recovery of zebrafish locomotor function. Additionally, rapamycin, an inhibitor of the mechanistic target of rapamycin downstream of PI3K, markedly hindered axonal regeneration. These findings suggest that Rab5 promotes the axonal regeneration of injured zebrafish Mauthner cells by activating the PI3K signaling pathway. Related Articles | Metrics