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15 July 2025, Volume 20 Issue 7 Previous Issue   

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The pivotal role of microglia in injury and the prognosis of subarachnoid hemorrhage Wenjing Ning, Shi Lv, Qian Wang, Yuzhen Xu 2025, 20 (7):  1829-1848.  doi: 10.4103/NRR.NRR-D-24-00241 Abstract ( 100 )   PDF (8733KB) ( 25 )   Save Subarachnoid hemorrhage leads to a series of pathological changes, including vascular spasm, cellular apoptosis, blood–brain barrier damage, cerebral edema, and white matter injury. Microglia, which are the key immune cells in the central nervous system, maintain homeostasis in the neural environment, support neurons, mediate apoptosis, participate in immune regulation, and have neuroprotective effects. Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage. Moreover, microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage. Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury. This provides new targets and ideas for the treatment of subarachnoid hemorrhage. However, an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking. This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm, neuroinflammation, neuronal apoptosis, blood–brain barrier disruption, cerebral edema, and cerebral white matter lesions. It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage. Currently, microglia in subarachnoid hemorrhage are targeted with TLR inhibitors, nuclear factor-κB and STAT3 pathway inhibitors, glycine/tyrosine kinases, NLRP3 signaling pathway inhibitors, Gasdermin D inhibitors, vincristine receptor α receptor agonists, ferroptosis inhibitors, genetic modification techniques, stem cell therapies, and traditional Chinese medicine. However, most of these are still being evaluated at the laboratory stage. More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage. Related Articles | Metrics

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Insights into spinal muscular atrophy from molecular biomarkers Xiaodong Xing, Xinzhu Liu, Xiandeng Li, Mi Li, Xian Wu, Xiaohui Huang, Ajing Xu, Yan Liu, Jian Zhang 2025, 20 (7):  1849-1863.  doi: 10.4103/NRR.NRR-D-24-00067 Abstract ( 81 )   PDF (4072KB) ( 21 )   Save Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness. It is one of the most common genetic causes of mortality among infants aged less than 2 years. Biomarker research is currently receiving more attention, and new candidate biomarkers are constantly being discovered. This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons. We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy, which are classified as either specific or non-specific biomarkers. This review provides new insights into the pathogenesis of spinal muscular atrophy, the mechanism of biomarkers in response to drug-modified therapies, the selection of biomarker candidates, and would promote the development of future research. Furthermore, the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy. Related Articles | Metrics

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Autophagy-targeting modulation to promote peripheral nerve regeneration Yan Chen, Hongxia Deng, Nannan Zhang 2025, 20 (7):  1864-1882.  doi: 10.4103/NRR.NRR-D-23-01948 Abstract ( 72 )   PDF (36388KB) ( 32 )   Save Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies. Related Articles | Metrics

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Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders: drug stability, targeting efficiency, and safety Mingyu Zhang, Chunyu Xiang, Renrui Niu, Xiaodong He, Wenqi Luo, Wanguo Liu, Rui Gu 2025, 20 (7):  1883-1899.  doi: 10.4103/NRR.NRR-D-24-00048 Abstract ( 133 )   PDF (5913KB) ( 96 )   Save Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied. However, their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies. Liposomes are nanoparticles composed of lipid bilayers, which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability. Therefore, they can potentially treat traumatic and nontraumatic central nervous system diseases. In this review, we outlined the common properties and preparation methods of liposomes, including thin-film hydration, reverse-phase evaporation, solvent injection techniques, detergent removal methods, and microfluidics techniques. Afterwards, we comprehensively discussed the current applications of liposomes in central nervous system diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and brain tumors. Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials. Additionally, their application as drug delivery systems in clinical practice faces challenges such as drug stability, targeting efficiency, and safety. Therefore, we proposed development strategies related to liposomes to further promote their development in neurological disease research. Related Articles | Metrics

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Inhibition of the cGAS–STING pathway: contributing to the treatment of cerebral ischemia-reperfusion injury Hang Yang, Yulei Xia, Yue Ma, Mingtong Gao, Shuai Hou, Shanshan Xu, Yanqiang Wang 2025, 20 (7):  1900-1918.  doi: 10.4103/NRR.NRR-D-24-00015 Abstract ( 132 )   PDF (20405KB) ( 57 )   Save The cGAS–STING pathway plays an important role in ischemia-reperfusion injury in the heart, liver, brain, and kidney, but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed. Here, we outline the components of the cGAS–STING pathway and then analyze its role in autophagy, ferroptosis, cellular pyroptosis, disequilibrium of calcium homeostasis, inflammatory responses, disruption of the blood–brain barrier, microglia transformation, and complement system activation following cerebral ischemia-reperfusion injury. We further analyze the value of cGAS– STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms. Inhibition of the cGAS–STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury. Related Articles | Metrics

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Stepping up after spinal cord injury: negotiating an obstacle during walking Alain Frigon, Charly G. Lecomte 2025, 20 (7):  1919-1929.  doi: 10.4103/NRR.NRR-D-24-00369 Abstract ( 39 )   PDF (1081KB) ( 65 )   Save Every day walking consists of frequent voluntary modifications in the gait pattern to negotiate obstacles. After spinal cord injury, stepping over an obstacle becomes challenging. Stepping over an obstacle requires sensorimotor transformations in several structures of the brain, including the parietal cortex, premotor cortex, and motor cortex. Sensory information and planning are transformed into motor commands, which are sent from the motor cortex to spinal neuronal circuits to alter limb trajectory, coordinate the limbs, and maintain balance. After spinal cord injury, bidirectional communication between the brain and spinal cord is disrupted and animals, including humans, fail to voluntarily modify limb trajectory to step over an obstacle. Therefore, in this review, we discuss the neuromechanical control of stepping over an obstacle, why it fails after spinal cord injury, and how it recovers to a certain extent. Related Articles | Metrics

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Unraveling brain aging through the lens of oral microbiota Qinchao Hu, Si Wang, Weiqi Zhang, Jing Qu, Guang-Hui Liu 2025, 20 (7):  1930-1943.  doi: 10.4103/NRR.NRR-D-23-01761 Abstract ( 94 )   PDF (5379KB) ( 102 )   Save The oral cavity is a complex physiological community encompassing a wide range of microorganisms. Dysbiosis of oral microbiota can lead to various oral infectious diseases, such as periodontitis and tooth decay, and even affect systemic health, including brain aging and neurodegenerative diseases. Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration, indicating potential avenues for intervention strategies. In this review, we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases, and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration. We also highlight advances in therapeutic development grounded in the realm of oral microbes, with the goal of advancing brain health and promoting healthy aging. Related Articles | Metrics

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Beyond wrecking a wall: revisiting the concept of blood-brain barrier breakdown in ischemic stroke Julia Castillo-González , Elena González-Rey 2025, 20 (7):  1944-1956.  doi: 10.4103/NRR.NRR-D-24-00392 Abstract ( 64 )   PDF (3686KB) ( 66 )   Save The blood–brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation. It tightly modulates the ion transport and nutrient influx, while restricting the entry of harmful factors, and selectively limiting the migration of immune cells, thereby maintaining brain homeostasis. Despite the well-established association between blood–brain barrier disruption and most neurodegenerative/neuroinflammatory diseases, much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown. Moreover, the role of blood–brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood. This review aims to revisit this concept of “blood–brain barrier breakdown,” delving into the most controversial aspects, prevalent challenges, and knowledge gaps concerning the lack of blood–brain barrier integrity. By moving beyond the oversimplistic dichotomy of an “open”/“bad” or a “closed”/“good” barrier, our objective is to provide a more comprehensive insight into blood–brain barrier dynamics, to identify novel targets and/or therapeutic approaches aimed at mitigating blood–brain barrier dysfunction. Furthermore, in this review, we advocate for considering the diverse time- and location-dependent alterations in the blood–brain barrier, which go beyond tight-junction disruption or brain endothelial cell breakdown, illustrated through the dynamics of ischemic stroke as a case study. Through this exploration, we seek to underscore the complexity of blood–brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases. Related Articles | Metrics

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MicroRNAs as potential biomarkers for diagnosis of post-traumatic stress disorder Bridget Martinez, Philip V. Peplow 2025, 20 (7):  1957-1970.  doi: 10.4103/NRR.NRR-D-24-00354 Abstract ( 31 )   PDF (664KB) ( 41 )   Save Post-traumatic stress disorder is a mental disorder caused by exposure to severe traumatic life events. Currently, there are no validated biomarkers or laboratory tests that can distinguish between trauma survivors with and without post-traumatic stress disorder. In addition, the heterogeneity of clinical presentations of post-traumatic stress disorder and the overlap of symptoms with other conditions can lead to misdiagnosis and inappropriate treatment. Evidence suggests that this condition is a multisystem disorder that affects many biological systems, raising the possibility that peripheral markers of disease may be used to diagnose post-traumatic stress disorder. We performed a PubMed search for microRNAs (miRNAs) in post-traumatic stress disorder (PTSD) that could serve as diagnostic biomarkers and found 18 original research articles on studies performed with human patients and published January 2012 to December 2023. These included four studies with whole blood, seven with peripheral blood mononuclear cells, four with plasma extracellular vesicles/ exosomes, and one with serum exosomes. One of these studies had also used whole plasma. Two studies were excluded as they did not involve microRNA biomarkers. Most of the studies had collected samples from adult male Veterans who had returned from deployment and been exposed to combat, and only two were from recently traumatized adult subjects. In measuring miRNA expression levels, many of the studies had used microarray miRNA analysis, miRNA Seq analysis, or NanoString panels. Only six studies had used real time polymerase chain reaction assay to determine/validate miRNA expression in PTSD subjects compared to controls. The miRNAs that were found/validated in these studies may be considered as potential candidate biomarkers for PTSD and include miR3130-5p in whole blood; miR-193a-5p, -7113-5p, -125a, -181c, and -671-5p in peripheral blood mononuclear cells; miR-10b-5p, -203a-3p, -4488, -502-3p, -874-3p, -5100, and -7641 in plasma extracellular vesicles/exosomes; and miR-18a-3p and -7-1-5p in blood plasma. Several important limitations identified in the studies need to be taken into account in future studies. Further studies are warranted with war veterans and recently traumatized children, adolescents, and adults having PTSD and use of animal models subjected to various stressors and the effects of suppressing or overexpressing specific microRNAs. Related Articles | Metrics

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New aspects of a small GTPase RAB35 in brain development and function Ikuko Maejima, Ken Sato 2025, 20 (7):  1971-1980.  doi: 10.4103/NRR.NRR-D-23-01543 Abstract ( 68 )   PDF (984KB) ( 47 )   Save In eukaryotic cells, organelles in the secretory, lysosomal, and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking, which is the process of transporting the cargo of proteins, lipids, and other molecules to appropriate compartments via transport vesicles or intermediates. These processes are strictly regulated by various small GTPases such as the RAS-like in rat brain (RAB) protein family, which is the largest subfamily of the RAS superfamily. Dysfunction of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases, including neurological disorders and neurodegenerative diseases. Therefore, it is important to understand the physiological and pathological roles of RAB proteins in brain function. RAB35, a member of the RAB family, is an evolutionarily conserved protein in metazoans. A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis, endocytic recycling, actin bundling, and cell migration. RAB35 is also involved in neurite outgrowth and turnover of synaptic vesicles. We generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and function. These mice exhibited defects in anxiety-related behaviors and spatial memory. Strikingly, RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development, and thereby for normal hippocampal lamination. In contrast, layer formation in the cerebral cortex occurred superficially, even in the absence of RAB35, suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex development. Recent studies have suggested an association between RAB35 and neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. In this review, we provide an overview of the current understanding of subcellular functions of RAB35. We also provide insights into the physiological role of RAB35 in mammalian brain development and function, and discuss the involvement of RAB35 dysfunction in neurodegenerative diseases. Related Articles | Metrics

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Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer’s disease Shan Ping Yu, Emily Choi , Michael Q. Jiang, Ling Wei 2025, 20 (7):  1981-1988.  doi: 10.4103/NRR.NRR-D-24-00398 Abstract ( 42 )   PDF (657KB) ( 58 )   Save Stroke and Alzheimer’s disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca2+ mainly via N-methyl-Daspartate receptors, particularly of those at the extrasynaptic site. This Ca2+-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer’s disease are not immediately toxic, but gradually set off deteriorating Ca2+-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca2+ hypothesis of Alzheimer’s disease and recent advances, this Ca2+-activated “silent” degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer’s disease, therefore, share an N-methyl-D-aspartate receptor- and Ca2+-mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer’s disease and Alzheimer’s disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging. Related Articles | Metrics

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Neuroinflammation revisited through the microglial lens Renato Socodato , João B. Relvas 2025, 20 (7):  1989-1990.  doi: 10.4103/NRR.NRR-D-24-00284 Abstract ( 47 )   PDF (620KB) ( 30 )   Save Neuroimmunology is emerging as a pivotal field, shedding light on the intricate dialogues between the central nervous system (CNS) and the immune system. This exploration is particularly significant in understanding microglia, the CNS’s innate immune cells, beyond the conventional conflation of “neuroinflammation” and “microglial activation.” This conflation has clouded the true complexity of these processes, potentially stalling scientific progress and the development of new therapies. We challenge the long-standing perspectives that have oversimplified these interactions, advocating for a deeper exploration of the dynamic relationship between neuroinflammation and microglial activation. By dissecting specific molecular pathways, we aim to illuminate their elaborate roles in neuroinflammatory responses, especially in the context of Alzheimer’s disease (AD). Here, neuroinflammation is not merely a passive observer or a direct antagonist but a complex agent in the disease’s progression. This article calls for a significant paradigm shift towards an integrative, multi-omics approach to neuroimmunology. Adopting such a comprehensive framework is crucial for advancing our understanding of neuroinflammatory conditions and paving the way for targeted therapeutic strategies for brain diseases. Related Articles | Metrics

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Neuropeptide cholecystokinin: a key neuromodulator for hippocampal functions Fengwen Huang , Stephen Temitayo Bello 2025, 20 (7):  1991-1992.  doi: 10.4103/NRR.NRR-D-24-00465 Abstract ( 44 )   PDF (471KB) ( 25 )   Save Spatial memory is crucial for survival within external surroundings and wild environments. The hippocampus, a critical hub for spatial learning and memory formation, has received extensive investigations on how neuromodulators shape its functions (Teixeira et al., 2018; Zhang et al., 2024). However, the landscape of neuromodulations in the hippocampal system remains poorly understood because most studies focus on classical monoamine neuromodulators, such as acetylcholine, serotonin, dopamine, and noradrenaline. The neuropeptides, comprising the most abundant neuromodulators in the central nervous system, play a pivotal role in neural information processing in the hippocampal system. Cholecystokinin (CCK), one of the most abundant neuropeptides, has been implicated in regulating various physiological and neurobiological statuses (Chen et al., 2019). CCK-A receptor (CCK-AR) and CCK-B receptors (CCK-BR) are two key receptors mediating the biological functions of CCK, both of which belong to class-A sevenfold transmembrane G protein-coupled receptors (Nishimura et al., 2015). CCK-AR preferentially reacts to sulfated CCK, whereas CCK-BR binds both CCK and gastrin with similar affinities (Ding et al., 2022). The expression patterns of CCK-AR and CCK-BR are distinct, implying that CCK has various functions in target regions. For instance, CCK-AR is widely expressed in the GI and brain subregions and is hence implicated in the control of digestive function and satiety regulation. Conversely, CCKBR is abundantly and widely distributed in the central nervous system, which majorly regulates anxiety, learning, and memory (Ding et al., 2022). However, the roles of endogenous CCK and CCK receptors in regulating hippocampal function at electrophysiological and behavioral levels have received less attention. Related Articles | Metrics

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PGLYRP1 protein as a novel mediator of cellular dialogue in neuroinflammation Anup Bhusal, Won-Ha Lee, Kyoungho Suk 2025, 20 (7):  1993-1994.  doi: 10.4103/NRR.NRR-D-24-00424 Abstract ( 66 )   PDF (451KB) ( 19 )   Save Neuroinflammation has been identified as a crucial element in several neurological disorders. Glial cells play a critical role in directing neuroinflammation, both in deleterious and beneficial ways. They communicate with one another, nearby neurons, and infiltrating cells following central nervous system (CNS) insult. Hence, understanding cellular crosstalk has become fundamental to comprehending neurodegenerative conditions at the micro level (Bhusal et al., 2023). In recent times, scientists have used various transcriptomics and proteomics analyses to identify molecules that are responsible for this cellular communication and to determine the resulting functional outcomes. Various molecules involved in interglial crosstalk have been identified to date. However, the role of peptidoglycan recognition proteins (PGRPs) in the nervous system has received considerably less attention. PGRPs are a unique class of innate immune pattern recognition molecules that bind to bacterial peptidoglycans (PGN) and act as antibacterial agents (Dziarski, 2004). Studies have demonstrated that PGRPs affect host-pathogen interactions not only through antibacterial activity but also through the regulation of inflammatory response. Mammals have four PGRPs initially named PGRP-S, PGRP-L, PGRP-Ia, and PGRP-Ib (for “short,” “long,” and “intermediate” transcripts, respectively), similar to the naming convention used for insect PGRPs. The Human Genome Organization Gene Nomenclature Committee later standardized the nomenclature of human PGRPs to peptidoglycan recognition protein 1 (PGLYRP1), PGLYRP2, PGLYRP3, and PGLYRP4, respectively, and this nomenclature has been adopted for all mammalian PGRPs (Dziarski and Gupta, 2010). Related Articles | Metrics

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Contribution of mechanical forces to structural synaptic plasticity: insights from 3D cellular motility mechanisms Rita O. Teodoro, Mafalda Ribeiro Ramos, Lara Carvalho 2025, 20 (7):  1995-1996.  doi: 10.4103/NRR.NRR-D-24-00498 Abstract ( 45 )   PDF (1074KB) ( 34 )   Save Cells, tissues, and organs are constantly subjected to the action of mechanical forces from the extracellular environment — and the nervous system is no exception. Cell-intrinsic properties such as membrane lipid composition, abundance of mechanosensors, and cytoskeletal dynamics make cells more or less likely to sense these forces. Intrinsic and extrinsic cues are integrated by cells and this combined information determines the rate and dynamics of membrane protrusion growth or retraction (Yamada and Sixt, 2019). Cell protrusions are extensions of the plasma membrane that play crucial roles in diverse contexts such as cell migration and neuronal synapse formation. In the nervous system, neurons are highly dynamic cells that can change the size and number of their pre- and postsynaptic elements (called synaptic boutons and dendritic spines, respectively), in response to changes in the levels of synaptic activity through a process called plasticity. Synaptic plasticity is a hallmark of the nervous system and is present throughout our lives, being required for functions like memory formation or the learning of new motor skills (Minegishi et al., 2023; Pillai and Franze, 2024). Related Articles | Metrics

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Data-driven drug repositioning using olfactory omics profiles: challenges and perspectives in neurodegeneration Paz Cartas-Cejudo, Adriana Cortés, Mercedes Lachén-Montes, Elena Anaya-Cubero, Joaquín Fernández-Irigoyen, Enrique Santamaría 2025, 20 (7):  1997-1998.  doi: 10.4103/NRR.NRR-D-24-00334 Abstract ( 33 )   PDF (1311KB) ( 31 )   Save Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous system. These diseases are often characterized as proteinopathies, which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells, leading to their dysfunction and eventual death. Despite the gainof-function hypothesis related to the aggregation of these proteins, recently, an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining currency. This last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body (Ezzat et al., 2023). It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased. In Alzheimer’s disease (AD), the brain accumulates abnormal protein aggregates forming amyloid-β (Aβ) plaques and Tau tangles. Although not all Aβ-positive individuals develop dementia, there is a 1:1 relationship between low soluble Aβ42 and dementia (Andreasen et al., 2001). When Aβ42 monomers transition into amyloid, both the Aβ42 pool and its neurotrophic properties diminish, consequently producing more harm to the brain than the accumulation of insoluble Aβ (Espay et al., 2023). Hence, the pathology signifies the loss of functional proteins rather than their conversion into a prion-like agent. Given this shift in the field, new ways to discover therapies are needed. For that, novel drug repositioning approaches are emerging with the aim to reverse more extensive metabolic imbalance instead of current approaches exclusively targeting protein toxic aggregates. Related Articles | Metrics

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Role of glutathione transferase in phase separation of FUS and TAF15 in neurons Kiyoung Kim 2025, 20 (7):  1999-2000.  doi: 10.4103/NRR.NRR-D-24-00409 Abstract ( 44 )   PDF (489KB) ( 21 )   Save Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness, paralysis, and ultimately death (Cleveland and Rothstein, 2001). Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease affecting the frontal and temporal lobes of the brain, leading to changes in behavior, personality, and language (Van Langenhove et al., 2012). Both ALS and FTLD are classified as proteinopathies in which abnormal protein aggregation and accumulation in neurons contribute to the disease pathogenesis. Fused in sarcoma (FUS) is a DNA/RNA-binding protein involved in various cellular processes, including transcriptional regulation, RNA splicing, and DNA repair. Mutations in the FUS gene have been linked to familial ALS, highlighting the importance of FUS in the disease pathogenesis (Vance et al., 2009). In ALS and FTLD, aberrant posttranslational modifications (PTMs) of FUS, such as phosphorylation, acetylation, and methylation, have been implicated in the promotion of FUS aggregation and neurotoxicity (Choi et al., 2023). Therefore, understanding the regulatory mechanisms of FUS PTMs is crucial for developing targeted therapies against these diseases. Related Articles | Metrics

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Like a G6-nal: transcriptional control of G-protein coupled receptors during oligodendroglial development Tim Aberle , Michael Wegner 2025, 20 (7):  2001-2002.  Abstract ( 41 )   PDF (1462KB) ( 27 )   Save Multilayered control of myelination: Quick, saltatory conduction of action potentials along nerve fibers requires the electrical insulation of axons by myelinating glia. In the central nervous system, this role is taken up by oligodendrocytes. Oligodendrocytes are marked by the expression of the lineage determinants Sox10 and Olig2 and arise from oligodendrocyte precursor cells (OPCs) during embryonal stages. While the majority of OPCs differentiate into mature oligodendrocytes when nearby axonal segments require myelination, a small subpopulation of OPCs persist as a progenitor pool. Therefore, the timing of myelination and maintenance of the OPC pool both need to be precisely regulated. Different transcription factors either positively or negatively affect oligodendrocyte differentiation and maintenance of the OPC pool as components of a complex gene regulatory network (reviewed in Sock and Wegner, 2021). Network activity is additionally influenced by extracellular signaling molecules that bind to receptors on the oligodendroglial cell surface and activate intracellular signaling pathways. How the receptors are linked to the network is poorly understood so far, but pivotal to understanding the overall regulation of central nervous system (CNS) myelination in response to environmental cues. Relevant insights were recently gained for Gpr37 (Schmidt et al., 2024), a G-protein coupled receptor (GPCR) with known relevance in differentiating oligodendrocytes (Yang et al, 2016). Related Articles | Metrics

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Cryptic exon inclusion in TDP-43 proteinopathies: opportunities and challenges Lorena Decker , Sonja Menge , Axel Freischmidt 2025, 20 (7):  2003-2004.  doi: 10.4103/NRR.NRR-D-24-00459 Abstract ( 62 )   PDF (770KB) ( 17 )   Save Transactive response DNA binding protein of 43 kDa (TDP-43) is a ubiquitously expressed RNA/ DNA binding protein crucial for coding and noncoding RNA metabolism including transcription, splicing, transport, translation, and turnover. TDP-43 shuttles between the nucleus and cytoplasm, but is predominantly localized in the nucleus. Neurodegenerative diseases (NDs) may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and beyond. This neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) with TDP-43- immunoreactive pathology (FTD-TDP), limbicpredominant age–related TDP-43 encephalopathy (LATE) and Perry syndrome, but also coexists with the primary pathology in subsets of patients suffering from other NDs, such as Alzheimer’s disease, Lewy body dementias, or Huntington’s disease. Variants in the gene encoding TDP-43 (TARDBP) are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging neurons. It is still controversial if loss of nuclear, or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons (Nag and Schneider, 2023). Recently, the role of nuclear TDP-43 in repressing the inclusion of intronic sequences, named cryptic exons (CEs), into mature mRNAs gained much attention. Related Articles | Metrics

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Brain endothelial cyclic GMPAMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway in aging and neurodegeneration Bryan Sun, Lulin Li, Jian Luo 2025, 20 (7):  2005-2007.  doi: 10.4103/NRR.NRR-D-24-00442 Abstract ( 112 )   PDF (502KB) ( 18 )   Save The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway has emerged as a key mediator of neuroinflammation. While current studies primarily attribute its effects to neurons and glial cells, emerging research suggests that cGAS-STING signaling may play a critical role in cerebral vasculature, particularly in brain endothelial cells. Therefore, studying the role of inflammation caused by the cGAS– STING pathway in brain endothelial cells could provide a more comprehensive understanding of neuroinflammatory disease and new avenues for therapeutic interventions. Here, we review the multifaceted role of global cGAS–STING signaling in various neurological and neuroinflammatory diseases and the potential contribution of cGAS– STING in brain endothelial cells. Related Articles | Metrics

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Calcium-sensitive protein MLC1 as a possible modulator of the astrocyte functional state Elena Ambrosini , Angela Lanciotti, Maria Stefania Brignone 2025, 20 (7):  2008-2010.  doi: 10.4103/NRR.NRR-D-24-00471 Abstract ( 48 )   PDF (756KB) ( 23 )   Save Astrocytes, the main population of glial cells in the central nervous system (CNS), exert essential tasks for the control of brain tissue homeostasis, supporting neuron and other glial cell activity from the developmental stage to adult life. To maintain the optimal functionality of the brain, astroglial cells are particularly committed to reacting to every change in tissue homeostatic conditions, from mild modifications of the physiological environment, a process called astrocyte activation, to the more severe alterations occurring in pathological situations causing astrocyte reactivity or reactive astrogliosis (Escartin et al., 2021). During these reactive states, astrocytes mount an active, progressive response encompassing morphological, molecular, and interactional remodeling, leading to the acquisition of new functions and the loss of others, whose intensity, duration, and reversibility are dependent on the nature of the stimulus and regulated in a contextspecific manner. Although astrogliopathology is a complex phenomenon including other pathophysiological entities beyond reactivity (atrophy, asthenia, loss of functions, aberrant phenotype, and death), decoding the still elusive molecular events involved in astrocyte reactivity is key to understanding how astrocytes contribute to CNS repair and realizing the full therapeutic potential of these capacities. Related Articles | Metrics

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Gene therapy for spinal muscular atrophy: perspectives on the possibility of optimizing SMN1 delivery to correct all neurological and systemic perturbations Sharon J. Brown, Rafael J. Yáñez-Muñoz, Heidi R. Fuller 2025, 20 (7):  2011-2012.  doi: 10.4103/NRR.NRR-D-24-00504 Abstract ( 72 )   PDF (1379KB) ( 19 )   Save Spinal muscular atrophy (SMA) is a genetic condition that results in selective lower motor neuron loss with concomitant muscle weakness and atrophy. The genetic cause of SMA was understood in 1995 when loss or impairment of the survival motor neuron 1 (SMN1) gene was identified as the main contributing factor (Lefebvre et al., 1995). This, in combination with the discovery that humans have a “backup” gene, SMN2, which can produce low levels (approximately 10%) of the full-length functional SMN protein, has led to the generation of SMAspecific gene therapies. SMA was traditionally classified according to age of symptom onset and developmental milestones achieved, with life expectancy and severity varying between individuals. Now, SMN2 copy number is used as a proxy for the prediction of disease severity, with higher SMN2 copy number typically being associated with reduced severity of SMA, although this relationship is not absolute: some individuals with low SMN2 copy number have less severe SMA phenotypes and vice versa. Additionally, the etiology of SMA is further complicated by other factors, such as non-typical nucleotide variants and SMN2-independent modifiers of disease severity. Related Articles | Metrics

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Generation of brain vascular heterogeneity: recent advances from the perspective of angiogenesis Nathanael J. Lee, Ryota L. Matsuoka 2025, 20 (7):  2013-2014.  doi: 10.4103/NRR.NRR-D-24-00496 Abstract ( 44 )   PDF (626KB) ( 24 )   Save Related Articles | Metrics

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Perilipin-2 mediates ferroptosis in oligodendrocyte progenitor cells and myelin injury after ischemic stroke Jian Yang, Jiang Wu, Xueshun Xie, Pengfei Xia, Jinxin Lu, Jiale Liu, Lei Bai, Xiang Li, Zhengquan Yu, Haiying Li 2025, 20 (7):  2015-2028.  doi: 10.4103/NRR.NRR-D-23-01540 Abstract ( 109 )   PDF (9101KB) ( 18 )   Save Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination. Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage. Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation, and plays an important role in the pathological process of ischemic stroke. However, there are few studies on oligodendrocyte progenitor cell ferroptosis. We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia. Bioinformatics analysis suggested that perilipin-2 (PLIN2) was involved in oligodendrocyte progenitor cell ferroptosis. PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation. For further investigation, we established a mouse model of cerebral ischemia/reperfusion. We found significant myelin damage after cerebral ischemia, as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area. The ferroptosis inhibitor, ferrostatin-1, rescued oligodendrocyte progenitor cell death and subsequent myelin injury. We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells. Plin2 knockdown rescued demyelination and improved neurological deficits. Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia. Key Words: bioinformatics; bulk RNA sequencing; ferroptosis; ischemic stroke; myelin injury; oligodendr Related Articles | Metrics

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A promising approach for quantifying focal stroke modeling and assessing stroke progression: optical resolution photoacoustic microscopy photothrombosis Xiao Liang, Xingping Quan, Xiaorui Geng, Yujing Huang, Yonghua Zhao, Lei Xi, Zhen Yuan, Ping Wang, Bin Liu 2025, 20 (7):  2029-2037.  doi: 10.4103/NRR.NRR-D-23-01617 Abstract ( 152 )   PDF (22965KB) ( 74 )   Save To investigate the mechanisms underlying the onset and progression of ischemic stroke, some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex. However, these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied, although ischemic stroke is strongly age-related. In this study, we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser. We observed the molding process in mice of different ages and presented agedependent vascular embolism differentiation. Moreover, we integrated optical coherence tomography angiography to investigate ageassociated trends in cerebrovascular variability following a stroke. Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages, thereby highlighting the technique’s potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes. Related Articles | Metrics

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NOX4 exacerbates Parkinson’s disease pathology by promoting neuronal ferroptosis and neuroinflammation Zhihao Lin, Changzhou Ying, Xiaoli Si, Naijia Xue, Yi Liu, Ran Zheng, Ying Chen, Jiali Pu , Baorong Zhang 2025, 20 (7):  2038-2052.  doi: 10.4103/NRR.NRR-D-23-01265 Abstract ( 141 )   PDF (28398KB) ( 53 )   Save Parkinson’s disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta. Ferroptosis, a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation, plays a vital role in the death of dopaminergic neurons. However, the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated. NADPH oxidase 4 is related to oxidative stress, however, whether it regulates dopaminergic neuronal ferroptosis remains unknown. The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis, and if so, by what mechanism. We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson’s disease model. NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson’s disease model animals and reduced the death of dopaminergic neurons. Moreover, NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson’s disease model animals. Mechanistically, we found that NADPH oxidase 4 interacted with activated protein kinase C α to prevent ferroptosis of dopaminergic neurons. Furthermore, by lowering the astrocytic lipocalin-2 expression, NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation. These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation, which contribute to dopaminergic neuron death, suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson’s disease. Related Articles | Metrics

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Prolonged intermittent theta burst stimulation restores the balance between A2AR- and A1R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson’s disease Milica Zeljkovic Jovanovic , Jelena Stanojevic, Ivana Stevanovic, Milica Ninkovic, Tihomir V. Ilic, Nadezda Nedeljkovic, Milorad Dragic 2025, 20 (7):  2053-2067.  doi: 10.4103/NRR.NRR-D-23-01542 Abstract ( 73 )   PDF (7982KB) ( 10 )   Save An imbalance in adenosine-mediated signaling, particularly the increased A2AR-mediated signaling, plays a role in the pathogenesis of Parkinson’s disease. Existing therapeutic approaches fail to alter disease progression, demonstrating the need for novel approaches in PD. Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson’s disease. However, the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown. The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling. Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test. Immunoblot, quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen. Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals. A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen. Treatment with intermittent theta burst stimulation began 7 days after the lesion, coinciding with the onset of motor symptoms. After treatment with prolonged intermittent theta burst stimulation, complete motor recovery was observed. This improvement was accompanied by downregulation of the eN/CD73- A2AR pathway and a return to physiological levels of A1R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation. Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A1R and elevated the expression of A2AR. Intermittent theta burst stimulation reversed these effects by restoring the abundances of A1R and A2AR to control levels. The shift in ARs expression likely restored the balance between dopamine-adenosine signaling, ultimately leading to the recovery of motor control. Related Articles | Metrics

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FUBP3 mediates the amyloid-β-induced neuronal NLRP3 expression Jing Yao, Yuan Li, Xi Liu, Wenping Liang, Yu Li , Liyong Wu, Zhe Wang, Weihong Song 2025, 20 (7):  2068-2083.  doi: 10.4103/NRR.NRR-D-23-01799 Abstract ( 107 )   PDF (7472KB) ( 24 )   Save Alzheimer’s disease is characterized by deposition of amyloid-β, which forms extracellular neuritic plaques, and accumulation of hyperphosphorylated tau, which aggregates to form intraneuronal neurofibrillary tangles, in the brain. The NLRP3 inflammasome may play a role in the transition from amyloid-β deposition to tau phosphorylation and aggregation. Because NLRP3 is primarily found in brain microglia, and tau is predominantly located in neurons, it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines. Here, we found that neurons also express NLRP3 in vitro and in vivo, and that neuronal NLRP3 regulates tau phosphorylation. Using biochemical methods, we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons. In primary neurons and the neuroblastoma cell line Neuro2A, FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-β is present. In the brains of aged wild-type mice and a mouse model of Alzheimer’s disease, FUBP3 expression was markedly increased in cortical neurons. Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses. We also found that FUBP3 trimmed the 5′ end of DNA fragments that it bound, implying that FUBP3 functions in stress-induced responses. These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3, and that amyloid-β fundamentally alters the regulatory mechanism of NLRP3 expression in neurons. Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer’s disease mice, FUBP3 could be a safe therapeutic target for preventing Alzheimer’s disease progression. Related Articles | Metrics

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A novel flexible nerve guidance conduit promotes nerve regeneration while providing excellent mechanical properties Tong Li, Quhan Cheng, Jingai Zhang, Boxin Liu, Yu Shi, Haoxue Wang, Lijie Huang, Su Zhang, Ruixin Zhang, Song Wang, Guangxu Lu, Peifu Tang, Zhongyang Liu, Kai Wang 2025, 20 (7):  2084-2094.  doi: 10.4103/NRR.NRR-D-23-01792 Abstract ( 143 )   PDF (2575KB) ( 41 )   Save Autografting is the gold standard for surgical repair of nerve defects > 5 mm in length; however, autografting is associated with potential complications at the nerve donor site. As an alternative, nerve guidance conduits may be used. The ideal conduit should be flexible, resistant to kinks and lumen collapse, and provide physical cues to guide nerve regeneration. We designed a novel flexible conduit using electrospinning technology to create fibers on the innermost surface of the nerve guidance conduit and employed melt spinning to align them. Subsequently, we prepared disordered electrospun fibers outside the aligned fibers and helical melt-spun fibers on the outer wall of the electrospun fiber lumen. The presence of aligned fibers on the inner surface can promote the extension of nerve cells along the fibers. The helical melt-spun fibers on the outer surface can enhance resistance to kinking and compression and provide stability. Our novel conduit promoted nerve regeneration and functional recovery in a rat sciatic nerve defect model, suggesting that it has potential for clinical use in human nerve injuries Related Articles | Metrics

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Polyethylene glycol fusion repair of severed rat sciatic nerves reestablishes axonal continuity and reorganizes sensory terminal fields in the spinal cord Emily A. Hibbard , Liwen Zhou , Cathy Z. Yang , Karthik Venkudusamy , Yessenia Montoya , Alexa Olivarez , George D. Bittner , Dale R. Sengelaub 2025, 20 (7):  2095-2107.  doi: 10.4103/NRR.NRR-D-23-01845 Abstract ( 58 )   PDF (5420KB) ( 83 )   Save Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions; behavioral recovery is typically poor. We used a plasmalemmal fusogen, polyethylene glycol (PEG), to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic nerves. We have previously reported that sciatic nerve axons repaired by PEGfusion do not undergo Wallerian degeneration, and PEG-fused animals exhibit rapid (within 2–6 weeks) and extensive locomotor recovery. Furthermore, our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific, i.e., spinal motoneurons in PEGfused animals were found to project to appropriate as well as inappropriate target muscles. In this study, we examined the consequences of PEG-fusion for sensory axons of the sciatic nerve. Young adult male and female rats (Sprague–Dawley) received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without (Negative Control) the application of PEG. Compound action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury site. The success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days postoperatively. At 2–42 days postoperatively, we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish peroxidase. PEG-fusion repair reestablished axonal continuity. Compared to unoperated animals, labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn, as well as inappropriate mediolateral and rostrocaudal areas. Unexpectedly, despite having intact peripheral nerves, similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repair. This central reorganization may contribute to the improved behavioral recovery seen after PEG-fusion repair, supporting the use of this novel repair methodology over currently available treatments. Related Articles | Metrics

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FK506 contributes to peripheral nerve regeneration by inhibiting neuroinflammatory responses and promoting neuron survival Yuhui Kou, Zongxue Jin, Yusong Yuan, Bo Ma, Wenyong Xie, Na Han 2025, 20 (7):  2108-2115.  doi: 10.4103/NRR.NRR-D-22-00867 Abstract ( 76 )   PDF (1943KB) ( 26 )   Save FK506 (Tacrolimus) is a systemic immunosuppressant approved by the U.S. Food and Drug Administration. FK506 has been shown to promote peripheral nerve regeneration, however, its precise mechanism of action and its pathways remain unclear. In this study, we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve, increased the numbers of motor and sensory neurons, reduced inflammatory responses, markedly improved the conduction function of the injured nerve, and promoted motor function recovery. These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons. Related Articles | Metrics

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Müller cells are activated in response to retinal outer nuclear layer degeneration in rats subjected to simulated weightlessness conditions Yuxue Mu, Ning Zhang, Dongyu Wei, Guoqing Yang , Lilingxuan Yao , Xinyue Xu , Yang Li , Junhui Xue, Zuoming Zhang, Tao Chen 2025, 20 (7):  2116-2128.  doi: 10.4103/NRR.NRR-D-23-01035 Abstract ( 41 )   PDF (13005KB) ( 7 )   Save A microgravity environment has been shown to cause ocular damage and affect visual acuity, but the underlying mechanisms remain unclear. Therefore, we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity. After 4 weeks of tail suspension, there were no notable alterations in retinal function and morphology, while after 8 weeks of tail suspension, significant reductions in retinal function were observed, and the outer nuclear layer was thinner, with abundant apoptotic cells. To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina, proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension. The results showed that the expression levels of fibroblast growth factor 2 (also known as basic fibroblast growth factor) and glial fibrillary acidic protein, which are closely related to Müller cell activation, were significantly upregulated. In addition, Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks, respectively, of simulated weightlessness. These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness. Related Articles | Metrics