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15 October 2025, Volume 20 Issue 10 Previous Issue   

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The gut–eye axis: from brain neurodegenerative diseases to age-related macular degeneration Qianzi Jin, Suyu Wang, Yujia Yao, Qin Jiang, Keran Li 2025, 20 (10):  2741-2757.  doi: 10.4103/NRR.NRR-D-24-00531 Abstract ( 160 )   PDF (13844KB) ( 46 )   Save Age-related macular degeneration is a serious neurodegenerative disease of the retina that significantly impacts vision. Unfortunately, the specific pathogenesis remains unclear, and effective early treatment options are consequently lacking. The microbiome is defined as a large ecosystem of microorganisms living within and coexisting with a host. The intestinal microbiome undergoes dynamic changes owing to age, diet, genetics, and other factors. Such dysregulation of the intestinal flora can disrupt the microecological balance, resulting in immunological and metabolic dysfunction in the host, and affecting the development of many diseases. In recent decades, significant evidence has indicated that the intestinal flora also influences systems outside of the digestive tract, including the brain. Indeed, several studies have demonstrated the critical role of the gut–brain axis in the development of brain neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Similarly, the role of the “gut–eye axis” has been confirmed to play a role in the pathogenesis of many ocular disorders. Moreover, age-related macular degeneration and many brain neurodegenerative diseases have been shown to share several risk factors and to exhibit comparable etiologies. As such, the intestinal flora may play an important role in age-related macular degeneration. Given the above context, the present review aims to clarify the gut–brain and gut–eye connections, assess the effect of intestinal flora and metabolites on age-related macular degeneration, and identify potential diagnostic markers and therapeutic strategies. Currently, direct research on the role of intestinal flora in age-related macular degeneration is still relatively limited, while studies focusing solely on intestinal flora are insufficient to fully elucidate its functional role in age-related macular degeneration. Organ-on-a-chip technology has shown promise in clarifying the gut–eye interactions, while integrating analysis of the intestinal flora with research on metabolites through metabolomics and other techniques is crucial for understanding their potential mechanisms. Related Articles | Metrics

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PI3K/AKT signaling and neuroprotection in ischemic stroke: molecular mechanisms and therapeutic perspectives Tianlong Liu, Xiaolin Li, Xiaowei Zhou, Wei Chen, Aidong Wen, Minna Liu, Yi Ding 2025, 20 (10):  2758-2775.  doi: 10.4103/NRR.NRR-D-24-00568 Abstract ( 229 )   PDF (9131KB) ( 61 )   Save It has been reported that the PI3K/AKT signaling pathway plays a key role in the pathogenesis of ischemic stroke. As a result, the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing attention from researchers. This article reviews the pathological mechanisms and advancements in research related to the signaling pathways in ischemic stroke, with a focus on the PI3K/AKT signaling pathway. The key findings include the following: (1) The complex pathological mechanisms of ischemic stroke can be categorized into five major types: excitatory amino acid toxicity, Ca2+ overload, inflammatory response, oxidative stress, and apoptosis. (2) The PI3K/AKTmediated signaling pathway is closely associated with the occurrence and progression of ischemic stroke, which primarily involves the NF-κB, NRF2, BCL-2, mTOR, and endothelial NOS signaling pathways. (3) Natural products, including flavonoids, quinones, alkaloids, phenylpropanoids, phenols, terpenoids, and iridoids, show great potential as candidate substances for the development of innovative anti-stroke medications. (4) Recently, novel therapeutic techniques, such as electroacupuncture and mesenchymal stem cell therapy, have demonstrated the potential to improve stroke outcomes by activating the PI3K/ AKT signaling pathway, providing new possibilities for the treatment and rehabilitation of patients with ischemic stroke. Future investigations should focus on the direct regulatory mechanisms of drugs targeting the PI3K/AKT signaling pathway and their clinical translation to develop innovative treatment strategies for ischemic stroke. Related Articles | Metrics

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Autism spectrum disorder: difficulties in diagnosis and microRNA biomarkers Bridget Martinez, Philip V. Peplow 2025, 20 (10):  2776-2786.  doi: 10.4103/NRR.NRR-D-24-00712 Abstract ( 50 )   PDF (669KB) ( 32 )   Save We performed a PubMed search for microRNAs in autism spectrum disorder that could serve as diagnostic biomarkers in patients and selected 17 articles published from January 2008 to December 2023, of which 4 studies were performed with whole blood, 4 with blood plasma, 5 with blood serum, 1 with serum neural cell adhesion molecule L1-captured extracellular vesicles, 1 with blood cells, and 2 with peripheral blood mononuclear cells. Most of the studies involved children and the study cohorts were largely males. Many of the studies had performed microRNA sequencing or quantitative polymerase chain reaction assays to measure microRNA expression. Only five studies had used real-time polymerase chain reaction assay to validate microRNA expression in autism spectrum disorder subjects compared to controls. The microRNAs that were validated in these studies may be considered as potential candidate biomarkers for autism spectrum disorder and include miR-500a-5p, -197-5p, -424-5p, -664a-3p, -365a-3p, -619-5p, -664a3p, -3135a, -328-3p, and -500a-5p in blood plasma and miR-151a-3p, -181b-5p, -320a, -328, -433, -489, -572, -663a, -101-3p, -106b-5p, -19b-3p, -195-5p, and -130a-3p in blood serum of children, and miR-15b-5p and -6126 in whole blood of adults. Several important limitations were identified in the studies reviewed, and need to be taken into account in future studies. Further studies are warranted with children and adults having different levels of autism spectrum disorder severity and consideration should be given to using animal models of autism spectrum disorder to investigate the effects of suppressing or overexpressing specific microRNAs as a novel therapy. Related Articles | Metrics

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Pyroptosis, ferroptosis, and autophagy in spinal cord injury: regulatory mechanisms and therapeutic targets Qingcong Zheng, Du Wang, Rongjie Lin, Weihong Xu 2025, 20 (10):  2787-2806.  doi: 10.4103/NRR.NRR-D-24-00112 Abstract ( 304 )   PDF (6880KB) ( 60 )   Save Regulated cell death is a form of cell death that is actively controlled by biomolecules. Several studies have shown that regulated cell death plays a key role after spinal cord injury. Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords. Autophagy, a complex form of cell death that is interconnected with various regulated cell death mechanisms, has garnered significant attention in the study of spinal cord injury. This injury triggers not only cell death but also cellular survival responses. Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis, ferroptosis, and autophagy. Therefore, this review aims to comprehensively examine the mechanisms underlying regulated cell deaths, the signaling pathways that modulate these mechanisms, and the potential therapeutic targets for spinal cord injury. Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury. Moreover, a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury. Related Articles | Metrics

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Multilevel analysis of the central–peripheral– target organ pathway: contributing to recovery after peripheral nerve injury Xizi Song, Ruixin Li, Xiaolei Chu, Qi Li, Ruihua Li, Qingwen Li, Kai-Yu Tong, Xiaosong Gu, Dong Ming 2025, 20 (10):  2807-2822.  doi: 10.4103/NRR.NRR-D-24-00641 Abstract ( 139 )   PDF (2505KB) ( 175 )   Save Peripheral nerve injury is a common neurological condition that often leads to severe functional limitations and disabilities. Research on the pathogenesis of peripheral nerve injury has focused on pathological changes at individual injury sites, neglecting multilevel pathological analysis of the overall nervous system and target organs. This has led to restrictions on current therapeutic approaches. In this paper, we first summarize the potential mechanisms of peripheral nerve injury from a holistic perspective, covering the central nervous system, peripheral nervous system, and target organs. After peripheral nerve injury, the cortical plasticity of the brain is altered due to damage to and regeneration of peripheral nerves; changes such as neuronal apoptosis and axonal demyelination occur in the spinal cord. The nerve will undergo axonal regeneration, activation of Schwann cells, inflammatory response, and vascular system regeneration at the injury site. Corresponding damage to target organs can occur, including skeletal muscle atrophy and sensory receptor disruption. We then provide a brief review of the research advances in therapeutic approaches to peripheral nerve injury. The main current treatments are conducted passively and include physical factor rehabilitation, pharmacological treatments, cell-based therapies, and physical exercise. However, most treatments only partially address the problem and cannot complete the systematic recovery of the entire central nervous system–peripheral nervous system–target organ pathway. Therefore, we should further explore multilevel treatment options that produce effective, long-lasting results, perhaps requiring a combination of passive (traditional) and active (novel) treatment methods to stimulate rehabilitation at the central–peripheral– target organ levels to achieve better functional recovery. Related Articles | Metrics

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Ultrasound technology in the treatment of Alzheimer's disease Qiuquan Cai, Lianghui Meng, Meina Quan, Ling Wang, Jing Ren, Chenguang Zheng, Jiajia Yang, Dong Ming 2025, 20 (10):  2823-2837.  doi: 10.4103/NRR.NRR-D-24-00539 Abstract ( 83 )   PDF (3388KB) ( 91 )   Save Alzheimer’s disease is a common neurodegenerative disorder defined by decreased reasoning abilities, memory loss, and cognitive deterioration. The presence of the blood–brain barrier presents a major obstacle to the development of effective drug therapies for Alzheimer’s disease. The use of ultrasound as a novel physical modulation approach has garnered widespread attention in recent years. As a safe and feasible therapeutic and drug-delivery method, ultrasound has shown promise in improving cognitive deficits. This article provides a summary of the application of ultrasound technology for treating Alzheimer’s disease over the past 5 years, including standalone ultrasound treatment, ultrasound combined with microbubbles or drug therapy, and magnetic resonance imaging–guided focused ultrasound therapy. Emphasis is placed on the benefits of introducing these treatment methods and their potential mechanisms. We found that several ultrasound methods can open the blood–brain barrier and effectively alleviate amyloid-β plaque deposition. We believe that ultrasound is an effective therapy for Alzheimer’s disease, and this review provides a theoretical basis for future ultrasound treatment methods. Key Words: Alzheimer’s disease; blood–brain barrier; drugs; magnetic resonance imaging–guided focused ultrasound; microbubbles; scanning ultrasound; ultrasound; ultrasound stimulation Related Articles | Metrics

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Inhibitory gamma-aminobutyric acidergic neurons in the anterior cingulate cortex participate in the comorbidity of pain and emotion Lu Guan, Mengting Qiu, Na Li, Zhengxiang Zhou, Ru Ye, Liyan Zhong, Yashuang Xu, Junhui Ren, Yi Liang, Xiaomei Shao, Jianqiao Fang, Junfan Fang, Junying Du 2025, 20 (10):  2838-2854.  doi: 10.4103/NRR.NRR-D-24-00429 Abstract ( 30 )   PDF (2279KB) ( 95 )   Save Pain is often comorbid with emotional disorders such as anxiety and depression. Hyperexcitability of the anterior cingulate cortex has been implicated in pain and painrelated negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission. This review primarily aims to outline the main circuitry (including the input and output connectivity) of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons; it also describes the neurotransmitters/neuromodulators affecting these neurons, their intercommunication with other neurons, and their importance in mental comorbidities associated with chronic pain disorders. Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions. However, the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive. It is also unclear as to whether the mechanisms are presynaptic or postsynaptic. Further exploration of the complexities of this system may reveal new pathways for research and drug development. Related Articles | Metrics

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Recovery of the injured neural system through gene delivery to surviving neurons in Parkinson’s disease Chanchal Sharma, Sehwan Kim, Hyemi Eo, Sang Ryong Kim 2025, 20 (10):  2855-2861.  doi: 10.4103/NRR.NRR-D-24-00724 Abstract ( 52 )   PDF (12070KB) ( 12 )   Save A critical unaddressed problem in Parkinson’s disease is the lack of therapy that slows or hampers neurodegeneration. While medications effectively manage symptoms, they offer no long-term benefit because they fail to address the underlying neuronal loss. This highlights that the elusive goals of halting progression and restoring damaged neurons limit the long-term impact of current approaches. Recent clinical trials using gene therapy have demonstrated the safety of various vector delivery systems, dosages, and transgenes expressed in the central nervous system, signifying tangible and substantial progress in applying gene therapy as a promising Parkinson’s disease treatment. Intriguingly, at diagnosis, many dopamine neurons remain in the substantia nigra, offering a potential window for recovery and survival. We propose that modulating these surviving dopamine neurons and axons in the substantia nigra and striatum using gene therapy offers a potentially more impactful therapeutic approach for future research. Moreover, innovative gene therapies that focus on preserving the remaining elements may have significant potential for enhancing long-term outcomes and the quality of life for patients with Parkinson’s disease. In this review, we provide a perspective on how gene therapy can protect vulnerable elements in the substantia nigra and striatum, offering a novel approach to addressing Parkinson’s disease at its core. Related Articles | Metrics

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Exploring the role of N-acetyltransferases in diseases: a focus on N-acetyltransferase 9 in neurodegeneration Prajakta Deshpande, Anuradha Venkatakrishnan Chimata, Amit Singh 2025, 20 (10):  2862-2871.  doi: 10.4103/NRR.NRR-D-24-00779 Abstract ( 39 )   PDF (1896KB) ( 31 )   Save Acetyltransferases, required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease. Protein acetylation is a common post-translational modification pivotal to basic cellular processes. Close to 80%– 90% of proteins are acetylated during translation, which is an irreversible process that affects protein structure, function, life, and localization. In this review, we have discussed the various N-acetyltransferases present in humans, their function, and how they might play a role in diseases. Furthermore, we have focused on N-acetyltransferase 9 and its role in microtubule stability. We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases. We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration. Related Articles | Metrics

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Small heat shock protein B8: from cell functions to its involvement in diseases and potential therapeutic applications Marta Chierichetti, Riccardo Cristofani, Valeria Crippa, Veronica Ferrari, Marta Cozzi, Elena Casarotto, Paola Pramaggiore, Laura Cornaggia, Guglielmo Patelli, Ali Mohamed, Margherita Piccolella, Mariarita Galbiati, Paola Rusmini, Barbara Tedesco, Angelo Poletti 2025, 20 (10):  2872-2886.  doi: 10.4103/NRR.NRR-D-24-00517 Abstract ( 61 )   PDF (2525KB) ( 35 )   Save Heat shock protein family B (small) member 8 (HSPB8) is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins. HSPB8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation, cell division, and migration. HSPB8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperoneassisted selective autophagy. In line with this function, the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and aggregation. In cancer, HSPB8 has a dual role being capable of exerting either a pro- or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under investigation. Moreover, HSPB8 exerts a protective function in different diseases by modulating the inflammatory response, which characterizes not only neurodegenerative diseases, but also other chronic or acute conditions affecting the nervous system, such as multiple sclerosis and intracerebellar hemorrhage. Of note, HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other diseases. This is the case of cognitive impairment related to diabetes mellitus, in which HSPB8 exerts a protective activity by assuring mitochondrial homeostasis. This review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions, focusing on the beneficial effects of its modulation. Drug-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed, emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments. Related Articles | Metrics

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Functions of nuclear factor Y in nervous system development, function and health Pedro Moreira, Roger Pocock 2025, 20 (10):  2887-2894.  doi: 10.4103/NRR.NRR-D-24-00684 Abstract ( 35 )   PDF (715KB) ( 18 )   Save Nuclear factor Y is a ubiquitous heterotrimeric transcription factor complex conserved across eukaryotes that binds to CCAAT boxes, one of the most common motifs found in gene promoters and enhancers. Over the last 30 years, research has revealed that the nuclear factor Y complex controls many aspects of brain development, including differentiation, axon guidance, homeostasis, disease, and most recently regeneration. However, a complete understanding of transcriptional regulatory networks, including how the nuclear factor Y complex binds to specific CCAAT boxes to perform its function remains elusive. In this review, we explore the nuclear factor Y complex’s role and mode of action during brain development, as well as how genomic technologies may expand understanding of this key regulator of gene expression. Related Articles | Metrics

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Tilting homeostatic and dyshomeostatic microglial balance in health and disease: transforming growth factor-beta1 as a critical protagonist Nicolas Hugues, Yu Luo 2025, 20 (10):  2895-2897.  doi: 10.4103/NRR.NRR-D-24-00700 Abstract ( 52 )   PDF (7696KB) ( 12 )   Save Adult microglia, by continuously sensing changes in their environment and communicating with nearly all brain cell types, are considered to be the immune sentinels of the brain. In the healthy central nervous system (CNS), microglia display a unique molecular homeostatic signature (i.e., Tmem119, P2ry12, Sall1, Siglech, Gpr34, and Hexb) (Figure 1A). These homeostatic microglia are distinct from activated microglia, the signature of which is highly microenvironmentand cellular context-dependent (Butovsky and Weiner, 2018; Paolicelli et al., 2022; Figure 1). The type and severity of insult, as well as the duration of stimulation, could influence either the beneficial or detrimental nature of the microglial response. On one hand, microglia could exert a protective function through phagocytosis and clearance of pathological protein aggregates. On the other hand, an excessive uptake of protein aggregates by microglia could lead to impairment of microglial phagocytic ability, induction of neuroinflammation, and eventually neurodegeneration. Neurodegenerative diseases, chronic neuroinflammatory states, and advanced aging could each induce dyshomeostatic profiles that can share some similarities while possessing distinct gene expression profiles (e.g., microglial neurodegenerative phenotype, MGnD; diseaseassociated microglia, DAM; aging-related microglia) (Paolicelli et al., 2022). This switch to a dyshomeostatic profile is reflected by an increased expression of neurodegenerative microglial genes (i.e., Apoe, Clec7a, Itgax, Lgals3, and Cst7; Figure 1C) tightly coupled with the downregulation of the above-mentioned microglial homeostatic genes. Related Articles | Metrics

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Lighting the shades of hidden pain: a role for spinal cord neurons and microglia in vestibulodynia Rosmara Infantino, Francesca Gargano, Serena Boccella, Carmela Belardo, Andrea Maria Morace, Francesca Guida, Sabatino Maione, Livio Luongo 2025, 20 (10):  2898-2900.  doi: 10.4103/NRR.NRR-D-24-00673 Abstract ( 48 )   PDF (1519KB) ( 12 )   Save Vulvodynia, a chronic pain disorder affecting the vulvar region, represents a significant challenge in both diagnosis and treatment within the field of women’s health. This condition is characterized by chronic pain that significantly affects the quality of life of afflicted women. The present perspective paper examines the role of spinal sensitization and microglial activation in vulvodynia. Traditionally, treatment approaches have focused on symptomatic relief without addressing the underlying biological mechanisms, largely due to the condition’s complex and poorly understood etiology. Recent scientific advancements underscore the crucial roles of spinal sensitization and microglial activation in vulvodynia’s pathophysiology. These findings suggest that microglia, which play a significant role in immune surveillance within the central nervous system, modulate pain pathways through their interactions with neurons, influencing cytokine release and neuronal excitability. This article explores how advancements in understanding these mechanisms could improve clinical practices, offering new, targeted treatments that address the root causes of pain. Thus, it discusses the potential of microglial activation as a therapeutic target, highlighted by successful interventions in various pain models, and considers the implications of these insights for future research and clinical applications. The challenges of translating these findings from animal models to human conditions are acknowledged, emphasizing the need for sophisticated imaging techniques and molecular biology to bridge this gap. Ultimately, the paper highlights a promising direction for improving the management and treatment of vulvodynia through focused research on spinal sensitization and microglial dynamics. Related Articles | Metrics

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Sex differences in aging and injured brain Jordan N. Williamson, Yuan Yang 2025, 20 (10):  2901-2902.  doi: 10.4103/NRR.NRR-D-24-00753 Abstract ( 51 )   PDF (614KB) ( 33 )   Save Background: The prevalence, age of onset, and symptomatology of traumatic brain injury, stroke, and neurodegenerative diseases (such as Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease) differ substantially between males and females. The higher prevalence of these brain disorders has been attributed to females having a greater longevity compared with males. Since one of the greatest risk factors of acquired brain injury (such as stroke, traumatic brain injury caused by fall) and neurodegenerative disease is age, it would be reasonable to state that more females would live long enough to develop a brain disorder. However, a recent systematic review and meta-analysis shows that even when baseline data is adjusted for demographic covariates such as age, females continue to have worse rehabilitation outcomes and account for more deaths compared to males (Ali, 2022). Increasing evidence suggests other factors are contributing to the sex-specific risk of brain diseases for females. These may include hormonal differences, genetics, menopause, pregnancy, and productivity, as well as gender differences in social and cultural roles, such as depression, education level, family burden, and sleep. Studying these sex differences is important because if sex is a crucial biological variable in disease heterogeneity, understanding these differences provides the potential for the generation of alternative approaches to identify the cause and provide treatment. This aids in the development of more precise medical interventions and better outcomes. Related Articles | Metrics

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Genistein: a possible solution for the treatment of Alzheimer’s disease Karolina Pierzynowska, Bartosz Karaszewski, Grzegorz Węgrzyn 2025, 20 (10):  2903-2905.  doi: 10.4103/NRR.NRR-D-24-00713 Abstract ( 43 )   PDF (909KB) ( 39 )   Save Neurodegenerative diseases are defined as disorders resulting from the slow and progressive loss of function and eventual death of neural cells that result from the primary pathology of nervous tissue. They can lead to severe nervous system dysfunction, eventually affecting multiple organs and systems. Several hundred neurodegenerative diseases have been described, and owing to their prevalence, severity, clinical characteristics, and generally low therapeutic efficiency, they constitute one of the greatest problems for healthcare providers and one of the heaviest issues in public health. Related Articles | Metrics

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Immunoassay development guidelines for neurodegenerative disorders: lessons from a failed pS129-α-synuclein electrochemiluminescence immunoassay Hash Brown Taha, Alanna Morris 2025, 20 (10):  2906-2908.  doi: 10.4103/NRR.NRR-D-24-00691 Abstract ( 30 )   PDF (983KB) ( 25 )   Save An aging population is a double-edged sword. On one hand, advancements in biotechnology and healthcare allow more people to enjoy longer lives. On the other hand, increases in the aging population accompany a surge in age-associated diseases, particularly neurodegenerative disorders. Since aging is the primary risk factor for many neurodegenerative disorders, living longer does not necessarily equate to maintaining a reasonable quality of life (Feigin et al., 2020). Related Articles | Metrics

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Brain scarring in infants: immunological insights from a neonatal hypoxic-ischemic encephalopathy model Pedro Moreno Pimentel-Coelho 2025, 20 (10):  2909-2910.  doi: 10.4103/NRR.NRR-D-24-00715 Abstract ( 43 )   PDF (672KB) ( 12 )   Save Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of disability in children. Improving brain function and accelerating neurological recovery may require a combination of neuroprotective and pro-regenerative treatments at different stages of HIE. While the first hours after the neonatal insult are the most critical period for neuroprotection, the existence of secondary and tertiary mechanisms of brain injury offers the possibility of preventing delayed neurodegeneration in the subsequent days, weeks, or months (Levison et al., 2022). This extended therapeutic window could also be utilized for therapies aimed at enhancing brain repair and regeneration. In this context, the formation of glial and fibrotic scars, while necessary to maintain or restore the integrity of brain tissue, is considered a major barrier to regeneration and might have delayed detrimental effects on brain function, thus representing a promising target for novel therapies. Related Articles | Metrics

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Revisiting cerebral endothelial cells in Alzheimer’s disease Amira S. Hanafy 2025, 20 (10):  2911-2912.  doi: 10.4103/NRR.NRR-D-24-00640 Abstract ( 38 )   PDF (457KB) ( 26 )   Save Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by slow and progressive decline of cognitive and memory functions. In only approximately 5% of the cases, AD is familial, as often predisposed by genetic mutations (Hoogmartens et al., 2021), while sporadic AD accounts for approximately 95% of the cases. The amyloid cascade hypothesis is one of the fundamental hypotheses put out to explain AD pathogenesis as dysregulated homeostasis of amyloid-β (Aβ) peptides that leads to the accumulation of Aβ plaques in the parenchyma, an anatomical hallmark of AD. Related Articles | Metrics

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Emerging role of A-kinase anchoring protein 5 signaling in reward circuit function William J. Flerlage, Mark L. Dell’Acqua, Brian M. Cox, Fereshteh S. Nugent 2025, 20 (10):  2913-2914.  doi: 10.4103/NRR.NRR-D-24-00759 Abstract ( 54 )   PDF (585KB) ( 25 )   Save There is a strong evidence supporting the hypothesis of synaptic dysfunction as a major contributor to neural circuit and network disruption underlying emotional and mood dysregulation in psychiatric disorders (Simmons et al., 2024). Diverse sets of distinct molecular signaling pathways converge on the synapse to regulate synaptogenesis, synaptic function, and synaptic plasticity in brain regions and circuits through complex interactions organized by numerous multivalent protein scaffolds, including the family of proteins known as A-kinase anchoring proteins (AKAPs). Extensive and ongoing research into molecular mechanisms regulating synaptic function and plasticity in memory-related brain circuits has highlighted the significance of a member of the AKAP family, namely AKAP5 (AKAP79 human/AKAP150 rodent/Akap5 gene), in cognitive and memory processes (Wild and Dell’Acqua, 2018). For simplicity, we use AKAP5 for AKAP79/150 throughout the review but specify AKAP150 in rodent studies discussed here. Emerging evidence also points out the potential role of AKAP5 in the development of depressive phenotypes (Corcoran et al., 2015; Guercio et al., 2018; Bai et al., 2023; Simmons et al., 2024; Wang et al., 2024) and the rapid-acting antidepressant effects of ketamine (Lopez et al., 2022). Yet our understanding of the potential dysregulation of AKAP5 signaling complexes in the promotion of specific synaptic abnormalities in neural circuits involved in mood disorders remains elusive. This is a significant gap in knowledge as human genetic studies strongly indicate that AKAP5 gene polymorphisms/mutations may play a role in the etiology of psychiatric illnesses such as schizophrenia, bipolar disorder, and depression (Simmons et al., 2024). The primary goal of this perspective is to briefly discuss a few recent developments in our understanding of AKAP5- related regulation of synaptic, neuronal excitability, and stress neuromodulation within brain reward circuits in the context of mood- and addictionrelated behaviors (Figure 1). We highlight some of the less explored aspects of AKAP signaling where AKAP5 is perfectly situated to serve as a molecular bridge integrating signals from multiple molecular pathways to specifically and efficiently regulate synaptic transmission and plasticity, and neuronal excitability vital for shaping neural circuits and networks underlying our behavior. We then conclude with a brief discussion of how a lack of well-organized AKAP5 signaling leads to synaptic dysfunction within the stress and reward-related brain regions, underscoring the therapeutic potential of drugs that target the AKAP5 protein– protein interactions in the treatment of psychiatric illnesses and substance use disorders. We further propose outstanding questions to be addressed in future research by leveraging technological advances in neuroscience and drug development to better understand the role of AKAP5 in the regulation of stress, motivation, and mood, and for AKAP5-targeted therapies using the emerging precision pharmacology and medicine in treatment of neurological and neuropsychiatric illnesses. Related Articles | Metrics

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Beyond neurodegeneration: engineering amyloids for biocatalysis Andrea Bartolomé-Nafría, Javier García-Pardo, Salvador Ventura 2025, 20 (10):  2915-2916.  doi: 10.4103/NRR.NRR-D-24-00711 Abstract ( 32 )   PDF (530KB) ( 43 )   Save Amyloid fibrils are highly organized protein or peptide aggregates, often characterized by a distinctive supramolecular cross-β-sheet structure. The formation and accumulation of these structures have been traditionally associated with neural or systemic human diseases, such as Alzheimer’s disease, Parkinson’s disease, type2 diabetes, or amyotrophic lateral sclerosis (Wei et al., 2017; Wittung-Stafshede, 2023). However, evidence exists that the amyloid fold is also exploited by nature to perform several functional, nonpathogenic roles across all kingdoms of life. For example, amyloids contribute to biofilm formation in bacteria (Peña‐Díaz et al., 2024) or are involved in the regulation of transcription and alternative splicing in humans. As a general trend, amyloids display highly rigid structures with high chemical and mechanical stability, which makes them ideal scaffolds for the design of novel nanostructured materials. Related Articles | Metrics

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Complementary roles of glial cells in generating region-specific neuroinflammatory responses and phagocytosis in Parkinson’s disease Leyre Ayerra, Maria S. Aymerich 2025, 20 (10):  2917-2918.  doi: 10.4103/NRR.NRR-D-24-00646 Abstract ( 49 )   PDF (1618KB) ( 8 )   Save N e u ro i n f l a m m a t i o n i s a s s o c i a te d w i t h Parkinson’s disease: Reactive gliosis and neuroinflammation are hallmarks of Parkinson’s disease (PD), a multisystem neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Neuroinflammation has long been considered a mere consequence of neuronal loss, but whether it promotes PD or is a key player in disease progression remains to be determined. Human leukocyte antigen, also known as major histocompatibility complex class II (MHCII), is expressed on all antigenpresenting cells of the immune system including microglia and central nervous system resident macrophages, and interestingly, its expression is increased in post-mortem PD samples (McGeer, 1988; Imamura, 2003). The strongest evidence for a link between the immune system and PD comes from genome-wide association studies, which have identified several polymorphisms in human leukocyte antigen-DR that are associated with an increased risk of idiopathic PD (Harms, 2023). Neuroinflammation is a complex and dynamic process that requires a cross-talk between glial and peripheral immune cells. Understanding these interactions is crucial for developing immunomodulatory interventions that could delay disease progression. Related Articles | Metrics

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Brain-derived neurotrophic factor plays with TRiC: focus on synaptic dysfunction in Huntington’s disease Yingli Gu, Kijung Sung, Chengbiao Wu 2025, 20 (10):  2919-2920.  doi: 10.4103/NRR.NRR-D-24-00679 Abstract ( 72 )   PDF (420KB) ( 19 )   Save Brain-derived neurotrophic factor (BDNF) exerts pleiotropic effects on brain processes including psychiatric disorders, aging, neurodegeneration, and metabolic homeostasis. A simple PubMed search using the key word “BDNF,” to date, yields over 33,000 publications. From fundamental biology to potential therapeutic applications, BDNF has clearly garnered extensive and significant attention in the field of neurobiology research. Related Articles | Metrics

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Navigating the pathways: TAR-DNAbinding-protein-43 aggregation, axonal transport, and local synthesis in amyotrophic lateral sclerosis pathology Ori Bar Avi, Eran Perlson 2025, 20 (10):  2921-2922.  doi: 10.4103/NRR.NRR-D-24-00726 Abstract ( 47 )   PDF (636KB) ( 29 )   Save Neurons are highly polarized cells with axons reaching over a meter long in adult humans. To survive and maintain their proper function, neurons depend on specific mechanisms that regulate spatiotemporal signaling and metabolic events, which need to be carried out at the right place, time, and intensity. Such mechanisms include axonal transport, local synthesis, and liquid–liquid phase separations. Alterations and malfunctions in these processes are correlated to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). ALS is a fast-progressing fatal motor neuron disease pathologically characterized by muscle atrophy, neuromuscular junction degeneration, and eventually, motor neuron death (Rothstein, 2009). While the precise mechanisms underlying ALS pathogenesis remain elusive, TAR DNA binding protein 43 (TDP-43) mislocalization and aggregation play a key role in the disease process (Buratti and Baralle, 2009; Lee et al., 2012; Piol et al., 2023). Concurrently, disruptions in axonal transport, and alterations in local synthesis, which are vital for neuronal function, have also been observed in ALS. Understanding the bidirectional interplay between TDP-43 aggregation and axonal transport/local synthesis events holds promise for elucidating ALS pathology and advancing therapeutic strategies. Related Articles | Metrics

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Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex Yan Li , Peng Hao, Hongmei Duan, Fei Hao, Wen Zhao, Yudan Gao, Zhaoyang Yang, Kwok-Fai So, Xiaoguang Li 2025, 20 (10):  2923-2937.  doi: 10.4103/NRR.NRR-D-23-01706 Abstract ( 88 )   PDF (9151KB) ( 19 )   Save The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury. However, whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions, such as the cortex, remains unknown. In this study, we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury. Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells, as well as their differentiation into mature and functionally integrated neurons. Importantly, these new neurons reconstructed the architecture of cortical layers II to VI, integrated into the existing neural circuitry, and ultimately led to improved brain function. These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries. Related Articles | Metrics

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Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish: unveiling the role of vascular endothelial growth factor signaling and microglia Danielle Fernezelian, Philippe Rondeau, Laura Gence, Nicolas Diotel 2025, 20 (10):  2938-2954.  doi: 10.4103/NRR.NRR-D-23-01881 Abstract ( 85 )   PDF (185585KB) ( 9 )   Save After brain damage, regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals, suggesting a close link between these processes. However, the mechanisms by which these processes interact are not well understood. In this work, we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury. To this end, we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms. First, using the Tg(fli1:EGFP × mpeg1.1:mCherry) zebrafish line, which enables visualization of blood vessels and microglia respectively, we analyzed regenerative angiogenesis from 1 to 21 days post-lesion. In parallel, we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry. We found that after brain damage, the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor (vegfaa and vegfbb) were increased. At the same time, neural stem cell proliferation was also increased, peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis, along with the recruitment of microglia. Then, through pharmacological manipulation by injecting an antiangiogenic drug (Tivozanib) or Vegf at the lesion site, we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes, as well as microglial recruitment. Finally, we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis, as previously described, as well as injury-induced angiogenesis. In conclusion, we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process. In addition, we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes. This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury. Related Articles | Metrics

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Inhibiting ceramide synthase 5 expression in microglia decreases neuroinflammation after spinal cord injury Wei Zhang, Yubao Lu, Ruoqi Shen, Yingjie Wu, Chenrui Liu, Xingxing Fang, Liangming Zhang, Bin Liu, Limin Rong 2025, 20 (10):  2955-2968.  doi: 10.4103/NRR.NRR-D-23-01933 Abstract ( 285 )   PDF (84172KB) ( 34 )   Save Microglia, the resident monocyte of the central nervous system, play a crucial role in the response to spinal cord injury. However, the precise mechanism remains unclear. To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury, we performed single-cell RNA sequencing dataset analysis, focusing on changes in microglial subpopulations. We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis, sphingomyelin metabolism, and neuroinflammation at high levels. Subsequently, we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury. Finally, we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells. Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis. Furthermore, ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway. Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function. Pla2g7 formed a “bridge” between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway. Collectively, these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3, thereby exerting neuroprotective effects. Related Articles | Metrics

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Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in a mouse model of Alzheimer’s disease Mackenzie M. Spicer, Jianqi Yang, Daniel Fu, Alison N. DeVore, Marisol Lauffer, Nilufer S. Atasoy, Deniz Atasoy, Rory A. Fisher 2025, 20 (10):  2969-2981.  doi: 10.4103/NRR.NRR-D-23-01993 Abstract ( 49 )   PDF (7325KB) ( 6 )   Save Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease. Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease. Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease. However, the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood. Recently, regulator of G protein signaling 6 (RGS6) was identified as the mediator of voluntary running–induced adult hippocampal neurogenesis in mice. Here, we generated novel RGS6fl/fl; APPSWE mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running–induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model. We found that voluntary running in APPSWE mice restored their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells, which also abolished running-mediated increases in adult hippocampal neurogenesis. Adult hippocampal neurogenesis was reduced in sedentary APPSWE mice versus control mice, with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells. RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons. Thus, RGS6 mediated voluntary running–induced rescue of impaired cognition and adult hippocampal neurogenesis in APPSWE mice, identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease. Related Articles | Metrics

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Longitudinal assessment of peripheral organ metabolism and the gut microbiota in an APP/PS1 transgenic mouse model of Alzheimer’s disease Hongli Li, Jianhua Huang, Di Zhao, Lemei Zhu, Zheyu Zhang, Min Yi, Weijun Peng 2025, 20 (10):  2982-2997.  doi: 10.4103/NRR.NRR-D-23-01979 Abstract ( 318 )   PDF (11216KB) ( 23 )   Save Alzheimer’s disease not only affects the brain, but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota. The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease, in particular the association between changes in peripheral organ metabolism, changes in gut microbial composition, and Alzheimer’s disease development. To do this, we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1 (APP/PS1) transgenic and control mice at 3, 6, 9, and 12 months of age. Twelve-month-old APP/PS1 mice exhibited cognitive impairment, Alzheimer’s disease–related brain changes, distinctive metabolic disturbances in peripheral organs and fecal samples (as detected by untargeted metabolomics sequencing), and substantial changes in gut microbial composition compared with younger APP/PS1 mice. Notably, a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice. These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development, indicating potential new directions for therapeutic strategies. Related Articles | Metrics

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Comparative proteomic analysis of plasma exosomes reveals the functional contribution of N-acetyl-alpha-glucosaminidase to Parkinson’s disease Yuan Zhao, Yidan Zhang, Xin Liu, Jian Zhang, Ya Gao, Shuyue Li, Cui Chang, Xiang Liu, Guofeng Yang 2025, 20 (10):  2998-3012.  doi: 10.4103/NRR.NRR-D-23-01500 Abstract ( 79 )   PDF (4250KB) ( 48 )   Save Parkinson’s disease is the second most common progressive neurodegenerative disorder, and few reliable biomarkers are available to track disease progression. The proteins, DNA, mRNA, and lipids carried by exosomes reflect intracellular changes, and thus can serve as biomarkers for a variety of conditions. In this study, we investigated alterations in the protein content of plasma exosomes derived from patients with Parkinson’s disease and the potential therapeutic roles of these proteins in Parkinson’s disease. Using a tandem mass tag-based quantitative proteomics approach, we characterized the proteomes of plasma exosomes derived from individual patients, identified exosomal protein signatures specific to patients with Parkinson’s disease, and identified N-acetyl-alpha-glucosaminidase as a differentially expressed protein. N-acetyl-alpha-glucosaminidase expression levels in exosomes from the plasma of patients and healthy controls were validated by enzyme-linked immunosorbent assay and western blot. The results demonstrated that the exosomal N-acetyl-alpha-glucosaminidase concentration was not only lower in Parkinson’s disease, but also decreased with increasing Hoehn–Yahr stage, suggesting that N-acetylalpha-glucosaminidase could be used to rapidly evaluate Parkinson’s disease severity. Furthermore, western blot and immunohistochemistry analysis showed that N-acetyl-alpha-glucosaminidase levels were markedly reduced both in cells treated with 1-methyl-4-phenylpyridinium and cells overexpressing α-synuclein compared with control cells. Additionally, N-acetyl-alpha-glucosaminidase overexpression significantly increased cell viability and inhibited α-synuclein expression in 1-methyl-4-phenylpyridinium-treated cells. Taken together, our findings demonstrate for the first time that exosomal N-acetyl-alpha-glucosaminidase may serve as a biomarker for Parkinson’s disease diagnosis, and that N-acetyl-alpha-glucosaminidase may reduce α-synuclein expression and 1-methyl-4-phenylpyridinium-induced neurotoxicity, thus providing a new therapeutic target for Parkinson’s disease. Related Articles | Metrics

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Persistent alterations in gray matter in COVID-19 patients experiencing sleep disturbances: a 3-month longitudinal study Kaixuan Zhou, Gaoxiong Duan, Ying Liu, Bei Peng, Xiaoyan Zhou, Lixia Qin, Lingyan Liang, Yichen Wei, Qingping Zhang, Xiaocheng Li, Haixia Qin, Yinqi Lai, Yian Lu, Yan Zhang, Jiazhu Huang, Jinli Huang, Yinfei Ouyang, Bolin Bin, Mingming Zhao, Jun Liu, Jianrong Yang, Demao Deng 2025, 20 (10):  3013-3024.  doi: 10.4103/NRR.NRR-D-23-01651 Abstract ( 64 )   PDF (3950KB) ( 37 )   Save Sleep disturbances are among the most prevalent neuropsychiatric symptoms in individuals who have recovered from severe acute respiratory syndrome coronavirus 2 infections. Previous studies have demonstrated abnormal brain structures in patients with sleep disturbances who have recovered from coronavirus disease 2019 (COVID-19). However, neuroimaging studies on sleep disturbances caused by COVID-19 are scarce, and existing studies have primarily focused on the long-term effects of the virus, with minimal acute phase data. As a result, little is known about the pathophysiology of sleep disturbances in the acute phase of COVID-19. To address this issue, we designed a longitudinal study to investigate whether alterations in brain structure occur during the acute phase of infection, and verified the results using 3-month follow-up data. A total of 26 COVID-19 patients with sleep disturbances (aged 51.5 ± 13.57 years, 8 women and 18 men), 27 COVID-19 patients without sleep disturbances (aged 47.33 ± 15.98 years, 9 women and 18 men), and 31 age- and gender-matched healthy controls (aged 49.19 ± 17.51 years, 9 women and 22 men) were included in this study. Eleven COVID-19 patients with sleep disturbances were included in a longitudinal analysis. We found that COVID-19 patients with sleep disturbances exhibited brain structural changes in almost all brain lobes. The cortical thicknesses of the left pars opercularis and left precuneus were significantly negatively correlated with Pittsburgh Sleep Quality Index scores. Additionally, we observed changes in the volume of the hippocampus and its subfield regions in COVID-19 patients compared with the healthy controls. The 3-month follow-up data revealed indices of altered cerebral structure (cortical thickness, cortical grey matter volume, and cortical surface area) in the frontal-parietal cortex compared with the baseline in COVID-19 patients with sleep disturbances. Our findings indicate that the sleep disturbances patients had altered morphology in the cortical and hippocampal structures during the acute phase of infection and persistent changes in cortical regions at 3 months post-infection. These data improve our understanding of the pathophysiology of sleep disturbances caused by COVID-19. Related Articles | Metrics

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Inhibition of the NLRP3 inflammasome attenuates spiral ganglion neuron degeneration in aminoglycoside-induced hearing loss Jia Fang, Zhuangzhuang Li, Pengjun Wang, Xiaoxu Zhang, Song Mao, Yini Li, Dongzhen Yu, Xiaoyan Li, Yazhi Xing, Haibo Shi, Shankai Yin 2025, 20 (10):  3025-3039.  doi: 10.4103/NRR.NRR-D-23-01879 Abstract ( 55 )   PDF (4540KB) ( 61 )   Save Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum. However, their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target. In addition, the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure. To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides, we used a C57BL/6J mouse model treated with kanamycin. We found that the mice exhibited auditory deficits following the acute loss of outer hair cells. Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time. Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response, particularly those related to the NLRP3 inflammasome. Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed, accompanied by infiltration of macrophages and the release of proinflammatory cytokines. Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model. These findings suggest that NLRP3 inflammasome–mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration. Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration. Related Articles | Metrics

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Commentary on: “Human neural stem cell–derived artificial organelles to improve oxidative phosphorylation” Kwok-Fai So 2025, 20 (10):  3040-3040.  doi: 10.4103/NRR.NRR-D-24-01079 Abstract ( 46 )   PDF (303KB) ( 15 )   Save Mitochondrial function is fundamental to neuroregeneration, particularly in neurons, where high energy demands are essential for repair and recovery (Patrón and Zinsmaier, 2016; Beckervordersandforth et al., 2017; Iwata et al., 2023). Mitochondrial dysfunction, characterized by an imbalance in ATP levels and excessive production of mitochondrial reactive oxygen species, is a key factor that impedes neural regeneration in neurodegenerative diseases and after neuronal injury (Han et al., 2016, 2020; Zheng et al., 2016; Zong et al., 2024). Targeting mitochondrial health is therefore crucial for advancing therapeutic strategies in neuroregeneration. Related Articles | Metrics