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15 September 2025, Volume 20 Issue 9 Previous Issue   

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Mitophagy in acute central nervous system injuries: regulatory mechanisms and therapeutic potentials Siyi Xu, Junqiu Jia, Rui Mao, Xiang Cao, Yun Xu 2025, 20 (9):  2437-2453.  doi: 10.4103/NRR.NRR-D-24-00432 Abstract ( 277 )   PDF (7709KB) ( 203 )   Save Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area Related Articles | Metrics

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Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage Victoria Jiménez Carretero, Iris Álvarez-Merz, Jorge Hernández-Campano, Sergei A. Kirov, Jesús M. Hernández-Guijo 2025, 20 (9):  2454-2463.  doi: 10.4103/NRR.NRR-D-24-00536 Abstract ( 60 )   PDF (1970KB) ( 41 )   Save The involvement of the excitatory amino acids glutamate and aspartate in cerebral ischemia and excitotoxicity is well-documented. Nevertheless, the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied. The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra. Our findings indicated that the reversible loss of field excitatory postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids (L-alanine, glycine, L-glutamine, and L-serine) at their plasma concentrations. These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia, along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors. Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia. It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels, leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation. Thus, previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury. Understanding these pathways could highlight new therapeutic targets to mitigate brain injury. Related Articles | Metrics

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Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction Said Hashemolhosseini , Lea Gessler 2025, 20 (9):  2464-2479.  doi: 10.4103/NRR.NRR-D-24-00417 Abstract ( 110 )   PDF (1853KB) ( 61 )   Save Skeletal muscles are essential for locomotion, posture, and metabolic regulation. To understand physiological processes, exercise adaptation, and muscle-related disorders, it is critical to understand the molecular pathways that underlie skeletal muscle function. The process of muscle contraction, orchestrated by a complex interplay of molecular events, is at the core of skeletal muscle function. Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction. Within muscle fibers, calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force. Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling. The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis. Myogenic regulators coordinate the differentiation of myoblasts into mature muscle fibers. Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability. Several muscle–related diseases, including congenital myasthenic disorders, sarcopenia, muscular dystrophies, and metabolic myopathies, are underpinned by dysregulated molecular pathways in skeletal muscle. Therapeutic interventions aimed at preserving muscle mass and function, enhancing regeneration, and improving metabolic health hold promise by targeting specific molecular pathways. Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway, a critical regulator of myogenesis, muscle regeneration, and metabolic function, and the Hippo signaling pathway. In recent years, more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers, and at the neuromuscular junction. In fact, research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers. In this review, we will summarize and discuss the data on these two pathways, focusing on their concerted action next to their contribution to skeletal muscle biology. However, an in-depth discussion of the noncanonical Wnt pathway, the fibro/adipogenic precursors, or the mechanosensory aspects of these pathways is not the focus of this review. Related Articles | Metrics

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Olfactory receptors in neural regeneration in the central nervous system Rafael Franco, Claudia Garrigós, Toni Capó, Joan Serrano-Marín, Rafael Rivas-Santisteban, Jaume Lillo 2025, 20 (9):  2480-2494.  doi: 10.4103/NRR.NRR-D-24-00495 Abstract ( 80 )   PDF (768KB) ( 124 )   Save Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell, influencing behaviors from food choices to emotional memories. These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring. The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration, a phenomenon largely absent in the central nervous system. Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system, where damage often results in permanent deficits. Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal cord injuries and neurodegenerative diseases like Alzheimer’s disease. Olfactory receptors are found in almost any cell of every organ/tissue of the mammalian body. This ectopic expression provides insights into the chemical structures that can activate olfactory receptors. In addition to odors, olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota. The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor’s role in proliferation and cell differentiation mechanisms. This review explores the ectopic expression of olfactory receptors and the role they may play in neural regeneration within the central nervous system, with particular attention to compounds that can activate these receptors to initiate regenerative processes. Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries. Related Articles | Metrics

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The dopaminergic system and Alzheimer’s disease Yuhan Zhang, Yuan Liang, Yixue Gu 2025, 20 (9):  2495-2512.  doi: 10.4103/NRR.NRR-D-24-00230 Abstract ( 84 )   PDF (2194KB) ( 62 )   Save Alzheimer’s disease is a common neurodegenerative disorder in older adults. Despite its prevalence, its pathogenesis remains unclear. In addition to the most widely accepted causes, which include excessive amyloid-beta aggregation, tau hyperphosphorylation, and deficiency of the neurotransmitter acetylcholine, numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition. Dopamine is a crucial catecholaminergic neurotransmitter in the human body. Dopamine-associated treatments, such as drugs that target dopamine receptor D and dopamine analogs, can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations. However, therapeutics targeting the dopaminergic system are associated with various adverse reactions, such as addiction and exacerbation of cognitive impairment. This review summarizes the role of the dopaminergic system in the pathology of Alzheimer’s disease, focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs. The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer’s disease, thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options. Related Articles | Metrics

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Acquired sensorineural hearing loss, oxidative stress, and microRNAs Desmond A. Nunez, Ru C. Guo 2025, 20 (9):  2513-2519.  doi: 10.4103/NRR.NRR-D-24-00579 Abstract ( 62 )   PDF (594KB) ( 71 )   Save Hearing loss is the third leading cause of human disability. Age-related hearing loss, one type of acquired sensorineural hearing loss, is largely responsible for this escalating global health burden. Noise-induced, ototoxic, and idiopathic sudden sensorineural are other less common types of acquired hearing loss. The etiology of these conditions is complex and multi-factorial involving an interplay of genetic and environmental factors. Oxidative stress has recently been proposed as a likely linking cause in most types of acquired sensorineural hearing loss. Short non-coding RNA sequences known as microRNAs (miRNAs) have increasingly been shown to play a role in cellular hypoxia and oxidative stress responses including promoting an apoptotic response. Sensory hair cell death is a central histopathological finding in sensorineural hearing loss. As these cells do not regenerate in humans, it underlies the irreversibility of human age-related hearing loss. Ovid EMBASE, Ovid MEDLINE, Web of Science Core Collection, and ClinicalTrials. gov databases over the period August 1, 2018 to July 31, 2023 were searched with “hearing loss,” “hypoxamiRs,” “hypoxia,” “microRNAs,” “ischemia,” and “oxidative stress” text words for English language primary study publications or registered clinical trials. Registered clinical trials known to the senior author were also assessed. A total of 222 studies were thus identified. After excluding duplicates, editorials, retractions, secondary research studies, and non-English language articles, 39 primary studies and clinical trials underwent full-text screening. This resulted in 11 animal, in vitro, and/or human subject journal articles and 8 registered clinical trial database entries which form the basis of this narrative review. MiRNAs miR-34a and miR-29b levels increase with age in mice. These miRNAs were demonstrated in human neuroblastoma and murine cochlear cell lines to target Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator-1-alpha (SIRT1/PGC-1α), SIRT1/p53, and SIRT1/hypoxia-inducible factor 1-alpha signaling pathways resulting in increased apoptosis. Furthermore, hypoxia and oxidative stress had a similar adverse apoptotic effect, which was inhibited by resveratrol and a myocardial inhibitor– associated transcript, a miR-29b competing endogenous mRNA. Gentamicin reduced miR-182-5p levels and increased cochlear oxidative stress and cell death in mice – an effect that was corrected by inner ear stem cell–derived exosomes. There is ongoing work seeking to determine if these findings can be effectively translated to humans. Related Articles | Metrics

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Glucocorticoid receptor signaling in the brain and its involvement in cognitive function Chonglin Su, Taiqi Huang, Meiyu Zhang, Yanyu Zhang, Yan Zeng, Xingxing Chen 2025, 20 (9):  2520-2537.  doi: 10.4103/NRR.NRR-D-24-00355 Abstract ( 71 )   PDF (3344KB) ( 82 )   Save The hypothalamic–pituitary–adrenal axis regulates the secretion of glucocorticoids in response to environmental challenges. In the brain, a nuclear receptor transcription factor, the glucocorticoid receptor, is an important component of the hypothalamic– pituitary–adrenal axis’s negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity. The glucocorticoid receptor influences cognitive processes, including glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor–mediated pathways, through a combination of genomic and non-genomic mechanisms. Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor, thereby affecting the hypothalamic–pituitary–adrenal axis and stress-related cognitive functions. An appropriate level of glucocorticoid receptor expression can improve cognitive function, while excessive glucocorticoid receptors or long-term exposure to glucocorticoids may lead to cognitive impairment. Patients with cognitive impairment–associated diseases, such as Alzheimer’s disease, aging, depression, Parkinson’s disease, Huntington’s disease, stroke, and addiction, often present with dysregulation of the hypothalamic–pituitary–adrenal axis and glucocorticoid receptor expression. This review provides a comprehensive overview of the functions of the glucocorticoid receptor in the hypothalamic–pituitary–adrenal axis and cognitive activities. It emphasizes that appropriate glucocorticoid receptor signaling facilitates learning and memory, while its dysregulation can lead to cognitive impairment. This provides clues about how glucocorticoid receptor signaling can be targeted to overcome cognitive disability-related disorders. Related Articles | Metrics

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Nanocarrier-mediated siRNA delivery: a new approach for the treatment of traumatic brain injury–related Alzheimer’s disease Jie Jin, Huajing Zhang, Qianying Lu, Linqiang Tian, Sanqiao Yao, Feng Lai, Yangfan Liang, Chuanchuan Liu, Yujia Lu, Sijia Tian, Yanmei Zhao, Wenjie Ren 2025, 20 (9):  2538-2555.  doi: 10.4103/NRR.NRR-D-24-00303 Abstract ( 57 )   PDF (2653KB) ( 123 )   Save Traumatic brain injury and Alzheimer’s disease share pathological similarities, including neuronal loss, amyloid-β deposition, tau hyperphosphorylation, blood–brain barrier dysfunction, neuroinflammation, and cognitive deficits. Furthermore, traumatic brain injury can exacerbate Alzheimer’s disease-like pathologies, potentially leading to the development of Alzheimer’s disease. Nanocarriers offer a potential solution by facilitating the delivery of small interfering RNAs across the blood–brain barrier for the targeted silencing of key pathological genes implicated in traumatic brain injury and Alzheimer’s disease. Unlike traditional approaches to neuroregeneration, this is a molecular-targeted strategy, thus avoiding non-specific drug actions. This review focuses on the use of nanocarrier systems for the efficient and precise delivery of siRNAs, discussing the advantages, challenges, and future directions. In principle, siRNAs have the potential to target all genes and non-targetable proteins, holding significant promise for treating various diseases. Among the various therapeutic approaches currently available for neurological diseases, siRNA gene silencing can precisely “turn off” the expression of any gene at the genetic level, thus radically inhibiting disease progression; however, a significant challenge lies in delivering siRNAs across the blood–brain barrier. Nanoparticles have received increasing attention as an innovative drug delivery tool for the treatment of brain diseases. They are considered a potential therapeutic strategy with the advantages of being able to cross the blood–brain barrier, targeted drug delivery, enhanced drug stability, and multifunctional therapy. The use of nanoparticles to deliver specific modified siRNAs to the injured brain is gradually being recognized as a feasible and effective approach. Although this strategy is still in the preclinical exploration stage, it is expected to achieve clinical translation in the future, creating a new field of molecular targeted therapy and precision medicine for the treatment of Alzheimer’s disease associated with traumatic brain injury. Related Articles | Metrics

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Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis Yongting Lv , Hongfu Li 2025, 20 (9):  2556-2570.  doi: 10.4103/NRR.NRR-D-24-00286 Abstract ( 65 )   PDF (3907KB) ( 27 )   Save Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited. The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain, brainstem, and spinal cord, as well as abnormal protein deposition in the cytoplasm of neurons and glial cells. The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid, blood, and even urine. Among these biomarkers, neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system, while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles. Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity. However, there are challenges in using neurofilament light chain to differentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury. Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment, oxygen saturation, and the glomerular filtration rate. TAR DNA-binding protein 43, a pathological protein associated with amyotrophic lateral sclerosis, is emerging as a promising biomarker, particularly with advancements in exosome-related research. Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers; however, they show potential in predicting disease prognosis. Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years, the quest for definitive diagnostic and prognostic biomarkers remains a formidable challenge. This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings. Related Articles | Metrics

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Spinal cord injury regenerative therapy development: integration of design of experiments Yuji Okano, Hideyuki Okano, Yoshitaka Kase 2025, 20 (9):  2571-2573.  doi: 10.4103/NRR.NRR-D-24-00553 Abstract ( 167 )   PDF (1501KB) ( 71 )   Save Spinal cord injury (SCI) can cause motor and sensory paralysis, and autonomic nervous system disorders including malfunction of urination and defecation, thereby significantly impairing the quality of life. Researchers continue to explore new stem cell strategies for the treatment of paralysis by transplanting human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSCNS/PCs) into spinal cord injured tissues. Related Articles | Metrics

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Many faces of neuronal activity manipulation in Drosophila Amber Krebs, Steffen Kautzmann, Christian Klämbt 2025, 20 (9):  2574-2576.  doi: 10.4103/NRR.NRR-D-24-00524 Abstract ( 40 )   PDF (4075KB) ( 9 )   Save Animals exhibit complex responses to external and internal stimuli. The information is computed by interconnected neurons that express numerous ion channels, which modulate the neuronal membrane potential. How can neuronal activity orchestrate complex motor patterns or allow learning from previous experience? To answer such questions, we need the ability not only to record, but also to modulate neuronal activity in both space (e.g., neuronal subsets) and time. Related Articles | Metrics

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Apolipoprotein E elicits target-directed miRNA degradation to maintain neuronal integrity Jiazi Tan, Chin-Tong Ong 2025, 20 (9):  2577-2578.  doi: 10.4103/NRR.NRR-D-24-00680 Abstract ( 82 )   PDF (694KB) ( 28 )   Save Apolipoprotein E has diverse functions in neurons: Apolipoprotein E (ApoE) is a glycoprotein that primarily regulates lipid metabolism and transport in the central nervous system. There are three predominant human ApoE protein isoforms with cysteine and arginine substitutions at amino acid positions 112 and 158 that impact their lipidation and related functions (Flowers and Rebeck, 2020). ApoE2 is characterized by Cys112 and Cys158, ApoE3 by Cys112 and Arg158, whereas ApoE4 contains Arg112 and Arg158. Among these genetic variants, ApoE4 allele is the strongest risk factor for late-onset sporadic Alzheimer’s disease whereas ApoE2 is linked to cardiovascular disease. ApoE is predominantly produced by astrocytes with lower levels detected in other cell types in the brain. While ApoE displayed strong immunoreactivity in astrocytes, its level in the neurons appeared to be affected by different pathological conditions. Higher ApoE level was detected in neurons surrounding ischemic foci in cerebral infarction or senile plaques from Alzheimer’s disease brains, suggesting that ApoE might participate in repair pathways following injuries (Aoki et al., 2003). In addition to lipid metabolism, several studies showed that ApoE may perform other molecular functions in the neurons. For instance, ApoE3 secreted by astrocytes vectored microRNAs (miRNAs) into neurons where they silenced cholesterol biosynthesis genes and facilitated H3K27ac-mediated activation of genes linked to memory consolidation (Li et al., 2021). Transcriptome profiling of neurons derived from human induced pluripotent stem cells also showed that ApoE3 and ApoE4 isoforms could elicit distinct genetic programs that are implicated in Alzheimer’s disease progression (Lin et al., 2018). In adult mouse dentate gyrus, ApoE suppressed the over-proliferation of neural stem cells (NSCs) to maintain the pool of neural progenitor cells (NPCs) (Yang et al., 2011). While these results highlight the diverse molecular roles played by ApoE in neurons, its regulatory mechanisms at different stages of neurogenesis remain elusive. Related Articles | Metrics

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Cellular models of stress resistance may pave ways to fight neurodegenerative diseases Thu Nguyen Minh Pham, Christian Behl 2025, 20 (9):  2579-2580.  doi: 10.4103/NRR.NRR-D-24-00476 Abstract ( 57 )   PDF (1071KB) ( 14 )   Save Alzheimer’s disease (AD), the most common form of neurodegeneration, is characterized by selective neuronal vulnerability and brain regionselective neuron demise. The entorhinal cortex and hippocampal CA1 projection neurons are at greater risk in AD whereas other regions display resistance to neurodegeneration. Interestingly, the cerebellum, a phylogenetically very old region, is affected only very late in the disease progression. Although AD has been investigated intensively for decades, the detailed causes of the observed selective neurodegeneration and the exact diseasedetermining factors remain enigmatic in larger parts. The fact that many elderly do show ADassociated neuropathological substrates, including amyloid plaques and neurofibrillary tangles, but display largely unimpaired cognitive functions suggests that the brain of some individuals shows effective adaptation and resistance to potentially challenging conditions (Zhang et al., 2023). In different neurodegenerative disorders, undiscovered resilience factors, and adaptive or stress-responsive mechanisms must exist and can maintain neuronal survival and functions. Uncovering such resistance factors and pathways could act as a blueprint to develop novel strategies for disease treatment and prevention. Multiomicstechnologies have been applied disclosing differential gene expressions and functions when disease-affected and disease-resistant brain areas are comparatively studied. An alternative approach to identify mediators of resistance is to mimic disease-relevant stress conditions in in vitro systems, for instance, via the generation of neuronal cell clones that are selected for partial or full resistance against disease-relevant challenges. Related Articles | Metrics

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Crosstalk between androgen signaling and the chemokine receptor CXCR4: a novel strategy to promote myelin regeneration Marianne Bardy-Lagarde, Narimène Asbelaoui, Abdel Mouman Ghoumari 2025, 20 (9):  2581-2582.  doi: 10.4103/NRR.NRR-D-24-00439 Abstract ( 61 )   PDF (1118KB) ( 19 )   Save Multiple sclerosis (MS) is the most common chronic disease of the central nervous system (CNS) in young adults and represents the first cause of severe handicap, originally non-traumatic (Oh et al., 2018). MS is characterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood–brain barrier, which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells, oligodendrocytes (Oh et al., 2018). There is a prevalence sexual with a ratio of three times more affected women than men. Although MS is more prevalent in women, men generally suffer from more aggressive forms of MS, being associated with a risk factor for worse disability progression (Voskuhl et al., 2020). In men with MS, low testosterone levels resulting from dysfunctions of the hypothalamus and pituitary gland, have been associated with neurological disability and worse clinical outcomes, which demonstrates the importance of this sexual hormone in this pathology (Safarinejad, 2008). Correspondingly, in the most used animal model to investigate MS pathology, which is experimental autoimmune encephalomyelitis, levels of testosterone are markedly reduced (Milosevic et al., 2021). Interestingly, it is possible to reduce the symptoms observed in experimental autoimmune encephalomyelitis mice by using testosterone treatment (Zahaf et al., 2023). Related Articles | Metrics

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Translational challenges in amyotrophic lateral sclerosis therapy with macrophage migration inhibitory factor Leenor Alfahel , Aleksandar Rajkovic , Adrian Israelson 2025, 20 (9):  2583-2584.  doi: 10.4103/NRR.NRR-D-24-00616 Abstract ( 47 )   PDF (1662KB) ( 23 )   Save Macrophage migration inhibitory factor (MIF): MIF acts as a pleiotropic inflammatory mediator, playing regulatory roles in innate and adaptive immunity, neuroinflammation, neuroendocrine functions, and nervous system development (Matejuk et al., 2024). In recent years, MIF has attracted significant interest from research groups as a potential target for the treatment of various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and glioblastoma (Matejuk et al., 2024). Due to its complex biological functions, recent findings suggest that MIF may play contrasting roles in the pathophysiology of various neurodegenerative diseases. Therefore, a precise understanding of MIF’s roles in these diseases could provide crucial insights into better monitoring and potentially treating these conditions. Related Articles | Metrics

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Soluble epoxide hydrolase: a next-generation drug target for Alzheimer’s disease and related dementias Andrew Gregory, Chengyun Tang, Fan Fan 2025, 20 (9):  2585-2586.  doi: 10.4103/NRR.NRR-D-24-00503 Abstract ( 56 )   PDF (569KB) ( 21 )   Save Alzheimer’s disease (AD) and Alzheimer’s diseaserelated dementias (ADRD) represent a significant public health challenge, with projections indicating a substantial increase in affected individuals due to the aging global population. From the World Health Organization, AD/ADRD has affected more than 55 million individuals worldwide, with an additional 10 million cases diagnosed each year. According to the latest data from the Alzheimer’s Association, in the United States alone, AD/ADRD has already affected millions of individuals over the age of 65 years; this number is expected to double by 2060. In 2023, total payments in the US for AD/ ADRD individuals aged 65 and older amounted to $345 billion. The global cost of dementia care amounts to 1.3 trillion US dollars annually. Despite these impacts, AD/ADRD remains without a cure. The Food and Drug Administration-approved treatments have primarily addressed amyloidbeta (Aβ) buildup (aducanumab and lecanemab), cholinesterase inhibition (donepezil, rivastigmine, and galantamine), and glutamate regulation (memantine) or its combination with donepezil. Yet, none of these Food and Drug Administrationapproved treatments focus on targeting cerebral vascular pathological changes that are often associated with AD/ADRD (Fang et al., 2022). Related Articles | Metrics

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Tale of mitochondria and mitochondria-associated ER membrane in patient-derived neuronal models of Wolfram syndrome Laetitia Aubry , Timothy Barrett , Sovan Sarkar 2025, 20 (9):  2587-2588.  doi: 10.4103/NRR.NRR-D-23-02021 Abstract ( 50 )   PDF (564KB) ( 34 )   Save Mitochondria and mitochondria-associated e n d o p l a s m i c r e t i c u l u m m e m b r a n e i n neurodegenerative diseases: Mitochondria generate most of the chemical energy needed to power the biochemical reactions of cells, and thus are often referred to as the “powerhouse” of the cell. Nevertheless, this organelle is also involved in a plethora of different cellular functions such as calcium (Ca2+) homeostasis, apoptosis, oxidative stress, and several metabolic pathways including oxidative phosphorylation, tricarboxylic acid cycle, and β-oxidation of fatty acids. Many of these functions require the contact between the mitochondria and the endoplasmic reticulum (ER), which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-associated ER membrane (MAMs). Given that the brain is one of the high-energy-demanding organs in the body, neurons are uniquely vulnerable to reactive oxygen species, and that Ca2+ homeostasis is crucial for neuronal functionality, there has been a longstanding interest in mitochondrial functions and their communications with the ER within the fields of neurology and neuropathology. Alterations in mitochondrial physical and functional tethers along with their biochemical dysfunction are now recognized as common hallmarks of different neurodegenerative and neurodevelopmental conditions including Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and autistic spectrum disorders, as well as rare, early-onset neurodegenerative diseases such as Wolfram syndrome 1 (WS) (Johri and Beal, 2012; Paillusson et al., 2016; Delprat et al., 2018; Mishra et al., 2021). Thus, the identification of effective treatments acting on biochemical pathways involving the mitochondria is of great biomedical interest. Related Articles | Metrics

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Disruption of neuronal actin barrier promotes the entry of disease-implicated proteins to exacerbate amyotrophic lateral sclerosis pathology Mikito Shimizu , Tatsusada Okuno 2025, 20 (9):  2589-2590.  doi: 10.4103/NRR.NRR-D-24-00661 Abstract ( 44 )   PDF (1071KB) ( 23 )   Save Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease characterized by the accumulation of aberrant proteins in motor neurons of the brain and spinal cord. Patients with ALS develop skeletal muscle weakness, resulting in death from respiratory paralysis, which usually occurs 2–4 years after clinical onset (Goutman et al., 2022). Although the precise pathological mechanisms remain elusive, several processes, including aberrant ribonucleic acid metabolism, altered proteostasis/autophagy, mitochondrial dysfunction, and compromised DNA repair, are reportedly involved in the onset and progression of ALS. Recently, increasing evidence suggests that disruption of cytoskeletal dysregulation could be attributed to ALS (Goutman et al., 2022). Profilin-1, an actin monomer-binding protein essential for the regulation of actin polymerization, has been identified as a causative gene of familial ALS. Profilin-1 mutations have been reported to result not only in a decreased F-actin arrangement (Fil et al., 2017) but also in altered stress granule dynamics and TAR DNA-binding protein of 43kD (TDP-43) aggregation (Fil et al., 2017). Transgenic mice with mutated profilin-1 not only recapitulate paralysis and motor neuron degeneration similar to ALS, but also show TDP-43 aggregation pathology, suggesting that actin dynamics are intrinsically involved in the pathogenesis of ALS. Cofilin, which is essential for actin depolymerization, has also been associated with the pathology of ALS. A previous report showed that cofilin is associated with the reduction of F-actin in induced pluripotent stem cell-derived motor neurons in patients with ALS with GGGGCC intronic repeat expansion in C9orf72, a common genetic form of familial ALS. Therefore, disruption of actin dynamics, including alterations in profilin-1 and cofilin, has been implicated in the pathogenesis of ALS, contributing to motor neuron degeneration and disease progression. In this perspective, we will focus on the role of actin dynamics as a neuronal barrier inhibiting aberrant protein deposition. Additionally, we will discuss on the potential of axon guidance molecules regulating actin dynamics as a novel therapeutic target. Related Articles | Metrics

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Emerging potential of progranulindependent SorCS2 signaling in healthy and diseased nervous systems Alena Salasova , Anders Nykjær 2025, 20 (9):  2591-2593.  doi: 10.4103/NRR.NRR-D-24-00734 Abstract ( 46 )   PDF (16861KB) ( 6 )   Save The formation of the mammalian nervous system and its maturation into sensory, motor, cognitive, and behavioral circuits is a complex process that begins during early embryogenesis and lasts until young adulthood. Impaired neurodevelopment can result in various neurological and psychiatric conditions, jointly named neurodevelopmental disorders (NDDs). Today ’s stringent NDD classification includes intellectual disabilities, communication disorders, autism spectrum disorder, attention-deficit hyperactivity disorder, movement disorders, and specific learning disorders. While the NDD incidence is on the rise, the available therapies are limited and provide only symptomatic relief (Cainelli and Bisiacchi, 2022). Related Articles | Metrics

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Syndecans in Alzheimer’s disease: pathogenetic mechanisms and potential therapeutic targets Carmela Rita Balistreri , Roberto Monastero 2025, 20 (9):  2594-2595.  doi: 10.4103/NRR.NRR-D-24-00659 Abstract ( 50 )   PDF (825KB) ( 32 )   Save With increasing age, humans become more susceptible to the onset of neurodegenerative diseases (NDs), and among these, Alzheimer’s disease (AD) is the most frequent (Nicoletti et al., 2023). NDs are primarily characterized by neuronal loss and atrophy, but also by lesions involving the cerebral and/or cardiovascular system (Balistreri, 2021). Lesions such as macroinfarcts, microinfarcts, hemorrhages, white matter lesions, atherosclerosis, and arteriolosclerosis have also been significantly described in the preclinical stages of cognitive impairment characterizing NDs (Mariani et al., 2007). Vascular lesions are described as being characterized by the lifelong accumulation of abnormally activated inflammatory cells and microglia in both brain tissue and vessel walls. This leads to a reduction in cerebral blood flow, causing insufficient energy to the neurons, particularly under conditions of increased cerebral energy demand or vasospasm (Balistreri, 2021). This alteration causes ischemiainduced neuronal apoptosis and necrosis, which can damage brain tissue and cause a range of functional symptoms. In addition, lesions of the inner vessel wall cause endothelial dysfunction, also characterized by alterations in the glycocalyx, which contribute both to the disruption of the blood–brain barrier (BBB) and further reduce cerebral blood flow, causing further damage to neurons with further infiltration of inflammatory cells. All this leads, like a vicious circle, to further neuronal damage with subsequent cortical atrophy and the onset of NDs, first and foremost AD (Balistreri, 2021). This growing evidence suggests the relevance of the vascular role in cognitive impairment and dementia, which needs to be further investigated. Accordingly, we have recently illustrated in a narrative review that the endothelium dysfunction, as well as the dysfunction of its glycocalyx and the related cellular and molecular mechanisms, represent one of the main pathological processes in the onset of NDs (Balistreri et al., 2024). Endothelial cells are, in fact, essential components of the stroma of all tissues and organs, as well as the neurovascular unit (NVU) and BBB. In the latter, endothelial cells, together with microglia cells regulate the transport of nutrients and toxins in the brain, but dysfunctional endothelial cells can also evocate brain inflammation (Balistreri and Monastero, 2023). Related Articles | Metrics

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Apples to oranges: environmentally derived, dynamic regulation of serotonin neuron subpopulations in adulthood? Christopher J. O’Connell, Matthew J. Robson 2025, 20 (9):  2596-2597.  doi: 10.4103/NRR.NRR-D-24-00507 Abstract ( 42 )   PDF (876KB) ( 23 )   Save Traumatic brain injury (TBI) is a public health problem with an undue economic burden that impacts nearly every age, ethnic, and gender group across the globe (Capizzi et al., 2020). TBIs are often sustained during a dynamic range of exposures to energetic environmental forces and as such outcomes are typically heterogeneous regarding severity and pathology (Capizzi et al., 2020). Clinically, closed head mild TBI (i.e., mTBI, concussion) is the most prevalent form of TBI with nearly 25% of individuals exhibiting symptoms that persist for greater than 3 months after the initial injury (McMahon et al., 2014). Enduring symptoms often include psychiatric complications (major depressive disorder, anxiety, and social withdrawal), sleep disturbances, fatigue, and persistent, intractable headaches (Ledreux et al., 2020). The field has identified these, and other clinically relevant symptoms and pathologies associated with various forms of brain injuries, however a comprehensive understanding of the precise molecular mechanisms driving these symptoms and their pathology is inadequate. Despite decades of research and resources allocated to identify targetable pathologies underlying the emergent psychiatric phenomena associated with TBI, no U.S. Food and Drug Administration-approved pharmacotherapies are currently available for any form of TBI. Exacerbating this issue, available pharmacotherapies for treating the aforementioned symptoms and comorbidities associated with TBI lack sufficient efficacy. Related Articles | Metrics

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Decreased levels of phosphorylated synuclein in plasma are correlated with poststroke cognitive impairment Yi Wang, Yuning Li, Yakun Gu, Wei Ma, Yuying Guan, Mengyuan Guo, Qianqian Shao, Xunming Ji, Jia Liu 2025, 20 (9):  2598-2610.  doi: 10.4103/NRR.NRR-D-23-01348 Abstract ( 145 )   PDF (4176KB) ( 51 )   Save Poststroke cognitive impairment is a major secondary effect of ischemic stroke in many patients; however, few options are available for the early diagnosis and treatment of this condition. The aims of this study were to (1) determine the specific relationship between hypoxic and α-synuclein during the occur of poststroke cognitive impairment and (2) assess whether the serum phosphorylated α-synuclein level can be used as a biomarker for poststroke cognitive impairment. We found that the phosphorylated α-synuclein level was significantly increased and showed pathological aggregation around the cerebral infarct area in a mouse model of ischemic stroke. In addition, neuronal α-synuclein phosphorylation and aggregation were observed in the brain tissue of mice subjected to chronic hypoxia, suggesting that hypoxia is the underlying cause of α-synuclein-mediated pathology in the brains of mice with ischemic stroke. Serum phosphorylated α-synuclein levels in patients with ischemic stroke were significantly lower than those in healthy subjects, and were positively correlated with cognition levels in patients with ischemic stroke. Furthermore, a decrease in serum high-density lipoprotein levels in stroke patients was significantly correlated with a decrease in phosphorylated α-synuclein levels. Although ischemic stroke mice did not show significant cognitive impairment or disrupted lipid metabolism 14 days after injury, some of them exhibited decreased cognitive function and reduced phosphorylated α-synuclein levels. Taken together, our results suggest that serum phosphorylated α-synuclein is a potential biomarker for poststroke cognitive impairment. Related Articles | Metrics

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High-dose dexamethasone regulates microglial polarization via the GR/JAK1/STAT3 signaling pathway after traumatic brain injury Mengshi Yang, Miao Bai, Yuan Zhuang, Shenghua Lu, Qianqian Ge, Hao Li, Yu Deng, Hongbin Wu, Xiaojian Xu, Fei Niu, Xinlong Dong, Bin Zhang, Baiyun Liu 2025, 20 (9):  2611-2623.  doi: 10.4103/NRR.NRR-D-23-01772 Abstract ( 109 )   PDF (7879KB) ( 33 )   Save Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury, the fundamental regulatory and functional mechanisms remain insufficiently understood. As potent anti-inflammatory agents, the use of glucocorticoids in traumatic brain injury is still controversial, and their regulatory effects on microglial polarization are not yet known. In the present study, we sought to determine whether exacerbation of traumatic brain injury caused by high-dose dexamethasone is related to its regulatory effects on microglial polarization and its mechanisms of action. In vitro cultured BV2 cells and primary microglia and a controlled cortical impact mouse model were used to investigate the effects of dexamethasone on microglial polarization. Lipopolysaccharide, dexamethasone, RU486 (a glucocorticoid receptor antagonist), and ruxolitinib (a Janus kinase 1 antagonist) were administered. RNA-sequencing data obtained from a C57BL/6 mouse model of traumatic brain injury were used to identify potential targets of dexamethasone. The Morris water maze, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence and confocal microscopy analysis, and TUNEL, Nissl, and Golgi staining were performed to investigate our hypothesis. High-throughput sequencing results showed that arginase 1, a marker of M2 microglia, was significantly downregulated in the dexamethasone group compared with the traumatic brain injury group at 3 days post–traumatic brain injury. Thus dexamethasone inhibited M1 and M2 microglia, with a more pronounced inhibitory effect on M2 microglia in vitro and in vivo. Glucocorticoid receptor plays an indispensable role in microglial polarization after dexamethasone treatment following traumatic brain injury. Additionally, glucocorticoid receptor activation increased the number of apoptotic cells and neuronal death, and also decreased the density of dendritic spines. A possible downstream receptor signaling mechanism is the GR/JAK1/STAT3 pathway. Overactivation of glucocorticoid receptor by high-dose dexamethasone reduced the expression of M2 microglia, which plays an antiinflammatory role. In contrast, inhibiting the activation of glucocorticoid receptor reduced the number of apoptotic glia and neurons and decreased the loss of dendritic spines after traumatic brain injury. Dexamethasone may exert its neurotoxic effects by inhibiting M2 microglia through the GR/JAK1/STAT3 signaling pathway. Related Articles | Metrics

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Small molecule inhibitor DDQ-treated hippocampal neuronal cells show improved neurite outgrowth and synaptic branching Jangampalli Adi Pradeepkiran, Priyanka Rawat, Arubala P. Reddy, Erika Orlov, P. Hemachandra Reddy 2025, 20 (9):  2624-2632.  doi: 10.4103/NRR.NRR-D-24-00157 Abstract ( 62 )   PDF (2449KB) ( 39 )   Save The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration. Axons and dendrites, sometimes referred to as neurites, are extensions of a neuron’s cellular body that are used to start networks. Here we explored the effects of diethyl (3,4-dihydroxyphenethylamino)(quinolin-4-yl) methylphosphonate (DDQ) on neurite developmental features in HT22 neuronal cells. In this work, we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22 cells expressing mutant Tau (mTau) cDNA. To investigate DDQ characteristics, cell viability, biochemical, molecular, western blotting, and immunocytochemistry were used. Neurite outgrowth is evaluated through the segmentation and measurement of neural processes. These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth. These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22. DDQ-treated mTau-HT22 cells (HT22 cells transfected with cDNA mutant Tau) were seen to display increased levels of synaptophysin, MAP-2, and β-tubulin. Additionally, we confirmed and noted reduced levels of both total and p-Tau, as well as elevated levels of microtubule-associated protein 2, β-tubulin, synaptophysin, vesicular acetylcholine transporter, and the mitochondrial biogenesis protein–peroxisome proliferator-activated receptor-gamma coactivator-1α. In mTau-expressed HT22 neurons, we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth. Our findings conclude that mTau-HT22 (Alzheimer’s disease) cells treated with DDQ have functional neurite developmental characteristics. The key finding is that, in mTau-HT22 cells, DDQ preserves neuronal structure and may even enhance nerve development function with mTau inhibition. Related Articles | Metrics

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Enhanced autophagic clearance of amyloid-β via histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer’s disease in vitro and in vivo Zhimin Long, Chuanhua Ge, Yueyang Zhao, Yuanjie Liu, Qinghua Zeng, Qing Tang, Zhifang Dong, Guiqiong He 2025, 20 (9):  2633-2644.  doi: 10.4103/NRR.NRR-D-23-01633 Abstract ( 115 )   PDF (6798KB) ( 23 )   Save Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-β in neurons, which is a key step in senile plaque formation. Therefore, restoring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer’s disease. Microtubule acetylation/deacetylation plays a central role in lysosomal acidification. Here, we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer’s disease. Furthermore, we found that treatment with valproic acid markedly enhanced autophagy, promoted clearance of amyloid-β aggregates, and ameliorated cognitive deficits in a mouse model of Alzheimer’s disease. Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer’s disease, in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification. Related Articles | Metrics

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Modulation of the Nogo signaling pathway to overcome amyloid-β-mediated neurite inhibition in human pluripotent stem cell–derived neurites Kirsty Goncalves, Stefan Przyborski 2025, 20 (9):  2645-2654.  doi: 10.4103/NRR.NRR-D-23-01628 Abstract ( 57 )   PDF (12196KB) ( 11 )   Save Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer’s disease. The accumulation of amyloid-β peptides, a key hallmark of Alzheimer’s disease, is believed to induce neuritic abnormalities, including reduced growth, extension, and abnormal growth cone morphology, all of which contribute to decreased connectivity. However, the precise cellular and molecular mechanisms governing this response remain unknown. In this study, we used an innovative approach to demonstrate the effect of amyloid-β on neurite dynamics in both two-dimensional and three-dimensional culture systems, in order to provide more physiologically relevant culture geometry. We utilized various methodologies, including the addition of exogenous amyloid-β peptides to the culture medium, growth substrate coating, and the utilization of human-induced pluripotent stem cell technology, to investigate the effect of endogenous amyloid-β secretion on neurite outgrowth, thus paving the way for potential future applications in personalized medicine. Additionally, we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite inhibition. We demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway, achieved through modulation with Y-27632 (a ROCK inhibitor) and Ibuprofen (a Rho A inhibitor), respectively, can restore and even enhance neuronal connectivity in the presence of amyloid-β. In summary, this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition, but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-β peptides, along with potential intervention points to restore neurite growth. Thereby, we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical, predictive outcomes of drugs and their ability to promote neurite outgrowth, both generally and in a patient-specific manner. Related Articles | Metrics

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Reduced mesencephalic astrocyte–derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology Yiyang Qin, Wenzhen Zhu , Tingting Guo, Yiran Zhang, Tingting Xing, Peng Yin, Shihua Li, Xiao-Jiang Li, Su Yang 2025, 20 (9):  2655-2666.  doi: 10.4103/NRR.NRR-D-23-01666 Abstract ( 68 )   PDF (7077KB) ( 12 )   Save Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene, which encodes a ligand-dependent transcription factor. The mutant androgen receptor protein, characterized by polyglutamine expansion, is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients. These aggregates alter protein–protein interactions and compromise transcriptional activity. In this study, we reported that in both cultured N2a cells and mouse brain, mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-derived neurotrophic factor. Overexpression of mesencephalic astrocyte-derived neurotrophic factor ameliorated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation. Conversely, knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation. Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy. Related Articles | Metrics

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Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains Liwen Zhou , Karthik Venkudusamy , Emily A. Hibbard , Yessenia Montoya , Alexa Olivarez , Cathy Z. Yang , Adelaide Leung , Varun Gokhale , Guhan Periyasamy , Zeal Pathak , Dale R. Sengelaub , George D. Bittner 2025, 20 (9):  2667-2681.  doi: 10.4103/NRR.NRR-D-23-01846 Abstract ( 44 )   PDF (3720KB) ( 12 )   Save Successful polyethylene glycol fusion (PEG-fusion) of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to: (1) rapidly restore electrophysiological continuity; (2) prevent distal Wallerian Degeneration and maintain their myelin sheaths; (3) promote primarily motor, voluntary behavioral recoveries as assessed by the Sciatic Functional Index; and, (4) rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex (e.g., toe twitch) or voluntary behaviors. The preceding companion paper describes sensory terminal field reorganization following PEG-fusion repair of sciatic nerve transections or ablations; however, sensory behavioral recovery has not been explicitly explored following PEG-fusion repair. In the current study, we confirmed the success of PEG-fusion surgeries according to criteria (1–3) above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague–Dawley and inbred Lewis rats. Mechanical nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the hindpaws. Dorsal von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve transections. Baseline withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not sex. Withdrawal thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated rats. Following sciatic transection, all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the injury. However, PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative Control rats. Furthermore, PEG-fused rats with significantly improved Sciatic Functional Index scores at or after 4 weeks postoperatively exhibited yet-earlier von Frey filament recovery compared with those without Sciatic Functional Index recovery, suggesting a correlation between successful PEG-fusion and both motor-dominant and sensory-dominant behavioral recoveries. This correlation was independent of the sex or strain of the rat. Furthermore, our data showed that the acceleration of von Frey filament sensory recovery to baseline was solely due to the PEG-fused sciatic nerve and not saphenous nerve collateral outgrowths. No chronic hypersensitivity developed in any rat up to 12 weeks. All these data suggest that PEG-fusion repair of transection peripheral nerve injuries could have important clinical benefits. Related Articles | Metrics

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Protein arginine methyltransferase-6 regulates heterogeneous nuclear ribonucleoprotein-F expression and is a potential target for the treatment of neuropathic pain Xiaoyu Zhang, Yuqi Liu, Fangxia Xu, Chengcheng Zhou, Kaimei Lu, Bin Fang, Lijuan Wang, Lina Huang, Zifeng Xu 2025, 20 (9):  2682-2696.  doi: 10.4103/NRR.NRR-D-23-01539 Abstract ( 95 )   PDF (5105KB) ( 41 )   Save Protein arginine methyltransferase-6 participates in a range of biological functions, particularly RNA processing, transcription, chromatin remodeling, and endosomal trafficking. However, it remains unclear whether protein arginine methyltransferase-6 modifies neuropathic pain and, if so, what the mechanisms of this effect. In this study, protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model, chronic constriction injury model and bone cancer pain model, using immunohistochemistry, western blotting, immunoprecipitation, and label-free proteomic analysis. The results showed that protein arginine methyltransferase-6 mostly co-localized with β-tubulin III in the dorsal root ganglion, and that its expression decreased following spared nerve injury, chronic constriction injury and bone cancer pain. In addition, PRMT6 knockout (Prmt6–/–) mice exhibited pain hypersensitivity. Furthermore, the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression. Moreover, when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury, increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn, and the response to mechanical stimuli was enhanced. Mechanistically, protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F. Additionally, protein arginine methyltransferase-6-mediated modulation of heterogeneous nuclear ribonucleoprotein-F expression required amino acids 319 to 388, but not classical H3R2 methylation. These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target for the treatment of peripheral neuropathic pain. Related Articles | Metrics

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A novel method for clustering cellular data to improve classification Diek W. Wheeler, Giorgio A. Ascoli 2025, 20 (9):  2697-2705.  doi: 10.4103/NRR.NRR-D-24-00532 Abstract ( 54 )   PDF (3294KB) ( 33 )   Save Many fields, such as neuroscience, are experiencing the vast proliferation of cellular data, underscoring the need for organizing and interpreting large datasets. A popular approach partitions data into manageable subsets via hierarchical clustering, but objective methods to determine the appropriate classification granularity are missing. We recently introduced a technique to systematically identify when to stop subdividing clusters based on the fundamental principle that cells must differ more between than within clusters. Here we present the corresponding protocol to classify cellular datasets by combining datadriven unsupervised hierarchical clustering with statistical testing. These general-purpose functions are applicable to any cellular dataset that can be organized as two-dimensional matrices of numerical values, including molecular, physiological, and anatomical datasets. We demonstrate the protocol using cellular data from the Janelia MouseLight project to characterize morphological aspects of neurons. Related Articles | Metrics

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Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor- and Cygb-associated signaling pathways Biao Xiao, Chaoyang Chu, Zhicheng Lin, Tianyuan Fang, Yuyu Zhou, Chuxia Zhang, Jianghui Shan, Shiyu Chen, Liping Li 2025, 20 (9):  2706-2726.  doi: 10.4103/NRR.NRR-D-23-01681 Abstract ( 74 )   PDF (26990KB) ( 11 )   Save A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer’s disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer’s disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2–8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5′-bromo-2′-deoxyuridine–positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5′-bromo-2′-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5′-bromo-2′-deoxyuridine-positive/ glial fibrillary acidic protein–positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis–related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore, serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis, oxidative damage, and cognition. Collectively, these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer’s disease. Related Articles | Metrics

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Recombinant chitinase-3-like protein 1 alleviates learning and memory impairments via M2 microglia polarization in postoperative cognitive dysfunction mice Yujia Liu, Xue Han, Yan Su, Yiming Zhou, Minhui Xu, Jiyan Xu, Zhengliang Ma, Xiaoping Gu, Tianjiao Xia 2025, 20 (9):  2727-2736.  doi: 10.4103/NRR.NRR-D-23-01233 Abstract ( 151 )   PDF (2743KB) ( 57 )   Save Postoperative cognitive dysfunction is a severe complication of the central nervous system that occurs after anesthesia and surgery, and has received attention for its high incidence and effect on the quality of life of patients. To date, there are no viable treatment options for postoperative cognitive dysfunction. The identification of postoperative cognitive dysfunction hub genes could provide new research directions and therapeutic targets for future research. To identify the signaling mechanisms contributing to postoperative cognitive dysfunction, we first conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the Gene Expression Omnibus GSE95426 dataset, which consists of mRNAs and long non-coding RNAs differentially expressed in mouse hippocampus 3 days after tibial fracture. The dataset was enriched in genes associated with the biological process “regulation of immune cells,” of which Chil1 was identified as a hub gene. Therefore, we investigated the contribution of chitinase-3–like protein 1 protein expression changes to postoperative cognitive dysfunction in the mouse model of tibial fracture surgery. Mice were intraperitoneally injected with vehicle or recombinant chitinase-3–like protein 1 24 hours post-surgery, and the injection groups were compared with untreated control mice for learning and memory capacities using the Y-maze and fear conditioning tests. In addition, protein expression levels of proinflammatory factors (interleukin-1β and inducible nitric oxide synthase), M2-type macrophage markers (CD206 and arginase-1), and cognition-related proteins (brain-derived neurotropic factor and phosphorylated NMDA receptor subunit NR2B) were measured in hippocampus by western blotting. Treatment with recombinant chitinase-3–like protein 1 prevented surgery-induced cognitive impairment, downregulated interleukin-1β and nducible nitric oxide synthase expression, and upregulated CD206, arginase-1, pNR2B, and brain-derived neurotropic factor expression compared with vehicle treatment. Intraperitoneal administration of the specific ERK inhibitor PD98059 diminished the effects of recombinant chitinase-3–like protein 1. Collectively, our findings suggest that recombinant chitinase-3-like protein 1 ameliorates surgery-induced cognitive decline by attenuating neuroinflammation via M2 microglial polarization in the hippocampus. Therefore, recombinant chitinase-3–like protein 1 may have therapeutic potential for postoperative cognitive dysfunction. Related Articles | Metrics