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15 November 2023, Volume 18 Issue 11 Previous Issue   

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Differentiation and functional connectivity of fetal tectal transplants Alan R. Harvey 2023, 18 (11):  2325-2331.  doi: 10.4103/1673-5374.371348 Abstract ( 118 )   PDF (6749KB) ( 80 )   Save Data from studies analyzing the differentiation and functional connectivity of embryonic neural tissue grafted into the mammalian nervous system has led to the clinical testing of the fetal graft approach in patients with neurodegenerative disease. While some success has been achieved, ethical concerns have led to a search for alternative therapeutic strategies, mostly exploring the use of neural precursors or neurons derived from pluripotent stem cells to replace damaged host neurons and restore lost circuitries. These more recent studies address questions of graft viability, differentiation, and connectivity similar to those posed by researchers in earlier fetal transplant work, thus reviews of the fetal graft literature may inform and help guide ongoing research in the stem cell/organoid field. This brief review describes some key observations from research into the transplantation of neural tissue into the rat visual system, focusing on grafts of the fetal superior colliculus (tectal grafts) into neonatal or adult hosts. In neonate hosts, grafts quickly develop connections with the underlying host midbrain and attain a morphology typical of mature grafts by about 2 weeks. Grafts consistently contain numerous localized regions which, based on neurofibrillar staining, neuronal morphology (Golgi), neurochemistry, receptor expression, and glial architecture, are homologous to the stratum griseum superficiale of normal superior colliculus. These localized “patches” are also seen after explant culture and when donor tectal tissue is dissociated and reaggregated prior to transplantation. In almost all circumstances, host retinal innervation is restricted to these localized patches, but only those that are located adjacent to the graft surface. Synapses are formed and there is evidence of functional drive. The only exception occurs when Schwann cells are added to dissociated tecta prior to reaggregation. In these co-grafts, the peripheral glia appear to compete with local target factors and host retinal ingrowth is more widespread. Other afferent systems (e.g., host cortex, serotonin) show different patterns of innervation. The host cortical input originates more from extrastriate regions and establishes functional excitatory synapses with grafted neurons. Finally, when grafted into optic tract lesions in adult rat hosts, spontaneously regrowing host retinal axons retain the capacity to selectively innervate the localized patches in embryonic tectal grafts, showing that the specific affinities between adult retinal axons and their targets are not lost during regeneration. While the research described here provides some pertinent information about development and plasticity in visual pathways, a more general aim is to highlight how the review of the extensive fetal graft literature may aid in an appreciation of the positive (and negative) factors that influence survival, differentiation, connectivity and functionality of engineered cells and organoids transplanted into the central nervous system. Related Articles | Metrics

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α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies Alessandra Bigi, Roberta Cascella, Cristina Cecchi 2023, 18 (11):  2332-2342.  doi: 10.4103/1673-5374.371345 Abstract ( 153 )   PDF (2479KB) ( 75 )   Save The misfolding and aggregation of α-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In such conditions, a range of different misfolded aggregates, including oligomers, protofibrils, and fibrils, are present both in neurons and glial cells. Growing experimental evidence supports the proposition that soluble oligomeric assemblies, formed during the early phases of the aggregation process, are the major culprits of neuronal toxicity; at the same time, fibrillar conformers appear to be the most efficient at propagating among interconnected neurons, thus contributing to the spreading of α-synuclein pathology. Moreover, α-synuclein fibrils have been recently reported to release soluble and highly toxic oligomeric species, responsible for an immediate dysfunction in the recipient neurons. In this review, we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused by α-synuclein oligomers and fibrils, both contributing to neurodegeneration in synucleinopathies. Related Articles | Metrics

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Do astrocytes respond to light, sound, or electrical stimulation? Audrey Le Naour, Emilien Beziat, Jaimie Hoh Kam, Pierre Magistretti, Alim-Louis Benabid, John Mitrofanis 2023, 18 (11):  2343-2347.  doi: 10.4103/1673-5374.371343 Abstract ( 131 )   PDF (663KB) ( 70 )   Save Astrocytes are not only the most populous cell type in the human brain, but they also have the most extensive and diverse sets of connections, across synapses, axons, blood vessels, as well as having their own internal network. Unsurprisingly, they are associated with many brain functions; from the synaptic transmission to energy metabolism and fluid homeostasis, and from cerebral blood flow and blood-brain barrier maintenance to neuroprotection, memory, immune defenses and detoxification, sleep, and early development. And yet, notwithstanding these key roles, so many current therapeutic approaches to a range of brain disorders have largely neglected their potential involvement. In this review, we consider the role of astrocytes in three brain therapies; two are emerging treatments (photobiomodulation and ultrasound), while the other is well-established (deep brain stimulation). In essence, we explore the issue of whether external sources, such as light, sound, or electricity, can influence the function of astrocytes, as they do neurons. We find that, when taken all together, each of these external sources can influence many, if not, all of the functions associated with astrocytes. These include influencing neuronal activity, prompting neuroprotection, reducing inflammation (astrogliosis) and potentially increasing cerebral blood flow and stimulating the glymphatic system. We suggest that astrocytes, just like neurons, can respond positively to each of these external applications and that their activation could each impart many beneficial outcomes on brain function; they are likely to be key players underpinning the mechanisms behind many therapeutic strategies.  Related Articles | Metrics

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Structural and functional alterations in the brains of patients with anisometropic and strabismic amblyopia: a systematic review of magnetic resonance imaging studies Yuxia Wang, Ye Wu, Lekai Luo, Fei Li 2023, 18 (11):  2348-2356.  doi: 10.4103/1673-5374.371349 Abstract ( 138 )   PDF (2033KB) ( 95 )   Save Amblyopia is the most common cause of vision loss in children and can persist into adulthood in the absence of effective intervention. Previous clinical and neuroimaging studies have suggested that the neural mechanisms underlying strabismic amblyopia and anisometropic amblyopia may be different. Therefore, we performed a systematic review of magnetic resonance imaging studies investigating brain alterations in patients with these two subtypes of amblyopia; this study is registered with PROSPERO (registration ID: CRD42022349191). We searched three online databases (PubMed, EMBASE, and Web of Science) from inception to April 1, 2022; 39 studies with 633 patients (324 patients with anisometropic amblyopia and 309 patients with strabismic amblyopia) and 580 healthy controls met the inclusion criteria (e.g., case-control designed, peer-reviewed articles) and were included in this review. These studies highlighted that both strabismic amblyopia and anisometropic amblyopia patients showed reduced activation and distorted topological cortical activated maps in the striate and extrastriate cortices during task-based functional magnetic resonance imaging with spatial-frequency stimulus and retinotopic representations, respectively; these may have arisen from abnormal visual experiences. Compensations for amblyopia that are reflected in enhanced spontaneous brain function have been reported in the early visual cortices in the resting state, as well as reduced functional connectivity in the dorsal pathway and structural connections in the ventral pathway in both anisometropic amblyopia and strabismic amblyopia patients. The shared dysfunction of anisometropic amblyopia and strabismic amblyopia patients, relative to controls, is also characterized by reduced spontaneous brain activity in the oculomotor cortex, mainly involving the frontal and parietal eye fields and the cerebellum; this may underlie the neural mechanisms of fixation instability and anomalous saccades in amblyopia. With regards to specific alterations of the two forms of amblyopia, anisometropic amblyopia patients suffer more microstructural impairments in the precortical pathway than strabismic amblyopia patients, as reflected by diffusion tensor imaging, and more significant dysfunction and structural loss in the ventral pathway. Strabismic amblyopia patients experience more attenuation of activation in the extrastriate cortex than in the striate cortex when compared to anisometropic amblyopia patients. Finally, brain structural magnetic resonance imaging alterations tend to be lateralized in the adult anisometropic amblyopia patients, and the patterns of brain alterations are more limited in amblyopic adults than in children. In conclusion, magnetic resonance imaging studies provide important insights into the brain alterations underlying the pathophysiology of amblyopia and demonstrate common and specific alterations in anisometropic amblyopia and strabismic amblyopia patients; these alterations may improve our understanding of the neural mechanisms underlying amblyopia. Related Articles | Metrics

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An overview on CV2/CRMP5 antibody-associated paraneoplastic neurological syndromes Sai Wang, Haiman Hou, Yao Tang, Shuang Zhang, Gege Wang, Ziyan Guo, Lina Zhu, Jun Wu 2023, 18 (11):  2357-2364.  doi: 10.4103/1673-5374.371400 Abstract ( 125 )   PDF (2207KB) ( 66 )   Save Paraneoplastic neurological syndrome refers to certain malignant tumors that have affected the distant nervous system and caused corresponding dysfunction in the absence of tumor metastasis. Patients with this syndrome produce multiple antibodies, each targeting a different antigen and causing different symptoms and signs. The CV2/collapsin response mediator protein 5 (CRMP5) antibody is a major antibody of this type. It damages the nervous system, which often manifests as limbic encephalitis, chorea, ocular manifestation, cerebellar ataxia, myelopathy, and peripheral neuropathy. Detecting CV2/CRMP5 antibody is crucial for the clinical diagnosis of paraneoplastic neurological syndrome, and anti-tumor and immunological therapies can help to alleviate symptoms and improve prognosis. However, because of the low incidence of this disease, few reports and no reviews have been published about it so far. This article intends to review the research on CV2/CRMP5 antibody-associated paraneoplastic neurological syndrome and summarize its clinical features to help clinicians comprehensively understand the disease. Additionally, this review discusses the current challenges that this disease poses, and the application prospects of new detection and diagnostic techniques in the field of paraneoplastic neurological syndrome, including CV2/CRMP5-associated paraneoplastic neurological syndrome, in recent years. Related Articles | Metrics

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Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex Alessandro Bortolami, Federico Sesti 2023, 18 (11):  2365-2369.  doi: 10.4103/1673-5374.371347 Abstract ( 137 )   PDF (822KB) ( 79 )   Save Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide. Epilepsies are triggered by an imbalance between excitatory and inhibitory conductances. However, pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function variants, all able to trigger epilepsy. Furthermore, certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype. This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought. Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox. The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes, including neuronal migration, neurite outgrowth, and synapse formation. Thus, pathogenic channel mutants can not only cause epileptic disorders by altering excitability, but further, by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain. Related Articles | Metrics

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Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases Wenlong Xue, Jie Zhang, Yang Li 2023, 18 (11):  2370-2376.  doi: 10.4103/1673-5374.371346 Abstract ( 129 )   PDF (947KB) ( 53 )   Save Millions of people are suffering from Alzheimer’s disease globally, but there is still no effective treatment for this neurodegenerative disease. Thus, novel therapeutic approaches for Alzheimer’s disease are needed, which requires further evaluation of the regulatory mechanisms of protein aggregate degradation. Lysosomes are crucial degradative organelles that maintain cellular homeostasis. Transcription factor EB-mediated lysosome biogenesis enhances autolysosome-dependent degradation, which subsequently alleviates neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In this review, we start by describing the key features of lysosomes, including their roles in nutrient sensing and degradation, and their functional impairments in different neurodegenerative diseases. We also explain the mechanisms — especially the post-translational modifications — which impact transcription factor EB and regulate lysosome biogenesis. Next, we discuss strategies for promoting the degradation of toxic protein aggregates. We describe Proteolysis-Targeting Chimera and related technologies for the targeted degradation of specific proteins. We also introduce a group of LYsosome-Enhancing Compounds, which promote transcription factor EB-mediated lysosome biogenesis and improve learning, memory, and cognitive function in APP-PSEN1 mice. In summary, this review highlights the key aspects of lysosome biology, the mechanisms of transcription factor EB activation and lysosome biogenesis, and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases. Related Articles | Metrics

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Quite amusing stem cells: Muse cells Molly Monsour, Cesar V. Borlongan 2023, 18 (11):  2377-2378.  doi: 10.4103/1673-5374.371351 Abstract ( 112 )   PDF (431KB) ( 27 )   Save Stem cells may be the future of therapeutics for stroke due to their regenerative and immunomodulatory capabilities. Major barriers faced when employing stem cells, however, include faulty migration, low cell survival, and diminished proliferation. Multilineage-differentiating stress ensuring (Muse) cells, a subset of mesenchymal stem cells, overcome these barriers. Muse cells aid in neuroregeneration, have immense regenerative potential, and are pluripotent, non-tumorigenic, and immunomodulatory. In stroke specifically, these cells may restore an anti-inflammatory environment, regenerate damaged neurons, and integrate into the neuronal architecture. In fact, Muse cells may be aptly designed to ameliorate neurovascular unit damage following stroke and observed in other neuroinflammatory disorders. Related Articles | Metrics

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Neuronal chemokines: new insights into neuronal communication after injury Francina Mesquida-Veny, Arnau Hervera 2023, 18 (11):  2379-2380.  doi: 10.4103/1673-5374.371352 Abstract ( 116 )   PDF (890KB) ( 67 )   Save Classically, chemokines were described as small proteins driving leukocyte migration. Nonetheless, more and more studies are showing the great variety of cell functions and tissues in which they participate, including neural cells.  Related Articles | Metrics

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Gut-brain axis: does intestinal inflammation affect hippocampal neurogenesis and medulloblastoma development?  Arianna Casciati, Mariateresa Mancuso, Roberta Vitali, Simonetta Pazzaglia 2023, 18 (11):  2381-2382.  doi: 10.4103/1673-5374.371353 Abstract ( 155 )   PDF (789KB) ( 64 )   Save Gut-brain axis: does intestinal inflammation affect hippocampal neurogenesis and medulloblastoma development? Inflammatory bowel diseases (IBD) are a group of disorders that cause chronic inflammation in the intestines, associated with altered intestinal permeability, which in turn causes an immune response to enteric antigens in a genetically susceptible host. IBD incidence is high in industrialized countries and continuously rises in emerging economies.  Related Articles | Metrics

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Targeting TRPM2- and TRPM4-extrasynaptic N-methyl-D-aspartate receptor coupling in ischemic stroke Pengyu Zong, Cindy X. Li, Jianlin Feng, Lixia Yue 2023, 18 (11):  2383-2384.  doi: 10.4103/1673-5374.371354 Abstract ( 149 )   PDF (485KB) ( 96 )   Save Ischemic stroke represents a heavy burden on public health. Currently, recanalization is the only effective therapy for ischemic stroke in a small population of eligible patients. However, there is no effective adjunct medication for preventing neuron loss after reperfusion to mitigate long-lasting brain injury. Extrasynaptic N-methyl-D-aspartate receptors (esNMDARs) are the major cause of ischemic neuronal death. However, there is no inhibitor selectively targeting esNMDARs without compromising the function of other “beneficial” synaptic NMDARs, which is due to the limited understanding of the underlying molecular mechanisms. Recently, two members of the transient receptor potential melastatin (TRPM) channel family, TRPM2 and TRPM4, were shown to be critical in amplifying esNMDAR-mediated neurotoxic effects during ischemic stroke without influencing the functions of synaptic NMDAR. Targeting the interaction between TRPM2- and TRPM4-esNMDAR provides a novel strategy in screening effective drugs for ischemic stroke. Related Articles | Metrics

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Mechanosensitive Piezo1 channel regulation of microglial cell function and implications to neurodegenerative diseases and neuroinflammation Mo Zhang, Philippa Malko, Lin-Hua Jiang 2023, 18 (11):  2385-2386.  doi: 10.4103/1673-5374.371355 Abstract ( 152 )   PDF (380KB) ( 89 )   Save Microglial cells are the key immunocompetent cells in the central nervous system (CNS) and play a crucial role in CNS health and disease (Paolicelli et al., 2022). Under the homeostatic conditions, microglial cells assume diverse and dynamic states, depending upon interactions with neighboring cells and structures in local contextual settings, continuously patrol brain parenchyma utilizing their highly mobile fine processes, phagocytize protein aggregates, unwanted synapses and cells to maintain CNS health, and secrete neurotrophic factors to support neuronal function (Colonna and Butovsky, 2017; Paolicelli et al., 2022). In response to damage or infection, microglial cells change to different functional states, in many cases accompanied with distinct morphology characterized by an enlarged cell body with short and thick processes. Mechanistically, such changes in the states of microglial cells, commonly referred to microglial activation, are initiated upon ligation of pattern recognition receptors to damage-associated molecular patterns from host cells, or pathogen-associated molecular patterns from invading pathogens, and enable microglial cells to coordinate an immune response to reinstate CNS homeostasis (Colonna and Butovsky, 2017; Paolicelli et al., 2022). However, incomplete resolution of the immune response leading to chronic inflammation or, more specifically, unwanted production of neurotoxic inflammatory mediators that can damage synapses and neurons and thereby impair CNS function. Such microglial cell-mediated action is an important factor driving the progression of age-related neurodegenerative diseases, including Alzheimer’s disease (AD) (Takata et al., 2021).  Related Articles | Metrics

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CD137L, a driver of harmful inflammation in the nervous system Hiu Yi Wong, Amanda C.Y. Chan, Anselm Mak, Herbert Schwarz 2023, 18 (11):  2387-2388.  doi: 10.4103/1673-5374.371357 Abstract ( 92 )   PDF (1364KB) ( 105 )   Save CD137 (TNFRSF9, 4-1BB) is a member of the tumor necrosis factor (TNF) receptor family and a potent costimulatory molecule. High levels of CD137 are expressed on T cells upon activation. CD137 signaling in T cells, either by cognate interaction with antigen-presenting cells (APC) or by agonistic anti-CD137 antibodies, strongly enhances proliferation, interferon-γ secretion, and cytolytic activity of T cells. Thus, CD137 signaling is a main driver of cellular, type 1 helper T cells (Th1) and type 1 cytolytic T cells (Tc1) polarised immune responses. CD137 costimulation enables the immune system to eliminate tumors as shown in a wide plethora of murine tumor models. Agonistic antibodies against human CD137 currently prove to be effective in clinical cancer therapy trials (Dharmadhikari et al., 2016).   Related Articles | Metrics

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Utility of droplet digital polymerase chain reaction for studying somatic mosaicism: brain malformations and beyond Wei Shern Lee, Paul J. Lockhart 2023, 18 (11):  2389-2390.  doi: 10.4103/1673-5374.371356 Abstract ( 96 )   PDF (11120KB) ( 18 )   Save Somatic variants and how to find them: One major challenge in studying somatic mosaicism is the low abundance of potentially pathogenic somatic variant(s). Unlike inherited germline variants, which are essentially present in all cells, pathogenic somatic variants only exist in a subset of cells and may be present at very low (< 1%) variant allele frequency (VAF). Despite the low VAF, these somatic variants are disease-relevant and considered pathogenic. In the context of focal brain malformations, which constitute a frequent cause of drug-resistant focal epilepsy, a pathogenic somatic mammalian target of rapamycin (MTOR) variant with a VAF of 0.3% has been described (Baldassari et al., 2019). The identification of pathogenic somatic variants has important implications both clinically and biologically. Clinically, a positive genetic diagnosis can provide diagnostic certainty and inform genetic counseling. A diagnosis can also improve patient care by informing treatment strategies, for example, justifying the use of an mTOR inhibitor such as sirolimus or everolimus. Biologically, identifying pathogenic somatic variants can provide insights into the origin of somatic mosaicism and the biological pathways that are involved in the condition of interest. As a result, somatic variants and the techniques to identify them are an area of interest to clinicians and the scientific community more broadly.  Related Articles | Metrics

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Plasma amyloid-beta oligomer and phosphorylated tau: diagnostic tools for progressive Alzheimer’s disease Seong Soo A. An, John P. Hulme 2023, 18 (11):  2391-2392.  doi: 10.4103/1673-5374.371361 Abstract ( 143 )   PDF (1984KB) ( 108 )   Save Introduction: Spanning the three stages of the Alzheimer’s disease (AD) continuum, amyloid-beta (Aβ40 and Aβ42) oligomers (AβO’s) and tau protein constitute a set of biomarkers ideally suited for the non-invasive monitoring of AD (Wolgin et al., 2022). AD progression is correlated with the presence of low molecular weight oligomers and not amyloid plaques. Moreover, low molecular weight AβO is present in the beginning and later stages of disease even when the plaque burden becomes prevalent. Furthermore, changes in AβO levels occur prior to the initial stages of the disease, suggesting they may be used to evaluate the risk of disease onset. Currently, the monoclonal antibody Crenezumab™ is considered the primary treatment for reducing low molecular weight oligomers in various animal models and humans. AβO’s can be sourced from blood, plasma, and cerebral spinal fluid (CSF) and acquired quickly, permitting long-term storage and retrospective analysis. However, samples usually contain single molecular oligomer concentrations often requiring amplification (spiking/seeding or ultrasonic) or enrichment prior to measurement with conventional instrumentation and antibody-based platforms such as SiMOA or Sigma Millipore (An et al., 2017; Dominguez et al., 2022). In addition to AβO, other protein biomarkers that span all three stages of AD include total tau (t-tau) and CSF phosphorylated tau (p-tau). Tau is a microtubule-binding protein subject to phosphorylation, and its aggregation is a major hallmark of AD pathology. t-tau and some p-tau isoforms, such as p-tau threonine 181 and p-tau threonine 217, are elevated in AD CSF. However, t-tau CSF levels poorly correlate with plasma levels due to peripheral interference restricting its usage as a biomarker (Janelidze et al., 2020). Related Articles | Metrics

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Targeting glial metabolism in neurodegenerative diseases: detail matters Ruqayya Afridi, Kyoungho Suk 2023, 18 (11):  2393-2394.  doi: 10.4103/1673-5374.371358 Abstract ( 109 )   PDF (1667KB) ( 51 )   Save Neurodegenerative diseases, a group of disorders associated with advanced age, are typified by the disease-specific accumulation of mutant proteins and neuroinflammation. For decades, treatment modalities for these disorders have focused on addressing neuronal malfunction, which has resulted in the failure of therapies. Recent studies have identified the crucial role of glial cells in exacerbating neurodegenerative processes via the release of neuroinflammatory mediators. Glia, the major immune component of the central nervous system (CNS), undergo numerous phenotypic transitions and regulate the outcomes of various pathologies (Afridi et al., 2022). Related Articles | Metrics

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Wrapping up the role of pericytes in Parkinson’s disease Taylor John Stevenson, Birger Victor Dieriks 2023, 18 (11):  2395-2396.  doi: 10.4103/1673-5374.371362 Abstract ( 117 )   PDF (1891KB) ( 66 )   Save Pericytes are classically defined as contractile cells within the central nervous system that regulate blood flow and permeability of the blood-brain barrier (BBB). This one-sided view is gradually changing, and pericytes are now considered versatile cells that can switch their function in response to different stimuli (Uemura et al., 2020). In addition to their role as gatekeepers of the BBB and maintaining homeostasis of the brain’s microenvironment through adjusting the vascular intraluminal diameter, pericytes are both sensors and initiators of inflammation, allowing communication between the cerebral parenchyma and the peripheral system (Dieriks et al., 2022). Pericytes can react quickly by releasing neurotrophins to promote neuroprotection or by secreting pro-inflammatory cytokines, which can exacerbate brain and BBB damage (Dieriks et al., 2022). BBB disruption, blood vessel alterations, and cerebral blood flow abnormalities are commonly seen in neurodegenerative disorders with loss of pericyte coverage present in Parkinson’s disease (PD) and Alzheimer’s disease (Uemura et al., 2020, Elabi et al., 2021).  Related Articles | Metrics

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Enrichment of novel Tau isoform with altered biochemical properties in Alzheimer’s disease Chin-Tong Ong 2023, 18 (11):  2397-2398.  doi: 10.4103/1673-5374.371359 Abstract ( 114 )   PDF (334KB) ( 95 )   Save Aberrant splicing in sporadic Alzheimer’s disease: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid-β plaques and Tau-containing intracellular neurofibrillary tangles (Knopman et al., 2021). Cognitive decline in AD due to neuronal and synaptic loss is caused by the complex interplay between pathological amyloid-β and Tau species with the impaired innate clearance pathways. There are two types of AD based on disease aetiology (Knopman et al., 2021). In early-onset familial AD, patients are inherited with autosomal dominant mutations in either amyloid precursor protein (APP) or presenilin-1/2 (PSEN1/2) genes which lead to elevated production of amyloid-β (Lanoiselee et al., 2017). On the other hand, late-onset sporadic AD is characterized by high pathological heterogeneity with aging and genetic variations as the major disease risk factors (Knopman et al., 2021). Recent high-throughput results from longitudinal, epidemiologic studies such as the Religious Orders Study and the Memory and Aging Project showed that aberrant mRNA splicing may participate in the progression of sporadic AD (Raj et al., 2018). Increased intron retention, an alternative splicing event where introns are not removed from mature mRNA transcripts, has also been linked to aging brains and AD pathogenesis (Adusumalli et al., 2019; Garcia-Escudero et al., 2021; Ngian et al., 2022). Related Articles | Metrics

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Role of the adipocyte immune brain axis in Parkinson’s disease: friend or foe? Martin Regensburger, Thomas M. Kinfe 2023, 18 (11):  2399-2400.  doi: 10.4103/1673-5374.369112 Abstract ( 96 )   PDF (1516KB) ( 75 )   Save The classical role of adipocytokines is a negative feedback mechanism, providing information about bodily energy reserves to the brain, and thus controlling satiety and food intake (Campfield et al., 1995). Adipose tissue forms the largest endocrine organ of the body. After the initial description of leptin and its receptor, LEPR/OBR, with its main active isoform OBRb, there was an initial hope for a drugable pathway to counteract the increasing burden of overweight/adiposity, metabolic syndrome, and related disorders (Figure 1). Compensatory pathways and tolerance effects, however, preclude a metabolic intervention using recombinant adipocytokines in metabolic syndrome. Leptin, for example, is increased in adiposity and metabolic syndrome. Nevertheless, recombinant leptin has been approved for leptin deficiency-associated lipodystrophy in the US.  Related Articles | Metrics

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Regulation of one-carbon metabolism may open new avenues to slow down the initiation and progression of Huntington’s disease Jiahua Xie, Farooqahmed S. Kittur, Chiu-Yueh Hung, Tomas T. Ding 2023, 18 (11):  2401-2402.  doi: 10.4103/1673-5374.371363 Abstract ( 103 )   PDF (411KB) ( 63 )   Save Huntington’s disease (HD) (OMIM 143100) is an autosomal dominant neurodegenerative disorder caused by a monogenic mutation in the huntingtin gene (HTT), which induces typical midlife onset and age-dependent progression with major symptoms including choreic movements, psychiatric disorders, and cognitive impairment (Gusella et al., 2021). After the 1993 discovery of a pathogenic expansion of the CAG trinucleotide repeat beyond 35 in HTT exon 1 as a causative factor for HD, many animal, mammalian cell and yeast models expressing mutant HTT (mHtt) with abnormal CAG repeats have been created to study CAG repeat-induced toxicity (Naphade et al., 2019; Gusella et al., 2021). With these models and studies on human subjects, some important insights into disease initiation and progression mechanisms have been elucidated, but the underlying mHtt-induced toxicity mechanisms are still not yet fully understood with no disease-modifying treatment in sight (Caron et al., 2018; Veldman and Yang, 2018; Gusella et al., 2021).  Related Articles | Metrics

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Combination of novel RNA sequencing and sophisticated network modeling to reveal a common denominator in amyotrophic lateral sclerosis? Banaja P. Dash, Andreas Hermann 2023, 18 (11):  2403-2405.  doi: 10.4103/1673-5374.371364 Abstract ( 115 )   PDF (800KB) ( 33 )   Save Amyotrophic lateral sclerosis (ALS) is one of the most dreadful neurodegenerative diseases leading to death within 1–5 years after symptom onset. The majority of ALS cases are sporadic (sALS), while the remaining 5–10% are familial (fALS). Genetic discoveries have identified ALS-causative mutations in more than 30 genes so far (Chia et al., 2018). Indeed, the four most common mutations observed in ALS genes in Europe are the hexanucleotide expansion repeat in Chromosome 9 Open Reading Frame 72 (C9ORF72), Cu-Zn superoxide dismutase 1 (SOD1)), transactive response DNA Binding protein 43kDa (TARDBP) and fused in sarcoma (FUS). These causative genes encode proteins with divergent sub-cellular functions, many of which are associated with defective DNA repair, altered axonal transport, abnormal protein aggregation including impairment of proteostasis and autophagy, mitochondrial dysfunction, and aberrant RNA metabolism (Chia et al., 2018). Related Articles | Metrics

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Mesenchymal stem cell-derived extracellular vesicles therapy in traumatic central nervous system diseases: a systematic review and meta-analysis#br# Zhelun Yang, Zeyan Liang, Jian Rao, Fabin Lin, Yike Lin, Xiongjie Xu, Chunhua Wang, Chunmei Chen 2023, 18 (11):  2406-2412.  doi: 10.4103/1673-5374.371376 Abstract ( 148 )   PDF (6215KB) ( 74 )   Save Although there are challenges in treating traumatic central nervous system diseases, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have recently proven to be a promising non-cellular therapy. We comprehensively evaluated the efficacy of mesenchymal stem cell-derived extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical studies. Our meta-analysis was registered at PROSPERO (CRD42022327904, May 24, 2022). To fully retrieve the most relevant articles, the following databases were thoroughly searched: PubMed, Web of Science, The Cochrane Library, and Ovid-Embase (up to April 1, 2022). The included studies were preclinical studies of mesenchymal stem cell-derived extracellular vesicles for traumatic central nervous system diseases. The Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)’s risk of bias tool was used to examine the risk of publication bias in animal studies. After screening 2347 studies, 60 studies were included in this study. A meta‐analysis was conducted for spinal cord injury (n = 52) and traumatic brain injury (n = 8). The results indicated that mesenchymal stem cell-derived extracellular vesicles treatment prominently promoted motor function recovery in spinal cord injury animals, including rat Basso, Beattie and Bresnahan locomotor rating scale scores (standardized mean difference [SMD]: 2.36, 95% confidence interval [CI]: 1.96–2.76, P < 0.01, I2 = 71%) and mouse Basso Mouse Scale scores (SMD = 2.31, 95% CI: 1.57–3.04, P = 0.01, I2 = 60%) compared with controls. Further, mesenchymal stem cell-derived extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals, including the modified Neurological Severity Score (SMD = –4.48, 95% CI: –6.12 to –2.84, P < 0.01, I2 = 79%) and Foot Fault Test (SMD = –3.26, 95% CI: –4.09 to –2.42, P = 0.28, I2 = 21%) compared with controls. Subgroup analyses showed that characteristics may be related to the therapeutic effect of mesenchymal stem cell-derived extracellular vesicles. For Basso, Beattie and Bresnahan locomotor rating scale scores, the efficacy of allogeneic mesenchymal stem cell-derived extracellular vesicles was higher than that of xenogeneic mesenchymal stem cell-derived extracellular vesicles (allogeneic: SMD = 2.54, 95% CI: 2.05–3.02, P = 0.0116, I2 = 65.5%; xenogeneic: SMD: 1.78, 95%CI: 1.1–2.45, P = 0.0116, I2 = 74.6%). Mesenchymal stem cell-derived extracellular vesicles separated by ultrafiltration centrifugation combined with density gradient ultracentrifugation (SMD = 3.58, 95% CI: 2.62–4.53, P < 0.0001, I2 = 31%) may be more effective than other EV isolation methods. For mouse Basso Mouse Scale scores, placenta-derived mesenchymal stem cell-derived extracellular vesicles worked better than bone mesenchymal stem cell-derived extracellular vesicles (placenta: SMD = 5.25, 95% CI: 2.45–8.06, P = 0.0421, I2 = 0%; bone marrow: SMD = 1.82, 95% CI: 1.23–2.41, P = 0.0421, I2 = 0%). For modified Neurological Severity Score, bone marrow-derived MSC-EVs worked better than adipose-derived MSC-EVs (bone marrow: SMD = –4.86, 95% CI: –6.66 to –3.06, P = 0.0306, I2 = 81%; adipose: SMD = –2.37, 95% CI: –3.73 to –1.01, P = 0.0306, I2 = 0%). Intravenous administration (SMD = –5.47, 95% CI: –6.98 to –3.97, P = 0.0002, I2 = 53.3%) and dose of administration equal to 100 μg (SMD = –5.47, 95% CI: –6.98 to –3.97, P < 0.0001, I2 = 53.3%) showed better results than other administration routes and doses. The heterogeneity of studies was small, and sensitivity analysis also indicated stable results. Last, the methodological quality of all trials was mostly satisfactory. In conclusion, in the treatment of traumatic central nervous system diseases, mesenchymal stem cell-derived extracellular vesicles may play a crucial role in promoting motor function recovery. Related Articles | Metrics

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A novel phenotype of B cells associated with enhanced phagocytic capability and chemotactic function after ischemic stroke Rui Wang, Huaming Li, Chenhan Ling, Xiaotao Zhang, Jianan Lu, Weimin Luan, Jianmin Zhang, Ligen Shi 2023, 18 (11):  2413-2423.  doi: 10.4103/1673-5374.371365 Abstract ( 191 )   PDF (3538KB) ( 96 )   Save Accumulating evidence has demonstrated the involvement of B cells in neuroinflammation and neuroregeneration. However, the role of B cells in ischemic stroke remains unclear. In this study, we identified a novel phenotype of macrophage-like B cells in brain-infiltrating immune cells expressing a high level of CD45. Macrophage-like B cells characterized by co-expression of B-cell and macrophage markers, showed stronger phagocytic and chemotactic functions compared with other B cells and showed upregulated expression of phagocytosis‐related genes. Gene Ontology analysis found that the expression of genes associated with phagocytosis, including phagosome- and lysosome-related genes, was upregulated in macrophage-like B cells. The phagocytic activity of macrophage-like B cells was verified by immunostaining and three-dimensional reconstruction, in which TREM2-labeled macrophage-like B cells enwrapped and internalized myelin debris after cerebral ischemia. Cell-cell interaction analysis revealed that macrophage-like B cells released multiple chemokines to recruit peripheral immune cells mainly via CCL pathways. Single-cell RNA sequencing showed that the transdifferentiation to macrophage-like B cells may be induced by specific upregulation of the transcription factor CEBP family to the myeloid lineage and/or by downregulation of the transcription factor Pax5 to the lymphoid lineage. Furthermore, this distinct B cell phenotype was detected in brain tissues from mice or patients with traumatic brain injury, Alzheimer’s disease, and glioblastoma. Overall, these results provide a new perspective on the phagocytic capability and chemotactic function of B cells in the ischemic brain. These cells may serve as an immunotherapeutic target for regulating the immune response of ischemic stroke. Related Articles | Metrics

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Dl-3-n-butylphthalide exerts neuroprotective effects by modulating hypoxia-inducible factor 1-alpha ubiquitination to attenuate oxidative stress-induced apoptosis Shuai Li, Jingyuan Zhao, Yan Xi, Jiaqi Ren, Yanna Zhu, Yan Lu, Deshi Dong 2023, 18 (11):  2424-2428.  doi: 10.4103/1673-5374.371366 Abstract ( 160 )   PDF (4022KB) ( 91 )   Save Dl-3-n-butylphthalide is used to treat mild and moderate acute ischemic stroke. However, the precise underlying mechanism requires further investigation. In this study, we investigated the molecular mechanism of Dl-3-n-butylphthalide action by various means. We used hydrogen peroxide to induce injury to PC12 cells and RAW264.7 cells to mimic neuronal oxidative stress injury in stroke in vitro and examined the effects of Dl-3-n-butylphthalide. We found that Dl-3-n-butylphthalide pretreatment markedly inhibited the reduction in viability and reactive oxygen species production in PC12 cells caused by hydrogen peroxide and inhibited cell apoptosis. Furthermore, Dl-3-n-butylphthalide pretreatment inhibited the expression of the pro-apoptotic genes Bax and Bnip3. Dl-3-n-butylphthalide also promoted ubiquitination and degradation of hypoxia inducible factor 1α, the key transcription factor that regulates Bax and Bnip3 genes. These findings suggest that Dl-3-n-butylphthalide exhibits a neuroprotective effect on stroke by promoting hypoxia inducible factor-1α ubiquitination and degradation and inhibiting cell apoptosis.  Related Articles | Metrics

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Cyclo (MQCNS) has the potential to treat ischemic stroke Zhibing Song, Xinyu Li, Mengting Lv, Yuchen Guo, Shanshan Deng, Yuefan Zhang, Tiejun Li 2023, 18 (11):  2429-2435.  doi: 10.4103/1673-5374.371367 Abstract ( 124 )   PDF (33729KB) ( 54 )   Save We previously found that monocyte locomotion inhibitory factor has a neuroprotective effect on ischemic brain injury during the acute phase of stroke. Therefore, we modified the structure of an anti-inflammatory monocyte locomotion inhibitory factor peptide to construct an active cyclic peptide—Cyclo (MQCNS) (LZ-3)—and investigated its effects on ischemic stroke. In this study, we established a rat model of ischemic stroke by occluding the middle cerebral artery and then administered LZ-3 (2 or 4 mg/kg) via the tail vein for 7 consecutive days. Our results showed that LZ-3 (2 or 4 mg/kg) substantially decreased infarct volume, reduced cortical nerve cell death, improved neurological function, reduced cortical and hippocampal injury, and decreased the levels of inflammatory factors in the blood and brain tissues. In a well-differentiated, oxygen-glucose deprivation/reoxygenation-induced BV2 cell model of post-stroke, LZ-3 (100 μM) inhibited the JAK1-STAT6 signaling pathway. LZ-3 regulated microglia/macrophage polarization from the M1 to the M2 type and inhibited microglia/macrophage phagocytosis and migration via the JAK1/STAT6 signaling pathway. To conclude, LZ-3 regulates microglial activation by inhibiting the JAK1/STAT6 signaling pathway and improves functional recovery post-stroke. Related Articles | Metrics

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Vav1 promotes inflammation and neuronal apoptosis in cerebral ischemia/reperfusion injury by upregulating microglial and NLRP3 inflammasome activation Jing Qiu, Jun Guo, Liang Liu, Xin Liu, Xianhui Sun, Huisheng Chen 2023, 18 (11):  2436-2442.  doi: 10.4103/1673-5374.371368 Abstract ( 194 )   PDF (6647KB) ( 161 )   Save Microglia, which are the resident macrophages of the central nervous system, are an important part of the inflammatory response that occurs after cerebral ischemia. Vav guanine nucleotide exchange factor 1 (Vav1) is a guanine nucleotide exchange factor that is related to microglial activation. However, how Vav1 participates in the inflammatory response after cerebral ischemia/reperfusion injury remains unclear. In this study, we subjected rats to occlusion and reperfusion of the middle cerebral artery and subjected the BV-2 microglia cell line to oxygen-glucose deprivation/reoxygenation to mimic cerebral ischemia/reperfusion in vivo and in vitro, respectively. We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral artery and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation. Silencing Vav1 reduced the cerebral infarct volume and brain water content, inhibited neuronal loss and apoptosis in the ischemic penumbra, and improved neurological function in rats subjected to occlusion and reperfusion of the middle cerebral artery. Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3 (NLRP3) inflammasome in the ischemic penumbra, as well as the expression of inflammatory factors. In addition, Vav1 knockdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxygenation. Taken together, these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/reperfusion through inhibiting the activation of microglia and NLRP3 inflammasome. Related Articles | Metrics

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Maternal dietary deficiencies in folic acid or choline worsen stroke outcomes in adult male and female mouse offspring McCoy Clementson, Lauren Hurley, Sarah Coonrod, Calli Bennett, Purvaja Marella, Agnes S. Pascual, Kasey Pull, Brandi Wasek, Teodoro Bottiglieri, Olga Malysheva, Marie A. Caudill, Nafisa M. Jadavji 2023, 18 (11):  2443-2448.  doi: 10.4103/1673-5374.371375 Abstract ( 113 )   PDF (1760KB) ( 81 )   Save Maternal one-carbon metabolism plays an important role in early life programming. There is a well-established connection between the fetal environment and the health status of the offspring. However, there is a knowledge gap on how maternal nutrition impacts stroke outcomes in offspring. The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcomes in 3-month-old offspring. Adult female mice were fed a folic acid-deficient diet, choline-deficient diet, or control diet 4 weeks before pregnancy. They were continued on diets during pregnancy and lactation. Male and female offspring were weaned onto a control diet and at 2 months of age were subjected to ischemic stroke within the sensorimotor cortex via photothrombotic damage. Mothers maintained on either a folic acid-deficient diet or choline-deficient diet had reduced levels of S-adenosylmethionine in the liver and S-adenosylhomocysteine in the plasma. After ischemic stroke, motor function was impaired in 3-month-old offspring from mothers receiving either a folic acid-deficient diet or choline-deficient diet compared to the animals receiving a control diet. In brain tissue, there was no difference in ischemic damage volume. When protein levels were assessed in ischemic brain tissue, there were lower levels of active caspase-3 and hypoxia-inducible factor 1α in males compared to females and betaine levels were reduced in offspring from the mothers receiving a choline-deficient diet. Our results demonstrate that a deficient maternal diet at critical time points in neurodevelopment results in worse stroke outcomes. This study emphasizes the importance of maternal diet and the impact it can have on offspring health.  Related Articles | Metrics

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Overexpression of Sirt6 ameliorates sleep deprivation induced-cognitive impairment by modulating glutamatergic neuron function Jinpiao Zhu, Chang Chen, Zhen Li, Xiaodong Liu, Jingang He, Ziyue Zhao, Mengying He, Binbin Nie, Zili Liu, Yingying Chen, Kuanpin Su, Xiang Li, Juxiang Chen, Hongbing Xiang, Fuqiang Xu, Kangguang Lin, Zongze Zhang, Jie Wang 2023, 18 (11):  2449-2458.  doi: 10.4103/1673-5374.371370 Abstract ( 270 )   PDF (10984KB) ( 68 )   Save Sleep benefits the restoration of energy metabolism and thereby supports neuronal plasticity and cognitive behaviors. Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes. The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation (CSD). We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex (PrL). We then assessed cerebral functional connectivity (FC) using resting-state functional MRI, neuron/astrocyte metabolism using a metabolic kinetics analysis; dendritic spine densities using sparse-labeling; and miniature excitatory postsynaptic currents (mEPSCs) and action potential (AP) firing rates using whole-cell patch-clamp recordings. In addition, we evaluated cognition via a comprehensive set of behavioral tests. Compared with controls, Sirt6 was significantly decreased (P < 0.05) in the PrL after CSD, accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus, piriform cortex, motor cortex, somatosensory cortex, olfactory tubercle, insular cortex, and cerebellum. Sirt6 overexpression reversed CSD-induced cognitive impairment and reduced FC. Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4 and GABA2 synthesis, which could be fully restored via forced Sirt6 expression. Furthermore, Sirt6 overexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons. These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network, neuronal glucose metabolism, and glutamatergic neurotransmission. Thus, Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases. Related Articles | Metrics

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Activation of medial septum cholinergic neurons restores cognitive function in temporal lobe epilepsy Junzi Chen, Yu Wang, Cong Chen, Qingyang Zhang, Shuang Wang, Yi Wang, Jiajia Fang, Ying Wang 2023, 18 (11):  2459-2465.  doi: 10.4103/1673-5374.371369 Abstract ( 232 )   PDF (4413KB) ( 135 )   Save Cognitive impairment is the most common complication in patients with temporal lobe epilepsy with hippocampal sclerosis. There is no effective treatment for cognitive impairment. Medial septum cholinergic neurons have been reported to be a potential target for controlling epileptic seizures in temporal lobe epilepsy. However, their role in the cognitive impairment of temporal lobe epilepsy remains unclear. In this study, we found that patients with temporal lobe epilepsy with hippocampal sclerosis had a low memory quotient and severe impairment in verbal memory, but had no impairment in nonverbal memory. The cognitive impairment was slightly correlated with reduced medial septum volume and medial septum-hippocampus tracts measured by diffusion tensor imaging. In a mouse model of chronic temporal lobe epilepsy induced by kainic acid, the number of medial septum cholinergic neurons was reduced and acetylcholine release was reduced in the hippocampus. Furthermore, selective apoptosis of medial septum cholinergic neurons mimicked the cognitive deficits in epileptic mice, and activation of medial septum cholinergic neurons enhanced hippocampal acetylcholine release and restored cognitive function in both kainic acid- and kindling-induced epilepsy models. These results suggest that activation of medial septum cholinergic neurons reduces cognitive deficits in temporal lobe epilepsy by increasing acetylcholine release via projections to the hippocampus. Related Articles | Metrics

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Potential sex differences in activation of pain-related brain regions in nonhuman primates with a unilateral spinal nerve ligation Kanae Murata, Kenya Nozawa, Mayumi Matsushita, Aozora Yamashita, Rintaro Fujii, Yuji Awaga, Aldric Hama, Takahiro Natsume, Go Yoshida, Yukihiro Matsuyama, Hiroyuki Takamatsu 2023, 18 (11):  2466-2473.  doi: 10.4103/1673-5374.371382 Abstract ( 132 )   PDF (7746KB) ( 24 )   Save The lack of truly robust analgesics for chronic pain is owed, in part, to the lack of an animal model that reflects the clinical pain state and of a mechanism-based, objective neurological indicator of pain. The present study examined stimulus-evoked brain activation with functional magnetic resonance imaging in male and female cynomolgus macaques following unilateral L7 spinal nerve ligation and the effects of clinical analgesics pregabalin, duloxetine, and morphine on brain activation in these macaques. A modified straight leg raise test was used to assess pain severity in awake animals and to evoke regional brain activation in anesthetized animals. The potential effects of clinical analgesics on both awake pain behavior and regional brain activation were examined. Following spinal nerve ligation, both male and female macaques showed significantly decreased ipsilateral straight leg raise thresholds, suggesting the presence of radicular-like pain. Morphine treatment increased straight leg raise thresholds in both males and females whereas duloxetine and pregabalin did not. In male macaques, the ipsilateral straight leg raise activated contralateral insular and somatosensory cortex (Ins/SII), and thalamus. In female macaques, the ipsilateral leg raise activated cingulate cortex and contralateral insular and somatosensory cortex. Straight leg raises of the contralateral, unligated leg did not evoke brain activation. Morphine reduced activation in all brain regions in both male and female macaques. In males, neither pregabalin nor duloxetine decreased brain activation compared with vehicle treatment. In females, however, pregabalin and duloxetine decreased the activation of cingulate cortex compared with vehicle treatment. The current findings suggest a differential activation of brain areas depending on sex following a peripheral nerve injury. Differential brain activation observed in this study could underlie qualitative sexual dimorphism in clinical chronic pain perception and responses to analgesics. Future pain management approaches for neuropathic pain will need to consider potential sex differences in pain mechanism and treatment efficacy. Related Articles | Metrics

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Ferroptosis inhibition protects vascular endothelial cells and maintains integrity of the blood-spinal cord barrier after spinal cord injury Wenxiang Li, Xiaoqing Zhao, Rong Zhang, Xinjie Liu, Zhangyang Qi, Yang Zhang, Weiqi Yang, Yilin Pang, Chenxi Zhao, Baoyou Fan, Ning Ran, Jiawei Zhang, Xiaohong Kong, Shiqing Feng, Xue Yao 2023, 18 (11):  2474-2481.  doi: 10.4103/1673-5374.371377 Abstract ( 180 )   PDF (10464KB) ( 51 )   Save Maintaining the integrity of the blood-spinal cord barrier is critical for the recovery of spinal cord injury. Ferroptosis contributes to the pathogenesis of spinal cord injury. We hypothesized that ferroptosis is involved in disruption of the blood-spinal cord barrier. In this study, we administered the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal cord injury in rats. Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord injury. Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein. Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury, as shown by the immunofluorescence of an endothelial cell marker (rat endothelium cell antigen-1, RECA-1) and ferroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Liproxstatin-1 reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Furthermore, inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment. In summary, liproxstatin-1 improved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-spinal cord barrier integrity. Related Articles | Metrics

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The ferroptosis activity is associated with neurological recovery following chronic compressive spinal cord injury Zhengran Yu, Xing Cheng, Wenxu Pan, Cheng Yu, Yang Duan 2023, 18 (11):  2482-2488.  doi: 10.4103/1673-5374.371378 Abstract ( 147 )   PDF (6751KB) ( 115 )   Save Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase, followed by partial self-recovery, and ultimately an equilibrium state of neurological dysfunction. Ferroptosis is a crucial pathological process in many neurodegenerative diseases; however, its role in chronic compressive spinal cord injury remains unclear. In this study, we established a chronic compressive spinal cord injury rat model, which displayed its most severe behavioral and electrophysiological dysfunction at 4 weeks and partial recovery at 8 weeks after compression. Bulk RNA sequencing data identified enriched functional pathways, including ferroptosis, presynapse, and postsynaptic membrane activity at both 4 and 8 weeks following chronic compressive spinal cord injury. Transmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression. Ferroptosis activity was negatively correlated with behavioral score. Immunofluorescence, quantitative polymerase chain reaction, and western blotting showed that expression of the anti-ferroptosis molecules, glutathione peroxidase 4 (GPX4) and MAF BZIP transcription factor G (MafG), in neurons was suppressed at 4 weeks and upregulated at 8 weeks following spinal cord compression. There was a positive correlation between the expression of these two molecules, suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury. In conclusion, our study determined the genome-wide expression profile and ferroptosis activity of a consistently compressed spinal cord at different time points. The results showed that anti-ferroptosis genes, specifically GPX4 and MafG, may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury. These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy. Related Articles | Metrics

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Reduced non-CpG methylation is a potential epigenetic target after spinal cord injury Zhourui Wu, Chen Li, Ran Zhu, Yiqiu Cao, Thomas C. Chen, Liming Cheng 2023, 18 (11):  2489-2496.  doi: 10.4103/1673-5374.371399 Abstract ( 147 )   PDF (6325KB) ( 84 )   Save DNA methylation is a critical epigenetic regulator in the occurrence and development of diseases and is closely related to various functional responses in relation to spinal cord injury. To investigate the role of DNA methylation in spinal cord injury, we constructed a library with reduced-representation bisulfite sequencing data obtained at various time points (day 0–42) after spinal cord injury in mice. Global DNA methylation levels, specifically non-CpG (CHG and CHH) methylation levels, decreased modestly following spinal cord injury. Stages post-spinal cord injury were classified as early (day 0–3), intermediate (day 7–14), and late (day 28–42) based on similarity and hierarchical clustering of global DNA methylation patterns. The non-CpG methylation level, which included CHG and CHH methylation levels, was markedly reduced despite accounting for a minor proportion of total methylation abundance. At multiple genomic sites, including the 5′ untranslated regions, promoter, exon, intron, and 3′ untranslated regions, the non-CpG methylation level was markedly decreased following spinal cord injury, whereas the CpG methylation level remained unchanged at these locations. Approximately one-half of the differentially methylated regions were located in intergenic areas; the other differentially methylated regions in both CpG and non-CpG regions were clustered in intron regions, where the DNA methylation level was highest. The function of genes associated with differentially methylated regions in promoter regions was also investigated. From Gene Ontology analysis results, DNA methylation was implicated in a number of essential functional responses to spinal cord injury, including neuronal synaptic connection creation and axon regeneration. Notably, neither CpG methylation nor non-CpG methylation was implicated in the functional response of glial or inflammatory cells. In summary, our work elucidated the dynamic pattern of DNA methylation in the spinal cord following injury and identified reduced non-CpG methylation as an epigenetic target after spinal cord injury in mice.  Related Articles | Metrics

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Long-term radiofrequency electromagnetic fields exposure attenuates cognitive dysfunction in 5×FAD mice by regulating microglial function Yeonghoon Son, Hye-Jin Park, Ye Ji Jeong, Hyung-Do Choi, Nam Kim, Hae-June Lee 2023, 18 (11):  2497-2503.  doi: 10.4103/1673-5374.371379 Abstract ( 95 )   PDF (5618KB) ( 237 )   Save We have previously found that long-term effects of exposure to radiofrequency electromagnetic fields in 5×FAD mice with severe late-stage Alzheimer’s disease reduced both amyloid-β deposition and glial activation, including microglia. To examine whether this therapeutic effect is due to the regulation of activated microglia, we analyzed microglial gene expression profiles and the existence of microglia in the brain in this study. 5×FAD mice at the age of 1.5 months were assigned to sham- and radiofrequency electromagnetic fields-exposed groups and then animals were exposed to 1950 MHz radiofrequency electromagnetic fields at a specific absorption rate of 5 W/kg for 2 hours/day and 5 days/week for 6 months. We conducted behavioral tests including the object recognition and Y-maze tests and molecular and histopathological analysis of amyloid precursor protein/amyloid-beta metabolism in brain tissue. We confirmed that radiofrequency electromagnetic field exposure for 6 months ameliorated cognitive impairment and amyloid-β deposition. The expression levels of Iba1 (pan-microglial marker) and colony-stimulating factor 1 receptor (CSF1R; regulates microglial proliferation) in the hippocampus in 5×FAD mice treated with radiofrequency electromagnetic fields were significantly reduced compared with those of the sham-exposed group. Subsequently, we analyzed the expression levels of genes related to microgliosis and microglial function in the radiofrequency electromagnetic fields-exposed group compared to those of a CSF1R inhibitor (PLX3397)-treated group. Both radiofrequency electromagnetic fields and PLX3397 suppressed the levels of genes related to microgliosis (Csf1r, CD68, and Ccl6) and pro-inflammatory cytokine interleukin-1β. Notably, the expression levels of genes related to microglial function, including Trem2, Fcgr1a, Ctss, and Spi1, were decreased after long-term radiofrequency electromagnetic field exposure, which was also observed in response to microglial suppression by PLX3397. These results showed that radiofrequency electromagnetic fields ameliorated amyloid-β pathology and cognitive impairment by suppressing amyloid-β deposition-induced microgliosis and their key regulator, CSF1R. Related Articles | Metrics

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Retinal thickness and vascular parameters using optical coherence tomography in Alzheimer’s disease: a meta-analysis#br# Samran Sheriff, Ting Shen, Sandra Abdal, Danit Saks, Mehdi Mirzaei, Veer Gupta, Nitin Chitranshi, Yuyi You, Angela Schultz, Stuart L. Graham, Vivek Gupta 2023, 18 (11):  2504-2513.  doi: 10.4103/1673-5374.371380 Abstract ( 108 )   PDF (2612KB) ( 63 )   Save Examining the retinal tissue has the potential to provide a unique method and technique to quantify Alzheimer’s disease-related changes in participants at various stages of the disease. In this meta-analysis, we aimed to investigate the association of various optical coherence tomography parameters with Alzheimer’s disease and whether retinal measurements can be used to differentiate between Alzheimer’s disease and control subjects. Scientific databases including Google Scholar, Web of Science, and PubMed were systematically searched for published articles that evaluated retinal nerve fiber layer thickness and retinal microvascular network in Alzheimer’s disease and control subjects. Seventy-three studies (5850 participants, including 2249 Alzheimer’s disease patients and 3601 controls) were included in this meta-analysis. Relative to controls, Alzheimer’s disease patients had a significantly lower global retinal nerve fiber layer thickness (standardized mean difference [SMD] = –0.79, 95% confidence intervals [CI]: –1.03 to –0.54, P < 0.00001) as well as each quadrant being thinner in Alzheimer’s disease versus controls. Regarding macular parameters, values measured by optical coherence tomography were significantly lower in Alzheimer’s disease than controls for macular thickness (pooled SMD: –0.44, 95% CI: –0.67 to –0.20, P = 0.0003), foveal thickness (pooled SMD = –0.39, 95% CI: –0.58 to –0.19, P < 0.0001), ganglion cell inner plexiform layer  (SMD = –1.26, 95% CI: –2.24 to –0.27, P = 0.01) and macular volume (pooled SMD = –0.41, 95% CI –0.76 to –0.07, P = 0.02). Analysis using optical coherence tomography angiography parameters revealed mixed results between Alzheimer’s disease and controls. Superficial vessel density (pooled SMD = –0.42, 95% CI: –0.68 to –0.17, P = 0.0001) and deep vessel density (pooled SMD = –0.46, 95% CI: –0.75 to –0.18, P = 0.001) were found to be thinner in Alzheimer’s disease patients whereas the foveal avascular zone (SMD = 0.84, 95% CI: 0.17–1.51, P = 0.01) was larger in controls. Vascular density and thickness of various retinal layers were decreased in Alzheimer’s disease patients compared to controls. Our results provide evidence for optical coherence tomography technology having the potential to detect retinal and microvascular changes in patients diagnosed with Alzheimer’s disease and aid in monitoring and early diagnosis methods.  Related Articles | Metrics

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Rapamycin reverses ferroptosis by increasing autophagy in MPTP/MPP+-induced models of Parkinson’s disease Tongyu Liu, Peihan Wang, Huan Yin, Xiangfei Wang, Jing Lv, Jiang Yuan, Jing Zhu, Yunfu Wang 2023, 18 (11):  2514-2519.  doi: 10.4103/1673-5374.371381 Abstract ( 336 )   PDF (4321KB) ( 125 )   Save Parkinson’s disease is a neurodegenerative disorder, and ferroptosis plays a significant role in the pathological mechanism underlying Parkinson’s disease. Rapamycin, an autophagy inducer, has been shown to have neuroprotective effects in Parkinson’s disease. However, the link between rapamycin and ferroptosis in Parkinson’s disease is not entirely clear. In this study, rapamycin was administered to a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease mouse model and a 1-methyl-4-phenylpyridinium-induced Parkinson’s disease PC12 cell model. The results showed that rapamycin improved the behavioral symptoms of Parkinson’s disease model mice, reduced the loss of dopamine neurons in the substantia nigra pars compacta, and reduced the expression of ferroptosis-related indicators (glutathione peroxidase 4, recombinant solute carrier family 7, member 11, glutathione, malondialdehyde, and reactive oxygen species). In the Parkinson’s disease cell model, rapamycin improved cell viability and reduced ferroptosis. The neuroprotective effect of rapamycin was attenuated by a ferroptosis inducer (methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahyyridoindole-3-carboxylate) and an autophagy inhibitor (3-methyladenine). Inhibiting ferroptosis by activating autophagy may be an important mechanism by which rapamycin exerts its neuroprotective effects. Therefore, the regulation of ferroptosis and autophagy may provide a therapeutic target for drug treatments in Parkinson’s disease. Related Articles | Metrics

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Correlation between cerebral cortex changes and clinical features in patients with neuromyelitis optica spectrum disorder with normal-appearing brain tissue: a case-control study Chuxin Huang, Yanyu Li, Yanjing Chen, Xuan Liao, Huiting Zhang, Zhiyuan Wang, Jun Liu, Wei Lu 2023, 18 (11):  2520-2525.  doi: 10.4103/1673-5374.371371 Abstract ( 115 )   PDF (4080KB) ( 50 )   Save Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system. However, whether and how cortical changes occur in NMOSD with normal-appearing brain tissue, or whether any cortical changes correlate with clinical characteristics, is not completely clear. The current study recruited 43 patients with NMOSD who had normal-appearing brain tissue and 45 healthy controls matched for age, sex, and educational background from December 2020 to February 2022. A surface-based morphological analysis of high-resolution T1-weighted structural magnetic resonance images was used to calculate the cortical thickness, sulcal depth, and gyrification index. Analysis showed that cortical thickness in the bilateral rostral middle frontal gyrus and left superior frontal gyrus was lower in the patients with NMOSD than in the control participants. Subgroup analysis of the patients with NMOSD indicated that compared with those who did not have any optic neuritis episodes, those who did have such episodes exhibited noticeably thinner cortex in the bilateral cuneus, superior parietal cortex, and pericalcarine cortex. Correlation analysis indicated that cortical thickness in the bilateral rostral middle frontal gyrus was positively correlated with scores on the Digit Symbol Substitution Test and negatively correlated with scores on the Trail Making Test and the Expanded Disability Status Scale. These results are evidence that cortical thinning of the bilateral regional frontal cortex occurs in patients with NMOSD who have normal-appearing brain tissue, and that the degree of thinning is correlated with clinical disability and cognitive function. These findings will help improve our understanding of the imaging characteristics in NMOSD and their potential clinical significance. Related Articles | Metrics

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Phosphorylated S6K1 and 4E-BP1 play different roles in constitutively active Rheb-mediated retinal ganglion cell survival and axon regeneration after optic nerve injury Jikuan Jiang, Lusi Zhang, Jingling Zou, Jingyuan Liu, Jia Yang, Qian Jiang, Peiyun Duan, Bing Jiang 2023, 18 (11):  2526-2534.  doi: 10.4103/1673-5374.371372 Abstract ( 167 )   PDF (36010KB) ( 19 )   Save Ras homolog enriched in brain (Rheb) is a small GTPase that activates mammalian target of rapamycin complex 1 (mTORC1). Previous studies have shown that constitutively active Rheb can enhance the regeneration of sensory axons after spinal cord injury by activating downstream effectors of mTOR. S6K1 and 4E-BP1 are important downstream effectors of mTORC1. In this study, we investigated the role of Rheb/mTOR and its downstream effectors S6K1 and 4E-BP1 in the protection of retinal ganglion cells. We transfected an optic nerve crush mouse model with adeno-associated viral 2-mediated constitutively active Rheb and observed the effects on retinal ganglion cell survival and axon regeneration. We found that overexpression of constitutively active Rheb promoted survival of retinal ganglion cells in the acute (14 days) and chronic (21 and 42 days) stages of injury. We also found that either co-expression of the dominant-negative S6K1 mutant or the constitutively active 4E-BP1 mutant together with constitutively active Rheb markedly inhibited axon regeneration of retinal ganglion cells. This suggests that mTORC1-mediated S6K1 activation and 4E-BP1 inhibition were necessary components for constitutively active Rheb-induced axon regeneration. However, only S6K1 activation, but not 4E-BP1 knockdown, induced axon regeneration when applied alone. Furthermore, S6K1 activation promoted the survival of retinal ganglion cells at 14 days post-injury, whereas 4E-BP1 knockdown unexpectedly slightly decreased the survival of retinal ganglion cells at 14 days post-injury. Overexpression of constitutively active 4E-BP1 increased the survival of retinal ganglion cells at 14 days post-injury. Likewise, co-expressing constitutively active Rheb and constitutively active 4E-BP1 markedly increased the survival of retinal ganglion cells compared with overexpression of constitutively active Rheb alone at 14 days post-injury. These findings indicate that functional 4E-BP1 and S6K1 are neuroprotective and that 4E-BP1 may exert protective effects through a pathway at least partially independent of Rheb/mTOR. Together, our results show that constitutively active Rheb promotes the survival of retinal ganglion cells and axon regeneration through modulating S6K1 and 4E-BP1 activity. Phosphorylated S6K1 and 4E-BP1 promote axon regeneration but play an antagonistic role in the survival of retinal ganglion cells.  Related Articles | Metrics

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High-intensity swimming alleviates nociception and neuroinflammation in a mouse model of chronic post-ischemia pain by activating the resolvin E1-chemerin receptor 23 axis in the spinal cord Xin Jia, Ziyang Li, Xiafeng Shen, Yu Zhang, Li Zhang, Ling Zhang 2023, 18 (11):  2535-2544.  doi: 10.4103/1673-5374.371373 Abstract ( 126 )   PDF (24280KB) ( 37 )   Save Physical exercise effectively alleviates chronic pain associated with complex regional pain syndrome type-I. However, the mechanism of exercise-induced analgesia has not been clarified. Recent studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous system. However, whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-I has not been demonstrated. In the present study, a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-I and subjected to an intervention involving swimming at different intensities. Chronic pain was reduced only in mice that engaged in high-intensity swimming. The resolvin E1-chemerin receptor 23 axis was clearly downregulated in the spinal cord of mice with chronic pain, while high-intensity swimming restored expression of resolvin E1 and chemerin receptor 23. Finally, shRNA-mediated silencing of chemerin receptor 23 in the spinal cord reversed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammatory polarization of microglia in the dorsal horn of the spinal cord. These findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the spinal cord. Related Articles | Metrics

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Epigenetic combined with transcriptomic analysis of the m6A methylome after spared nerve injury-induced neuropathic pain in mice Fanning Zeng, Jun Cao, Zexuan Hong, Yitian Lu, Zaisheng Qin, Tao Tao 2023, 18 (11):  2545-2552.  doi: 10.4103/1673-5374.371374 Abstract ( 163 )   PDF (13199KB) ( 51 )   Save Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuropathic pain. N6-methyladenosine (m6A) is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases. However, the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown. In this study, we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve. High-throughput methylated RNA immunoprecipitation sequencing results showed that after spared nerve injury, there were 55 m6A methylated and differentially expressed genes in the spinal cord. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury. Over time, the differential gene function at postoperative day 7 was enriched in “positive regulation of neurogenesis” and “positive regulation of neural precursor cell proliferation.” These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance. Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes, such as “very-low-density lipoprotein particle clearance,” “negative regulation of cholesterol transport” and “membrane lipid catabolic process.” We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling. We speculate that m6A reader enzymes also have an important role in neuropathic pain. These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at different stages after injury. Related Articles | Metrics