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15 October 2023, Volume 18 Issue 10 Previous Issue   

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From static to dynamic: live observation of the support system after ischemic stroke by two photon-excited fluorescence laser-scanning microscopy Xuan Wu, Jia-Rui Li, Yu Fu, Dan-Yang Chen, Hao Nie, Zhou-Ping Tang 2023, 18 (10):  2093-2107.  doi: 10.4103/1673-5374.369099 Abstract ( 226 )   PDF (30480KB) ( 110 )   Save Ischemic stroke is one of the most common causes of mortality and disability worldwide. However, treatment efficacy and the progress of research remain unsatisfactory. As the critical support system and essential components in neurovascular units, glial cells and blood vessels (including the blood-brain barrier) together maintain an optimal microenvironment for neuronal function. They provide nutrients, regulate neuronal excitability, and prevent harmful substances from entering brain tissue. The highly dynamic networks of this support system play an essential role in ischemic stroke through processes including brain homeostasis, supporting neuronal function, and reacting to injuries. However, most studies have focused on postmortem animals, which inevitably lack critical information about the dynamic changes that occur after ischemic stroke. Therefore, a high-precision technique for research in living animals is urgently needed. Two-photon fluorescence laser-scanning microscopy is a powerful imaging technique that can facilitate live imaging at high spatiotemporal resolutions. Two-photon fluorescence laser-scanning microscopy can provide images of the whole-cortex vascular 3D structure, information on multicellular component interactions, and provide images of structure and function in the cranial window. This technique shifts the existing research paradigm from static to dynamic, from flat to stereoscopic, and from single-cell function to multicellular intercommunication, thus providing direct and reliable evidence to identify the pathophysiological mechanisms following ischemic stroke in an intact brain. In this review, we discuss exciting findings from research on the support system after ischemic stroke using two-photon fluorescence laser-scanning microscopy, highlighting the importance of dynamic observations of cellular behavior and interactions in the networks of the brain’s support systems. We show the excellent application prospects and advantages of two-photon fluorescence laser-scanning microscopy and predict future research developments and directions in the study of ischemic stroke. Related Articles | Metrics

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MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets Bridget Martinez, Philip V. Peplow 2023, 18 (10):  2108-2118.  doi: 10.4103/1673-5374.369093 Abstract ( 132 )   PDF (660KB) ( 94 )   Save Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals (mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,  -146a-5p,  -10a-5p, -21a-3p, -27a-3p,  -142a-5p,  -212-3p,  -431-5p, and -155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451, -10a-5p, -21a-5p,  -27a-5p, -142a-5p, -431-5p, -155, and -134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p, -27a-3p, -155, -134, -181a, and -146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid. Related Articles | Metrics

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The generation and properties of human cortical organoids as a disease model for malformations of cortical development Xiu-Ping Zhang, Xi-Yuan Wang, Shu-Na Wang, Chao-Yu Miao 2023, 18 (10):  2119-2126.  doi: 10.4103/1673-5374.369100 Abstract ( 170 )   PDF (3036KB) ( 142 )   Save As three-dimensional “organ-like” aggregates, human cortical organoids have emerged as powerful models for studying human brain evolution and brain disorders with unique advantages of human-specificity, fidelity and manipulation. Human cortical organoids derived from human pluripotent stem cells can elaborately replicate many of the key properties of human cortical development at the molecular, cellular, structural, and functional levels, including the anatomy, functional neural network, and interaction among different brain regions, thus facilitating the discovery of brain development and evolution. In addition to studying the neuro-electrophysiological features of brain cortex development, human cortical organoids have been widely used to mimic the pathophysiological features of cortical-related disease, especially in mimicking malformations of cortical development, thus revealing pathological mechanism and identifying effective drugs. In this review, we provide an overview of the generation of human cortical organoids and the properties of recapitulated cortical development and further outline their applications in modeling malformations of cortical development including pathological phenotype, underlying mechanisms and rescue strategies. Related Articles | Metrics

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Nanotechnology-based gene therapy as a credible tool in the treatment of Alzheimer’s disease Aziz Unnisa, Nigel H. Greig, Mohammad Amjad Kamal 2023, 18 (10):  2127-2133.  doi: 10.4103/1673-5374.369096 Abstract ( 144 )   PDF (2457KB) ( 101 )   Save Toxic aggregated amyloid-β accumulation is a key pathogenic event in Alzheimer’s disease. Treatment approaches have focused on the suppression, deferral, or dispersion of amyloid-β fibers and plaques. Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease, owing to its rapid advancement over the recent decade. Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets, including those that were once considered undruggable. However, lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application, necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the blood-brain barrier. Nanotechnology has emerged as a possible solution, and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery. By reducing the enzymatic breakdown of genetic components, nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy. Liposomes, polymeric nanoparticles, magnetic nanoparticles, dendrimers, and micelles are examples of nanocarriers that have been designed, and each has its own set of features. Furthermore, recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities. In this paper, we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease. Related Articles | Metrics

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Detection of Alzheimer’s disease onset using MRI and PET neuroimaging: longitudinal data analysis and machine learning Iroshan Aberathne, Don Kulasiri, Sandhya Samarasinghe 2023, 18 (10):  2134-2140.  doi: 10.4103/1673-5374.367840 Abstract ( 182 )   PDF (4655KB) ( 236 )   Save The scientists are dedicated to studying the detection of Alzheimer’s disease onset to find a cure, or at the very least, medication that can slow the progression of the disease. This article explores the effectiveness of longitudinal data analysis, artificial intelligence, and machine learning approaches based on magnetic resonance imaging and positron emission tomography neuroimaging modalities for progression estimation and the detection of Alzheimer’s disease onset. The significance of feature extraction in highly complex neuroimaging data, identification of vulnerable brain regions, and the determination of the threshold values for plaques, tangles, and neurodegeneration of these regions will extensively be evaluated. Developing automated methods to improve the aforementioned research areas would enable specialists to determine the progression of the disease and find the link between the biomarkers and more accurate detection of Alzheimer’s disease onset. Related Articles | Metrics

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A pancreatic player in dementia: pathological role for islet amyloid polypeptide accumulation in the brain Angelina S. Bortoletto, Ronald J. Parchem 2023, 18 (10):  2141-2146.  doi: 10.4103/1673-5374.369095 Abstract ( 143 )   PDF (1039KB) ( 72 )   Save Type 2 diabetes mellitus patients have a markedly higher risk of developing dementia. While multiple factors contribute to this predisposition, one of these involves the increased secretion of amylin, or islet amyloid polypeptide, that accompanies the pathophysiology of type 2 diabetes mellitus. Islet amyloid polypeptide accumulation has undoubtedly been implicated in various forms of dementia, including Alzheimer’s disease and vascular dementia, but the exact mechanisms underlying islet amyloid polypeptide’s causative role in dementia are unclear. In this review, we have summarized the literature supporting the various mechanisms by which islet amyloid polypeptide accumulation may cause neuronal damage, ultimately leading to the clinical symptoms of dementia. We discuss the evidence for islet amyloid polypeptide deposition in the brain, islet amyloid polypeptide interaction with other amyloids implicated in neurodegeneration, neuroinflammation caused by islet amyloid polypeptide deposition, vascular damage induced by islet amyloid polypeptide accumulation, and islet amyloid polypeptide-induced cytotoxicity. There are very few therapies approved for the treatment of dementia, and of these, clinical responses have been controversial at best. Therefore, investigating new, targetable pathways is vital for identifying novel therapeutic strategies for treating dementia. As such, we conclude this review by discussing islet amyloid polypeptide accumulation as a potential therapeutic target not only in treating type 2 diabetes mellitus but as a future target in treating or even preventing dementia associated with type 2 diabetes mellitus.  Related Articles | Metrics

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The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier Shuang-Shuang Wei, Le Chen, Feng-Yuan Yang, Si-Qi Wang, Peng Wang 2023, 18 (10):  2147-2155.  doi: 10.4103/1673-5374.369102 Abstract ( 273 )   PDF (1647KB) ( 103 )   Save Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression. Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis. Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis, thus inhibiting remyelination. Although many advances have been made in the mechanisms and treatment of multiple sclerosis, it remains very difficult for drugs to reach pathological brain tissues; this is due to the complexity of brain structure and function, especially the existence of the blood-brain barrier. Therefore, herein, we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease. Related Articles | Metrics

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Alexander disease: the road ahead María A. Pajares, Elena Hernández-Gerez, Milos Pekny, Dolores Pérez-Sala 2023, 18 (10):  2156-2160.  doi: 10.4103/1673-5374.369097 Abstract ( 314 )   PDF (3212KB) ( 118 )   Save Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein, a type III intermediate filament protein expressed in astrocytes. Both early (infantile or juvenile) and adult onsets of the disease are known and, in both cases, astrocytes present characteristic aggregates, named Rosenthal fibers. Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner. Although the presence of aggregates suggests a proteostasis problem of the mutant forms, this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased. Additionally, several isoforms of glial fibrillary acidic protein have been described to date, while the impact of the mutations on their expression and proportion has not been exhaustively studied. Moreover, the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered, leading to functional changes that may modify the morphology, positioning, and/or the function of several organelles, in turn, impairing astrocyte normal function and subsequently affecting neurons. In particular, mitochondrial function, redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes. To study the disease and to develop putative therapeutic strategies, several experimental models have been developed, a collection that is in constant growth. The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations, together with the availability of new and more relevant experimental models, holds promise for the design and assay of novel therapeutic strategies. Related Articles | Metrics

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Mitochondrial dysfunction as a target in spinal cord injury: intimate correlation between pathological processes and therapeutic approaches Julieta Schmidt, Héctor Ramiro Quintá 2023, 18 (10):  2161-2166.  doi: 10.4103/1673-5374.369094 Abstract ( 217 )   PDF (901KB) ( 134 )   Save Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. This interruption results in either temporary or permanent alterations in the locomotor, sensory, and autonomic functions. Damage in the spinal tissue prevents the re-growth of severed axons across the lesion and their reconnection with neuronal targets. Therefore, the absence of spontaneous repair leads to sustained impairment in voluntary control of movement below the injury. For decades, axonal regeneration and reconnection have been considered the opitome of spinal cord injury repair with the goal being the repair of the damaged long motor and sensory tracts in a complex process that involves: (1) resealing injured axons; (2) reconstructing the cytoskeletal structure inside axons; (3) re-establishing healthy growth cones; and (4) assembling axonal cargos. These biological processes require an efficient production of adenosine triphosphate, which is affected by mitochondrial dysfunction after spinal cord injury. From a pathological standpoint, during the secondary stage of spinal cord injury, mitochondrial homeostasis is disrupted, mainly in the distal segments of severed axons. This result in a reduction of adenosine triphosphate levels and subsequent inactivation of adenosine triphosphate-dependent ion pumps required for the regulation of ion concentrations and reuptake of neurotransmitters, such as glutamate. The consequences are calcium overload, reactive oxygen species formation, and excitotoxicity. These events are intimately related to the activation of necrotic and apoptotic cell death programs, and further exacerbate the secondary stage of the injury, being a hallmark of spinal cord injury. This is why restoring mitochondrial function during the early stage of secondary injury could represent a potentially effective therapeutic intervention to overcome the motor and sensory failure produced by spinal cord injury. This review discusses the most recent evidence linking mitochondrial dysfunction with axonal regeneration failure in the context of spinal cord injury. It also covers the future of mitochondria-targeted therapeutical approaches, such as antioxidant molecules, removing mitochondrial anchor proteins, and increasing energetic metabolism through creatine treatment. These approaches are intended to enhance functional recovery by promoting axonal regeneration-reconnection after spinal cord injury. Related Articles | Metrics

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The role of Rho GTPase family in cochlear hair cells and hearing Yu-Bei Dai, Xiang Gao, Dong Liu, Jie Gong 2023, 18 (10):  2167-2172.  doi: 10.4103/1673-5374.369101 Abstract ( 195 )   PDF (959KB) ( 141 )   Save Rho GTPases are essential regulators of the actin cytoskeleton. They are involved in various physiological and biochemical processes such as the regulation of cytoskeleton dynamics, development, proliferation, survival, and regeneration. During the development of cochlear hair cells, Rho GTPases are activated by various extracellular signals through membrane receptors to further stimulate multiple downstream effectors. Specifically, RhoA, Cdc42, and Rac1, members of the classical subfamily of the Rho GTPase family, regulate the development and maintenance of cilia by inducing the polymerization of actin monomers and stabilizing actin filaments. In addition, they also regulate the normal morphology orientation of ciliary bundles in auditory hair cells, which is an important element of cell polarity regulation. Moreover, the actin-related pathways mediated by RhoA, Cdc42, and Rac1 also play a role in the motility of outer hair cells, indicating that the function of Rho GTPases is crucial in the highly polar auditory sensory system. In this review, we focus on the expression of RhoA, Cdc42, and Rac1 in cochlear hair cells and how these small molecules participate in ciliary bundle morphogenesis and cochlear hair cell movement. We also discuss the progress of current research investigating the use of these small molecules as drug targets for deafness treatment. Related Articles | Metrics

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Oxidative stress in retinal pigment epithelium degeneration: from pathogenesis to therapeutic targets in dry age-related macular degeneration Meenakshi Maurya, Kiran Bora, Alexandra K. Blomfield, Madeline C. Pavlovich, Shuo Huang, Chi-Hsiu Liu, Jing Chen 2023, 18 (10):  2173-2181.  doi: 10.4103/1673-5374.369098 Abstract ( 328 )   PDF (3329KB) ( 182 )   Save Age-related macular degeneration is a primary cause of blindness in the older adult population. Past decades of research in the pathophysiology of the disease have resulted in breakthroughs in the form of anti-vascular endothelial growth factor therapies against neovascular age-related macular degeneration; however, effective treatment is not yet available for geographical atrophy in dry age-related macular degeneration or for preventing the progression from early or mid to the late stage of age-related macular degeneration. Both clinical and experimental investigations involving human age-related macular degeneration retinas and animal models point towards the atrophic alterations in retinal pigment epithelium as a key feature in age-related macular degeneration progression. Retinal pigment epithelium cells are primarily responsible for cellular-structural maintenance and nutrition supply to keep photoreceptors healthy and functional. The retinal pigment epithelium constantly endures a highly oxidative environment that is balanced with a cascade of antioxidant enzyme systems regulated by nuclear factor erythroid-2-related factor 2 as a main redox sensing transcription factor. Aging and accumulated oxidative stress triggers retinal pigment epithelium dysfunction and eventually death. Exposure to both environmental and genetic factors aggravates oxidative stress damage in aging retinal pigment epithelium and accelerates retinal pigment epithelium degeneration in age-related macular degeneration pathophysiology. The present review summarizes the role of oxidative stress in retinal pigment epithelium degeneration, with potential impacts from both genetic and environmental factors in age-related macular degeneration development and progression. Potential strategies to counter retinal pigment epithelium damage and protect the retinal pigment epithelium through enhancing its antioxidant capacity are also discussed, focusing on existing antioxidant nutritional supplementation, and exploring nuclear factor erythroid-2-related factor 2 and its regulators including REV-ERBα as therapeutic targets to protect against age-related macular degeneration development and progression. Related Articles | Metrics

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Boosting corticospinal system synaptic plasticity to recover motor functions Weiguo Song, John H. Martin 2023, 18 (10):  2182-2183.  doi: 10.4103/1673-5374.369103 Abstract ( 112 )   PDF (298KB) ( 64 )   Save An important strategy to promote voluntary movements after motor system injury is to strengthen the connections between the motor cortex and muscles by taking advantage of the plasticity of the corticospinal motor system. Many neuromodulation approaches are directed to activate the spinal cord and peripheral axons to strengthen muscle activation. We discuss in this perspective that, the cortex and spinal cord should be targeted together to enhance cortex-to-muscle function (Amer and Martin, 2022). Among these protocols, we have used epidural intermittent theta burst stimulation (iTBS) of the motor cortex and transspinal direct current stimulation (tsDCS), a non-invasive approach targeting the cervical and rostral thoracic spinal cord (Song et al., 2016; Song and Martin, 2017; Amer et al., 2021; Amer and Martin, 2022; Williams et al., 2022). In a rodent model, we were the first to combine motor cortex iTBS and tsDCS, an approach that shows promise for clinical efficacy and translational potential for corticospinal tract lesion and spinal cord injury (SCI) (Song et al., 2016; Zareen et al., 2018; Figure 1). To move this, and other approaches, forward for translation it is important to understand the underlying mechanisms better. This will help guide the development of new synergistic strategies to boost the power of plasticity, and further, to guide plasticity for functional recovery after injury. Related Articles | Metrics

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Stable isotope labeling-mass spectrometry as a new approach to determine remyelination Anddre Osmar Valdivia, Faith Christine Harvey, Sanjoy K. Bhattacharya 2023, 18 (10):  2184-2185.  doi: 10.4103/1673-5374.369104 Abstract ( 107 )   PDF (967KB) ( 41 )   Save Remyelination and need to access it: A range of diseases such as Guillain-Barre syndrome, Pelizaeus Merzbacher disease, relapsing-remitting and secondary progressive multiple sclerosis is associated with various degrees of nerve demyelination. These diseases present with various degrees of demyelination and different clinical manifestations. Treatments leading to remyelination are important for the restoration of functionality in these diseases with various clinical outcomes. Obtaining proper remyelination remains one of the current limitations for the treatment of demyelinating conditions. Establishing normal nerve function after axonal regeneration also necessitates proper myelination (Franklin et al., 2020). The process of remyelination is in many aspects very similar to the events that occur during development, with the exception that remyelination often does not reach the same myelin sheath thickness as observed during development. Therefore, understanding how these two processes (remyelination versus normal myelination after regeneration) differ can help develop novel translational applications in the field of regenerative medicine. With the scientific exploration of pharmacological compounds and therapies that can induce remyelination, there has been a surge of drugs with the potential to promote remyelination (Wooliscroft et al., 2019). Several of these are currently under clinical trials and include monoclonal antibody therapies, myelin protein stimulants, and non-selective G protein coupled receptor antagonists to name a few (Wooliscroft et al., 2019). However, the question arises as to whether these compounds are promoting remyelination or preventing demyelination. Thus, creating a need to identify newly synthesized myelin from previously existing myelin. Related Articles | Metrics

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Regulation of cytohesins by their interactors in the nervous system Yuqi Zhai, King To Leung, Kwok-Fai Lau 2023, 18 (10):  2186-2187.  doi: 10.4103/1673-5374.369105 Abstract ( 131 )   PDF (331KB) ( 57 )   Save Adenosine diphosphate ribosylation factors (ARFs) are small GTP-binding proteins of the Ras superfamily which are involved in membrane trafficking and actin cytoskeleton remodeling. Like other small GTPases, their functions are attributed to the cycling of ARF between GTP (active) and GDP (inactive) states through the actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins, respectively. Cytohesins are a GEF subfamily of ARFs in mammals with four members, namely, cytohesin-1, -2, -3, and -4. Related Articles | Metrics

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Pediatric GNAO1 encephalopathies: from molecular etiology of the disease to drug discovery Vladimir L. Katanaev, Jana Valnohova, Denis N. Silachev, Yonika A. Larasati, Alexey Koval 2023, 18 (10):  2188-2189.  doi: 10.4103/1673-5374.369106 Abstract ( 133 )   PDF (401KB) ( 60 )   Save Gαo is the major G protein in neurons, where it transduces signals from numerous G protein-coupled receptors (GPCRs) such as D2 dopamine, μ-opioid, M2 muscarinic, or α2-adrenergic receptors. In 2013, the first mutations in GNAO1, the gene encoding Gαo, were described in pediatric patients with encephalopathies (Nakamura et al., 2013), suffering from movement disorders, epileptic seizures, and developmental delay. As of today, over 200 patients have been identified as GNAO1 mutation carriers (https://gnao1.org/) mainly thanks to the availability of the whole exome sequencing technique. The mutations are typically single amino acid substitutions that mostly occur de novo, however unique cases of inheritance of the mutations are reported as well. In the OMIM (Online Mendelian Inheritance in Man) catalog, the two following disorders are associated with the heterozygous mutation in GNAO1 (the homozygous mutations have never been detected in humans; thus, it is likely that mutations in both alleles are lethal): Related Articles | Metrics

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A perspective on recent findings and future strategies for reactive aldehyde removal in spinal cord injury Seth A. Herr, Anna J. Prall, Riyi Shi 2023, 18 (10):  2190-2191.  doi: 10.4103/1673-5374.369107 Abstract ( 127 )   PDF (3543KB) ( 72 )   Save Acrolein in spinal cord injury: The propensity of reactive aldehydes such as acrolein to both initiate and perpetuate tissue damage after spinal cord injury (SCI) is well established. Formed primarily from lipid peroxidation, acrolein is known to be one of the most reactive aldehydes. Acrolein will quickly overwhelm endogenous clearance mechanisms and antioxidants, and form adducts with lipids, proteins, and DNA. Acrolein is pro-inflammatory and contributes significantly to cellular stress, eventually leading to cell death of neurons (Figure 1). After a neurotrauma, acrolein forms immediately and remains significantly elevated for at least 2 weeks (Burcham, 2017). When injected at physiologically relevant concentrations, acrolein-induced pathologies mirror those seen in trauma (Burcham, 2017). On the other hand, when acrolein is successfully sequestered, significant benefits including reduction of pain, increased locomotion, and restoration of cord tissue structure are observed. Yet, more complete removal of acrolein proves challenging given the high concentrations of acrolein that are generated after injury. There are currently no Food and Drug Administration (FDA)-approved medications for SCI patients that remove acrolein, and promote recovery, despite the known benefits. One of the main challenges of establishing an effective anti-acrolein based therapy for clinical usage is the need for small molecule aldehyde scavengers to cross the blood-brain barrier and do so at concentrations that will remove acrolein effectively without harmful side effects. Related Articles | Metrics

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Disease-associated oligodendrocyte signatures in neurodegenerative disease: the known and unknown Kristen H. Schuster, Hayley S. McLoughlin 2023, 18 (10):  2192-2193.  doi: 10.4103/1673-5374.368302 Abstract ( 116 )   PDF (2113KB) ( 47 )   Save Oligodendrocytes are one of the most abundant cell types in the central nervous system (CNS) and act in close contact with neurons to assist with their cellular function and health (Kuhn et al., 2019). Oligodendrocytes play particular roles in rapid nerve impulse conduction through the wrapping of their myelinating projections around a nerve axon, as well as by offering trophic and metabolic support for the high energy expenditure of neurons. Additionally, oligodendrocytes have been found to regulate axonal health directly or indirectly by monitoring immune networks between glia and neurons. Unlike neurons, apoptotic mature oligodendrocytes can be replaced via differentiation from a pool of oligodendrocyte precursor cells (OPCs). Proliferative OPCs remain within the CNS throughout adulthood (Yalcin and Monje, 2021) and function as more than just a progenitor pool to replace lost myelinating oligodendrocytes. OPCs have been shown to interact with other oligodendrocytes, neurons, astrocytes, and microglia, and have roles in myelin maintenance, synaptic formation, blood-brain barrier support, and immune responses (Yalcin and Monje, 2021). These intercellular interactions, in addition to their capacity to become myelinating oligodendrocytes, could make OPCs an intriguing target for therapeutic intervention in demyelinating diseases, such as multiple sclerosis, and other neurodegenerative disorders with recent reports of white matter abnormalities and oligodendrocyte dysfunction (Philips et al., 2013; Ferrari Bardile et al., 2019; Errea and Rodriguez-Oroz, 2021; Kenigsbuch et al., 2022; Schuster et al., 2022).  Related Articles | Metrics

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Repurposing ibrutinib: therapeutic effects and implications for translational approaches in Alzheimer’s disease Hyun-ju Lee, Hyang-Sook Hoe 2023, 18 (10):  2194-2195.  doi: 10.4103/1673-5374.369108 Abstract ( 110 )   PDF (375KB) ( 124 )   Save Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, and the number of patients with AD is estimated to double by 2060 (Alzheimer’s Association, 2022). The AD mortality rate has increased by 145% over the last decade, the largest increase among the ten leading causes of death in the US (Alzheimer’s Association, 2022). In 2022, the targets of novel disease-modifying agents for AD in phase 3 clinical trials expanded from amyloid β (Aβ)/tau to include synaptic plasticity, the gut-brain axis, oxidative stress, the vasculature, metabolism, and proteostasis (Cummings et al., 2022). Despite the identification of innovative AD therapeutic targets and high R&D investment in AD research, the clinical failure rate for AD therapeutics is 99.6% (Cummings et al., 2022). A major reason for this high failure rate may be the use of single-target approaches for AD drug development.  Related Articles | Metrics

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Metabotropic glutamate receptor 1 alpha: a unique receptor variant with variable implications for Alzheimer’s disease pathogenesis Jason HY Yeung, Andrea Kwakowsky 2023, 18 (10):  2196-2197.  doi: 10.4103/1673-5374.369109 Abstract ( 118 )   PDF (698KB) ( 88 )   Save Alzheimer’s disease (AD) is the leading neurodegenerative disorder globally. Despite this, there is minimal effective therapeutics proven to reduce or prevent the progression of this disease. Glutamate is the main excitatory neurotransmitter within the central nervous system and plays a crucial role in neuronal and synaptic functions. As such, the glutamatergic system is finely regulated within normal physiology, with multiple mechanisms to prevent excessive or insufficient glutamatergic receptor activation. This perspective article aims to highlight pertinent findings regarding metabotropic glutamate receptor (mGluR) expression and function in the AD brain, with a particular focus on the mGluR1α variant and its functional significance, concluding with a discussion regarding its potential as a therapeutic target in future AD studies.  Related Articles | Metrics

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Multi-faceted small molecule for Alzheimer’s disease Min Hee Park, Hee Kyung Jin, Jae-sung Bae 2023, 18 (10):  2198-2199.  doi: 10.4103/1673-5374.369110 Abstract ( 117 )   PDF (729KB) ( 91 )   Save The main pathologies of Alzheimer’s disease (AD) are the accumulation of amyloid-β (Aβ) and tau tangles, and these two fundamental pathologies accompany the various neuropathological features, such as neuroinflammation, loss of synapse and neurogenesis, disruption of the blood-brain barrier (BBB), autophagy dysfunction, and cognitive impairment (Lee et al., 2014; Sweeney et al., 2018; Kashyap et al., 2019; Park et al., 2022). AD is thus considered a multi-factorial disease in which each of these complex neuropathological features somehow interrelates, eventually leading to neuronal and functional loss in the nervous system. Although researchers have focused on Aβ and tau tangles for the development of therapeutics for AD, the clinical efficacy of drugs targeting these major pathologies remains controversial. Moreover, other currently available drugs that are not effective in treating AD solely provide symptomatic relief to patients with AD. For this reason, researchers are on the onlook for new strategies to treat AD and emphasize the importance of multi-target directed drugs.  Related Articles | Metrics

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Reevaluating the cause of laminopathy in Alzheimer’s disease Md Imamul Islam, Eftekhar Eftekharpour 2023, 18 (10):  2200-2201.  doi: 10.4103/1673-5374.367841 Abstract ( 102 )   PDF (1967KB) ( 57 )   Save Alzheimer’s disease (AD) is the most common form of dementia and is diagnosed clinically by cognitive deficits, and anatomically by accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT) containing hyper-phosphorylated Tau. Over the past three decades of AD research, the “amyloid hypothesis” gained the most attention as the main player in neurodegeneration. This was mostly based on specific hereditary forms of AD and patients with Down syndrome that linked the level of amyloid-beta (Aβ) directly to the risk of developing these diseases. However, in non-hereditary forms of AD, little correlation exists between Aβ levels or its location with the clinical stages of the disease. While still a hotly debated topic, a large body of literature based on years of preclinical models, suggests that Aβ deposition alone is not sufficient to induce AD, rather it is a pre-requisite for formation of NFT by promoting Tau hyper-phosphorylation. Neuropathology and imaging studies also suggest that hyper-phosphorylation of Tau and its spreading through the brain, better conform to the clinical stages of the disease  (Long and Holtzman, 2019). Related Articles | Metrics

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The importance of being connected: membrane contact sites and Parkinson’s disease Matthew E. Gegg 2023, 18 (10):  2202-2203.  doi: 10.4103/1673-5374.369111 Abstract ( 191 )   PDF (387KB) ( 70 )   Save Membrane contact sites (MCS) occur between closely apposed organelles and are a means to transport ions and macromolecules between themselves, co-ordinate cellular metabolism, and direct organelle fission and transport. While MCS between the endoplasmic reticulum (ER) and mitochondria has long been investigated, the importance of MCS in both lipid droplet (LD) function and the endolysosomal system are now being recognized. The identification of VPS13C and LRRK2 at MCS, protein products of the familial Parkinson’s disease (PD) loci PARK23 and PARK8, respectively, and the well-established dysfunction of the endolysosomal system and mitochondria in disease pathogenesis, arguably put PD at the forefront of MCS involvement in neurological disease.  Related Articles | Metrics

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Clues from a missense mutation of the adenosine A1 receptor gene associated with early-onset Parkinson’s disease Sergi Ferré, Leonardo Pardo, Francisco Ciruela 2023, 18 (10):  2204-2205.  doi: 10.4103/1673-5374.369113 Abstract ( 116 )   PDF (558KB) ( 68 )   Save Parkinson’s disease (PD) is a complex neurodegenerative disorder for which rare and common genetic variants contribute to disease risk, onset, and progression. The genetic contribution to PD can be classified mainly in, first, rare DNA variants that are highly penetrant and therefore causal, which are typically associated with monogenic PD; and second, more common risk polymorphic variants, which individually exert a small increase in the risk of the disease, which are usually identified in the most prevalent and apparently sporadic PD (Blauwendraat et al., 2020).  Related Articles | Metrics

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Renin-angiotensin system in the central nervous system: focus on Huntington’s disease Aline Silva de Miranda, Antonio Lucio Teixeira 2023, 18 (10):  2206-2207.  doi: 10.4103/1673-5374.368301 Abstract ( 99 )   PDF (601KB) ( 51 )   Save The renin-angiotensin system (RAS) was originally conceived as a circulating hormonal system involved in the regulation of cardiovascular and renal homeostasis. With the discovery of local RAS components in diverse organs, including the brain, and related biologically active peptides, enzymes, and receptors, the understanding of the physiological and pathophysiological roles of RAS has changed significantly. Accordingly, RAS has been conceptualized as a system composed of two major axes: a “classical” one formed by the angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and angiotensin type 1 (AT1) receptor (ACE/Ang II/AT1), and a ‘counter-regulatory’ one composed by the ACE2, Ang-(1-7), Mas receptor (ACE2/Ang-(1-7)/Mas). The classical arm promotes vasoconstriction, pro-inflammatory, pro-thrombotic, and pro-fibrotic effects mainly through the activation of AT1 receptors. Ang II can also bind to AT type 2 receptor but with much less affinity and with distinct effects of AT1. The counter-regulatory axis ACE2/Ang-(1-7)/Mas often opposes the actions of the classical arm, promoting anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-fibrotic effects (Miranda et al., 2022).  Related Articles | Metrics

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M2 macrophages mediate fibrotic scar formation in the early stages after cerebral ischemia in rats Jia-Gui Huang, Jiang-Xia Ren, Yue Chen, Ming-Fen Tian, Li Zhou, Jun Wen, Xiao-Song Song, You-Lin Wu, Qing-Huan Yang, Pei-Ran Jiang, Jia-Ni Wang, Qin Yang 2023, 18 (10):  2208-2218.  doi: 10.4103/1673-5374.368299 Abstract ( 321 )   PDF (17825KB) ( 134 )   Save In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury (within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4 (IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.  Related Articles | Metrics

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Eph receptor A4 regulates motor neuron ferroptosis in spinal cord ischemia/reperfusion injury in rats Yan Dong, Chunyu Ai, Ying Chen, Zaili Zhang, Dong Zhang, Sidan Liu, Xiangyi Tong, Hong Ma 2023, 18 (10):  2219-2228.  doi: 10.4103/1673-5374.369118 Abstract ( 155 )   PDF (12056KB) ( 81 )   Save Previous studies have shown that the receptor tyrosine kinase Eph receptor A4 (EphA4) is abundantly expressed in the nervous system. The EphA4 signaling pathway plays an important role in regulating motor neuron ferroptosis in motor neuron disease. To investigate whether EphA4 signaling is involved in ferroptosis in spinal cord ischemia/reperfusion injury, in this study we established a rat model of spinal cord ischemia/reperfusion injury by clamping the left carotid artery and the left subclavian artery. We found that spinal cord ischemia/reperfusion injury increased EphA4 expression in the neurons of anterior horn, markedly worsened ferroptosis-related indicators, substantially increased the number of mitochondria exhibiting features consistent with ferroptosis, promoted deterioration of motor nerve function, increased the permeability of the blood-spinal cord barrier, and increased the rate of motor neuron death. Inhibition of EphA4 largely rescued these effects. However, intrathecal administration of the ferroptosis inducer Erastin counteracted the beneficial effects conferred by treatment with the EphA4 inhibitor. Mass spectrometry and a PubMed search were performed to identify proteins that interact with EphA4, with the most notable being Beclin1 and Erk1/2. Our results showed that inhibition of EphA4 expression reduced binding to Beclin1, markedly reduced p-Beclin1, and reduced Beclin1-XCT complex formation. Inhibition of EphA4 also reduced binding to p-Erk1/2 and markedly decreased the expression of c-Myc, transferrin receptor 1, and p-Erk1/2. Additionally, we observed co-localization of EphA4 and p-Beclin1 and of EphA4 and p-ERK1/2 in neurons in the anterior horn. In conclusion, EphA4 participates in regulating ferroptosis of spinal motor neurons in the anterior horn in spinal cord ischemia/reperfusion injury by promoting formation of the Beclin1-XCT complex and activating the Erk1/2/c-Myc/transferrin receptor 1 axis. Related Articles | Metrics

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Reperfusion after hypoxia-ischemia exacerbates brain injury with compensatory activation of the anti- ferroptosis system: based on a novel rat model  Tian-Lei Zhang, Zhi-Wei Zhang, Wei Lin, Xin-Ru Lin, Ke-Xin Lin, Ming-Chu Fang, Jiang-Hu Zhu, Xiao-Ling Guo, Zhen-Lang Lin 2023, 18 (10):  2229-2236.  doi: 10.4103/1673-5374.369117 Abstract ( 185 )   PDF (6702KB) ( 185 )   Save Hypoxic-ischemic encephalopathy, which predisposes to neonatal death and neurological sequelae, has a high morbidity, but there is still a lack of effective prevention and treatment in clinical practice. To better understand the pathophysiological mechanism underlying hypoxic-ischemic encephalopathy, in this study we compared hypoxic-ischemic reperfusion brain injury and simple hypoxic-ischemic brain injury in neonatal rats. First, based on the conventional Rice-Vannucci model of hypoxic-ischemic encephalopathy, we established a rat model of hypoxic-ischemic reperfusion brain injury by creating a common carotid artery muscle bridge. Then we performed tandem mass tag-based proteomic analysis to identify differentially expressed proteins between the hypoxic-ischemic reperfusion brain injury model and the conventional Rice-Vannucci model and found that the majority were mitochondrial proteins. We also performed transmission electron microscopy and found typical characteristics of ferroptosis, including mitochondrial shrinkage, ruptured mitochondrial membranes, and reduced or absent mitochondrial cristae. Further, both rat models showed high levels of glial fibrillary acidic protein and low levels of myelin basic protein, which are biological indicators of hypoxic-ischemic brain injury and indicate similar degrees of damage. Finally, we found that ferroptosis-related Ferritin (Fth1) and glutathione peroxidase 4 were expressed at higher levels in the brain tissue of rats with hypoxic-ischemic reperfusion brain injury than in rats with simple hypoxic-ischemic brain injury. Based on these results, it appears that the rat model of hypoxic-ischemic reperfusion brain injury is more closely related to the pathophysiology of clinical reperfusion. Reperfusion not only aggravates hypoxic-ischemic brain injury but also activates the anti-ferroptosis system.  Related Articles | Metrics

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The circular RNA Rap1b promotes Hoxa5 transcription by recruiting Kat7 and leading to increased Fam3a expression, which inhibits neuronal apoptosis in acute ischemic stroke Fang-Fang Zhang, Liang Zhang, Lin Zhao, Yu Lu, Xin Dong, Yan-Qi Liu, Yu Li, Shuang Guo, Si-Yuan Zheng, Ying Xiao, Yu-Zhu Jiang 2023, 18 (10):  2237-2245.  doi: 10.4103/1673-5374.369115 Abstract ( 230 )   PDF (13182KB) ( 62 )   Save Circular RNAs can regulate the development and progression of ischemic cerebral disease. However, it remains unclear whether they play a role in acute ischemic stroke. To investigate the role of the circular RNA Rap1b (circRap1b) in acute ischemic stroke, in this study we established an in vitro model of acute ischemia and hypoxia by subjecting HT22 cells to oxygen and glucose deprivation and a mouse model of acute ischemia and hypoxia by occluding the right carotid artery. We found that circRap1b expression was remarkably down-regulated in the hippocampal tissue of the mouse model and in the HT22 cell model. In addition, Hoxa5 expression was strongly up-regulated in response to circRap1b overexpression. Hoxa5 expression was low in the hippocampus of a mouse model of acute ischemia and in HT22-AIS cells, and inhibited HT22-AIS cell apoptosis. Importantly, we found that circRap1b promoted Hoxa5 transcription by recruiting the acetyltransferase Kat7 to induce H3K14ac modification in the Hoxa5 promoter region. Hoxa5 regulated neuronal apoptosis by activating transcription of Fam3a, a neuronal apoptosis-related protein. These results suggest that circRap1b regulates Hoxa5 transcription and expression, and subsequently Fam3a expression, ultimately inhibiting cell apoptosis. Lastly, we explored the potential clinical relevance of circRap1b and Hoxa5 in vivo. Taken together, these findings demonstrate the mechanism by which circRap1b inhibits neuronal apoptosis in acute ischemic stroke. Related Articles | Metrics

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Exosomes from bone marrow mesenchymal stem cells are a potential treatment for ischemic stroke Chang Liu, Tian-Hui Yang, Hong-Dan Li, Gong-Zhe Li, Jia Liang, Peng Wang 2023, 18 (10):  2246-2251.  doi: 10.4103/1673-5374.369114 Abstract ( 192 )   PDF (4363KB) ( 117 )   Save Exosomes derived from human bone marrow mesenchymal stem cells (MSC-Exo) are characterized by easy expansion and storage, low risk of tumor formation, low immunogenicity, and anti-inflammatory effects. The therapeutic effects of MSC-Exo on ischemic stroke have been widely explored. However, the underlying mechanism remains unclear. In this study, we established a mouse model of ischemic brain injury induced by occlusion of the middle cerebral artery using the thread bolt method and injected MSC-Exo into the tail vein. We found that administration of MSC-Exo reduced the volume of cerebral infarction in the ischemic brain injury mouse model, increased the levels of interleukin-33 (IL-33) and suppression of tumorigenicity 2 receptor (ST2) in the penumbra of cerebral infarction, and improved neurological function. In vitro results showed that astrocyte-conditioned medium of cells deprived of both oxygen and glucose, to simulate ischemia conditions, combined with MSC-Exo increased the survival rate of primary cortical neurons. However, after transfection by IL-33 siRNA or ST2 siRNA, the survival rate of primary cortical neurons was markedly decreased. These results indicated that MSC-Exo inhibited neuronal death induced by oxygen and glucose deprivation through the IL-33/ST2 signaling pathway in astrocytes. These findings suggest that MSC-Exo may reduce ischemia-induced brain injury through regulating the IL-33/ST2 signaling pathway. Therefore, MSC-Exo may be a potential therapeutic method for ischemic stroke. Related Articles | Metrics

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Substance P promotes epidural fibrosis via induction of type 2 macrophages Feng Hua, Hao-Ran Wang, Yun-Feng Bai, Jin-Peng Sun, Wei-Shun Wang, Ying Xu, Ming-Shun Zhang, Jun Liu 2023, 18 (10):  2252-2259.  doi: 10.4103/1673-5374.369120 Abstract ( 151 )   PDF (8350KB) ( 40 )   Save In response to spinal surgery, neurons secrete a large amount of substance P into the epidural area. Substance P is involved in macrophage differentiation and fibrotic disease. However, the specific roles and mechanisms of substance P in epidural fibrosis remain unclear. In this study, we established a mouse model of L1–L3 laminectomy and found that dorsal root ganglion neurons and the macrophages infiltrating into the wound area released sphingolipids. In vitro experiments revealed that type 1 macrophages secreted substance P, which promoted differentiation of type 1 macrophages towards a type 2 phenotype. High-throughput mRNA-seq analysis revealed that the sphingolipid metabolic pathway may be involved in the regulation of type 2 macrophages by substance P. Specifically, sphingomyelin synthase 2, a component of the sphingolipid metabolic pathway, promoted M2 differentiation in substance P-treated macrophages, while treating the macrophages with LY93, a sphingomyelin synthase 2 inhibitor, suppressed M2 differentiation. In addition, substance P promoted the formation of neutrophil extracellular traps, which further boosted M2 differentiation. Blocking substance P with the neurokinin receptor 1 inhibitor RP67580 decreased the number of M2 macrophages in the wound area after spinal surgery and alleviated epidural fibrosis, as evidenced by decreased fibronectin, α-smooth muscle actin, and collagen I in the scar tissue. These results demonstrated that substance P promotes M2 macrophage differentiation in epidural fibrosis via sphingomyelin synthase 2 and neutrophil extracellular traps. These findings provide a novel strategy for the treatment of epidural fibrosis. Related Articles | Metrics

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A new peptide, VD11, promotes structural and functional recovery after spinal cord injury Shan-Shan Li, Bai-Yu Zhang, Sai-Ge Yin, Zi-Qi Wei, Nai-Xin Liu, Yi-Lin Li, Si-Yu Wang, Yu-Heng Shi, Jian Zhao, Li-Juan Wang, Yue Zhang, Jun Sun, Ying Wang, Xin-Wang Yang 2023, 18 (10):  2260-2267.  doi: 10.4103/1673-5374.369119 Abstract ( 211 )   PDF (7027KB) ( 48 )   Save The regenerative capacity of the central nervous system is very limited and few effective treatments are currently available for spinal cord injury. It is therefore a priority to develop new drugs that can promote structural and functional recovery after spinal cord injury. Previous studies have shown that peptides can promote substantial repair and regeneration of injured tissue. While amphibians have a pronounced ability to regenerate the spinal cord, few studies have investigated the effect of amphibian spinal cord-derived peptides on spinal cord injury. Here we report for the first time the successful identification and isolation of a new polypeptide, VD11 (amino acid sequence: VDELWPPWLPC), from the spinal cord of an endemic Chinese amphibian (Odorrana schmackeri). In vitro experiments showed that VD11 promoted the secretion of nerve growth factor and brain-derived neurotrophic factor in BV2 cells stimulated with lipopolysaccharide, as well as the proliferation and synaptic elongation of PC12 cells subjected to hypoxia. In vivo experiments showed that intravertebral injection of VD11 markedly promoted recovery of motor function in rats with spinal cord injury, alleviated pathological damage, and promoted axonal regeneration. Furthermore, RNA sequencing and western blotting showed that VD11 may affect spinal cord injury through activation of the AMPK and AKT signaling pathways. In summary, we discovered a novel amphibian-derived peptide that promotes structural and functional recovery after spinal cord injury.  Related Articles | Metrics

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Characteristics of traumatic brain injury models: from macroscopic blood flow changes to microscopic mitochondrial changes Ding-Ding Yang, Xiang-Dong Wan, An-Di Chen, Zi-Qian Yan, Yi-Fan Lu, Jun-Chen Liu, Ya-Zhou Wang, Jing Wang, Yan Zhao, Sheng-Xi Wu, Guo-Hong Cai 2023, 18 (10):  2268-2277.  doi: 10.4103/1673-5374.369125 Abstract ( 358 )   PDF (9230KB) ( 100 )   Save Controlled cortical impingement is a widely accepted method to induce traumatic brain injury to establish a traumatic brain injury animal model. A strike depth of 1 mm at a certain speed is recommended for a moderate brain injury and a depth of > 2 mm is used to induce severe brain injury. However, the different effects and underlying mechanisms of these two model types have not been proven. This study investigated the changes in cerebral blood flow, differences in the degree of cortical damage, and differences in motor function under different injury parameters of 1 and 2 mm at injury speeds of 3, 4, and 5 m/s. We also explored the functional changes and mitochondrial damage between the 1 and 2 mm groups in the acute (7 days) and chronic phases (30 days). The results showed that the cerebral blood flow in the injured area of the 1 mm group was significantly increased, and swelling and bulging of brain tissue, increased vascular permeability, and large-scale exudation occurred. In the 2 mm group, the main pathological changes were decreased cerebral blood flow, brain tissue loss, and cerebral vasospasm occlusion in the injured area. Substantial motor and cognitive impairments were found on day 7 after injury in the 2 mm group; at 30 days after injury, the motor function of the 2 mm group mice recovered significantly while cognitive impairment persisted. Transcriptome sequencing showed that compared with the 1 mm group, the 2 mm group expressed more ferroptosis-related genes. Morphological changes of mitochondria in the two groups on days 7 and 30 using transmission electron microscopy revealed that on day 7, the mitochondria in both groups shrank and the vacuoles became larger; on day 30, the mitochondria in the 1 mm group became larger, and the vacuoles in the 2 mm group remained enlarged. By analyzing the proportion of mitochondrial subgroups in different groups, we found that the model mice had different patterns of mitochondrial composition at different time periods, suggesting that the difference in the degree of damage among traumatic brain injury groups may reflect the mitochondrial changes. Taken together, differences in mitochondrial morphology and function between the 1 and 2 mm groups provide a new direction for the accurate classification of traumatic brain injury. Our results provide reliable data support and evaluation methods for promoting the establishment of standard mouse controlled cortical impingement model guidelines. Related Articles | Metrics

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TUG-891 inhibits neuronal endoplasmic reticulum stress and pyroptosis activation and protects neurons in a mouse model of intraventricular hemorrhage Hao-Xiang Wang, Chang Liu, Yuan-You Li, Yi Cao, Long Zhao, Yan-Jie Zhao, Zi-Ang Deng, Ai-Ping Tong, Liang-Xue Zhou 2023, 18 (10):  2278-2284.  doi: 10.4103/1673-5374.369116 Abstract ( 141 )   PDF (1832KB) ( 326 )   Save Pyroptosis plays an important role in hemorrhagic stroke. Excessive endoplasmic reticulum stress can cause endoplasmic reticulum dysfunction and cellular pyroptosis by regulating the nucleotide-binding oligomerization domain and leucine-rich repeat pyrin domain-containing protein 3 (NLRP3) pathway. However, the relationship between pyroptosis and endoplasmic reticulum stress after intraventricular hemorrhage is unclear. In this study, we established a mouse model of intraventricular hemorrhage and found pyroptosis and endoplasmic reticulum stress in brain tissue. Intraperitoneal injection of the selective GPR120 agonist TUG-891 inhibited endoplasmic reticulum stress, pyroptosis, and inflammation and protected neurons. The neuroprotective effect of TUG-891 appears related to inhibition of endoplasmic reticulum stress and pyroptosis activation.  Related Articles | Metrics

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Astrocyte-neuron communication mediated by the Notch signaling pathway: focusing on glutamate transport and synaptic plasticity Ke-Xin Li, Meng Lu, Meng-Xu Cui, Xiao-Ming Wang, Yang Zheng 2023, 18 (10):  2285-2290.  doi: 10.4103/1673-5374.369124 Abstract ( 245 )   PDF (3203KB) ( 129 )   Save Maintaining glutamate homeostasis after hypoxic ischemia is important for synaptic function and neural cell activity, and regulation of glutamate transport between astrocyte and neuron is one of the important modalities for reducing glutamate accumulation. However, further research is needed to investigate the dynamic changes in and molecular mechanisms of glutamate transport and the effects of glutamate transport on synapses. The aim of this study was to investigate the regulatory mechanisms underlying Notch pathway mediation of glutamate transport and synaptic plasticity. In this study, Yorkshire neonatal pigs (male, age 3 days, weight 1.0–1.5 kg, n = 48) were randomly divided into control (sham surgery group) and five hypoxic ischemia subgroups, according to different recovery time, which were then further subdivided into subgroups treated with dimethyl sulfoxide or a Notch pathway inhibitor (N-[N-(3, 5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester). Once the model was established, immunohistochemistry, immunofluorescence staining, and western blot analyses of Notch pathway-related proteins, synaptophysin, and glutamate transporter were performed. Moreover, synapse microstructure was observed by transmission electron microscopy. At the early stage (6–12 hours after hypoxic ischemia) of hypoxic ischemic injury, expression of glutamate transporter excitatory amino acid transporter-2 and synaptophysin was downregulated, the number of synaptic vesicles was reduced, and synaptic swelling was observed; at 12–24 hours after hypoxic ischemia, the Notch pathway was activated, excitatory amino acid transporter-2 and synaptophysin expression was increased, and the number of synaptic vesicles was slightly increased. Excitatory amino acid transporter-2 and synaptophysin expression decreased after treatment with the Notch pathway inhibitor. This suggests that glutamate transport in astrocytes-neurons after hypoxic ischemic injury is regulated by the Notch pathway and affects vesicle release and synaptic plasticity through the expression of synaptophysin. Related Articles | Metrics

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Exosomes derived from human umbilical cord mesenchymal stem cells alleviate Parkinson’s disease and neuronal damage through inhibition of microglia Zhong-Xia Zhang, Yong-Jie Zhou, Ping Gu, Wei Zhao, Hong-Xu Chen, Ruo-Yu Wu, Lu-Yang Zhou, Qing-Zhuo Cui, Shao-Kang Sun, Lin-Qi Zhang, Ke Zhang, Hong-Jun Xu, Xi-Qing Chai, , Sheng-Jun An, 2023, 18 (10):  2291-2300.  doi: 10.4103/1673-5374.368300 Abstract ( 207 )   PDF (6711KB) ( 116 )   Save Microglia-mediated inflammatory responses have been shown to play a crucial role in Parkinson’s disease. In addition, exosomes derived from mesenchymal stem cells have shown anti-inflammatory effects in the treatment of a variety of diseases. However, whether they can protect neurons in Parkinson’s disease by inhibiting microglia-mediated inflammatory responses is not yet known. In this study, exosomes were isolated from human umbilical cord mesenchymal stem cells and injected into a 6-hydroxydopamine-induced rat model of Parkinson’s disease. We found that the exosomes injected through the tail vein and lateral ventricle were absorbed by dopaminergic neurons and microglia on the affected side of the brain, where they repaired nigral-striatal dopamine system damage and inhibited microglial activation. Furthermore, in an in vitro cell model, pretreating lipopolysaccharide-stimulated BV2 cells with exosomes reduced interleukin-1β and interleukin-18 secretion, prevented the adoption of pyroptosis-associated morphology by BV2 cells, and increased the survival rate of SH-SY5Y cells. Potential targets for treatment with human umbilical cord mesenchymal stem cells and exosomes were further identified by high-throughput microRNA sequencing and protein spectrum sequencing. Our findings suggest that human umbilical cord mesenchymal stem cells and exosomes are a potential treatment for Parkinson’s disease, and that their neuroprotective effects may be mediated by inhibition of excessive microglial proliferation.  Related Articles | Metrics

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Neuroprotective effect of mesenchymal stem cell-derived extracellular vesicles on optic nerve injury in chronic ocular hypertension Fei Yu, Yao Wang, Chang-Quan Huang, Si-Jie Lin, Ru-Xin Gao, Ren-Yi Wu 2023, 18 (10):  2301-2306.  doi: 10.4103/1673-5374.369121 Abstract ( 160 )   PDF (3999KB) ( 118 )   Save Mesenchymal stem cells have neuroprotective effects that limit damage to the retina and photoreceptors, and which may be mediated by extracellular vesicles (or exosomes) released by mesenchymal stem cells. To investigate the neuroprotective effect of extracellular vesicles derived from umbilical cord mesenchymal stem cells on glaucoma, we established rat models of chronic ocular hypertension by injecting conjunctival fibroblasts into the anterior chamber to mimic optic nerve injury caused by glaucoma. One week after injury, extracellular vesicles derived from umbilical cord-derived mesenchymal stem cells were injected into the vitreous cavity. We found that extracellular vesicles derived from mesenchymal stem cells substantially reduced retinal damage, increased the number of retinal ganglion cells, and inhibited the activation of caspase-3. These findings suggest that mesenchymal stem cell-derived extracellular vesicles can help alleviate optic nerve injury caused by chronic ocular hypertension, and this effect is achieved by inhibiting cell apoptosis. Related Articles | Metrics

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Srgap2 suppression ameliorates retinal ganglion cell degeneration in mice Yi-Jing Gan, Ying Cao, Zu-Hui Zhang, Jing Zhang, Gang Chen, Ling-Qin Dong, Tong Li, Mei-Xiao Shen, Jia Qu, Zai-Long Chi 2023, 18 (10):  2307-2314.  doi: 10.4103/1673-5374.369122 Abstract ( 145 )   PDF (7140KB) ( 47 )   Save Slit-Robo GTPase-activating protein 2 (SRGAP2) plays important roles in axon guidance, neuronal migration, synapse formation, and nerve regeneration. However, the role of SRGAP2 in neuroretinal degenerative disease remains unclear. In this study, we found that SRGAP2 protein was first expressed in the retina of normal mice at the embryonic stage and was mainly located in the mature retinal ganglion cell layer and the inner nuclear layer. SRGAP2 protein in the retina and optic nerve increased after optic nerve crush. Then, we established a heterozygous knockout (Srgap2+/–) mouse model of optic nerve crush and found that Srgap2 suppression increased retinal ganglion cell survival, lowered intraocular pressure, inhibited glial cell activation, and partially restored retinal function. In vitro experiments showed that Srgap2 suppression activated the mammalian target of rapamycin signaling pathway. RNA sequencing results showed that the expression of small heat shock protein genes (Cryaa, Cryba4, and Crygs) related to optic nerve injury were upregulated in the retina of Srgap2+/– mice. These results suggest that Srgap2 suppression reduced the robust activation of glial cells, activated the mammalian target of rapamycin signaling pathway related to nerve protein, increased the expression of small heat shock protein genes, inhibited the degeneration of retinal ganglion cells, and partially restored optic nerve function.  Related Articles | Metrics

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Adipose mesenchymal stem cell-derived extracellular vesicles reduce glutamate-induced excitotoxicity in the retina Tian-Qi Duan, Zhao-Lin Gao, Ai-Xiang Luo, Dan Chen, Jian-Bin Tong, Ju-Fang Huang 2023, 18 (10):  2315-2320.  doi: 10.4103/1673-5374.369123 Abstract ( 211 )   PDF (2221KB) ( 106 )   Save Adipose mesenchymal stem cells (ADSCs) have protective effects against glutamate-induced excitotoxicity, but ADSCs are limited in use for treatment of optic nerve injury. Studies have shown that the extracellular vesicles (EVs) secreted by ADSCs (ADSC-EVs) not only have the function of ADSCs, but also have unique advantages including non-immunogenicity, low probability of abnormal growth, and easy access to target cells. In the present study, we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography. In addition, R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium, downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) subunit GluA2, and phosphorylation of GluA2 and protein kinase C alpha in vitro. A protein kinase C alpha agonist, 12-O-tetradecanoylphorbol 13-acetate, inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells. These findings suggest that ADSC-EVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.  Related Articles | Metrics