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15 August 2023, Volume 18 Issue 8 Previous Issue   

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Autophagy regulation combined with stem cell therapy for treatment of spinal cord injury Yao Shen, Yi-Piao Wang, Xin Cheng, Xuesong Yang, Guang Wang 2023, 18 (8):  1629-1636.  doi: 10.4103/1673-5374.363189 Abstract ( 141 )   PDF (3638KB) ( 98 )   Save Stem cells are a group of cells with unique self-renewal and differentiation abilities that have great prospects in the repair of spinal cord injury. However, stem cell renewal and differentiation require strict control of protein turnover in the stem cells to achieve cell remodeling. As a highly conserved “gatekeeper” of cell homeostasis, autophagy can regulate cell remodeling by precisely controlling protein turnover in cells. Recently, it has been found that the expression of autophagy markers changes in animal models of spinal cord injury. Therefore, understanding whether autophagy can affect the fate of stem cells and promote the repair of spinal cord injury is of considerable clinical value. This review expounds the importance of autophagy homeostasis control for the repair of spinal cord injury from three aspects—pathophysiology of spinal cord injury, autophagy and stem cell function, and autophagy and stem cell function in spinal cord injury—and proposes the synergistic therapeutic effect of autophagy and stem cells in spinal cord injury. Related Articles | Metrics

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FcRn inhibitors: a novel option for the treatment of myasthenia gravis Li-Na Zhu, Hai-Man Hou, Sai Wang, Shuang Zhang, Ge-Ge Wang, Zi-Yan Guo, Jun Wu 2023, 18 (8):  1637-1344.  doi: 10.4103/1673-5374.363824 Abstract ( 225 )   PDF (2454KB) ( 116 )   Save Myasthenia gravis is an acquired, humoral immunity-mediated autoimmune disease characterized by the production of autoantibodies that impair synaptic transmission at the neuromuscular junction. The intervention-mediated clearance of immunoglobulin G (IgG) was shown to be effective in controlling the progression of the disease. The neonatal Fc receptor (FcRn) plays a key role in prolonging the serum half-life of IgG. Antagonizing FcRn to prevent its binding to IgG can accelerate the catabolism of the latter, resulting in decreased levels of IgG, including pathogenic autoantibodies, thereby achieving a therapeutic effect. In this review, we detail the substantial research progress, both basic and clinical, relating to the use of FcRn inhibitors in the treatment of myasthenia gravis. Related Articles | Metrics

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Mesenchymal stem cell- and extracellular vesicle-based therapies for Alzheimer’s disease: progress, advantages, and challenges Renata Guedes de Jesus Gonçalves, Juliana Ferreira Vasques, Almir Jordão da Silva-Junior, Fernanda Gubert, Rosalia Mendez-Otero 2023, 18 (8):  1645-1651.  doi: 10.4103/1673-5374.361546 Abstract ( 116 )   PDF (2837KB) ( 101 )   Save Alzheimer’s disease is a severe, highly disabling neurodegenerative disease, clinically characterized by a progressive decline in cognitive functions, and is the most common form of dementia in the elderly. For decades, the search for disease-modifying therapies has focused on the two main Alzheimer’s disease histopathological hallmarks, seeking to prevent, mitigate, or clear the formation of extracellular aggregates of β-amyloid peptide and intracellular neurofibrillary tangles of tau protein, although without clinical success. Mesenchymal stem cell-based therapy has emerged as a promising alternative for the treatment of Alzheimer’s disease, especially because it also targets other crucial players in the pathogenesis of the disease, such as neuroinflammation, synaptic dysfunction/loss, oxidative stress, and impaired neurogenesis. Herein, we review current knowledge of the therapeutic potential of mesenchymal stem cells and their extracellular vesicles for Alzheimer’s disease, discussing the most recent findings in both preclinical and clinical trials as well as how advanced technologies have helped to overcome some limitations and contributed to stimulate the development of more effective treatments. Related Articles | Metrics

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The transient receptor potential melastatin 2: a new therapeutical target for Parkinson’s disease? Ana Flávia F. Ferreira, Luiz Roberto G. Britto 2023, 18 (8):  1652-1656.  doi: 10.4103/1673-5374.360343 Abstract ( 86 )   PDF (17449KB) ( 28 )   Save The transient receptor potential melastatin 2 is a calcium-permeable cation channel member of the TRP family. Also known as an oxidative stress-activated channel, the transient receptor potential melastatin 2 gating mechanism is dependent on reactive oxygen species. In pathological conditions, transient receptor potential melastatin 2 is overactivated, leading to a Ca2+ influx that alters cell homeostasis and promotes cell death. The role of transient receptor potential melastatin 2 in neurodegenerative diseases, including Alzheimer’s disease and ischemia, has already been described and reviewed. However, data on transient receptor potential melastatin 2 involvement in Parkinson’s disease pathology has emerged only in recent years and the issue lacks review studies that focus specifically on this topic. The present review aims to elucidate the role of the transient receptor potential melastatin 2 channel in Parkinson’s disease by reviewing, summarizing, and discussing the in vitro, in vivo, and human studies published until August 2022. Here we describe fourteen studies that evaluated the transient receptor potential melastatin 2 channel in Parkinson’s disease. The Parkinson’s disease model used, transient receptor potential melastatin 2 antagonist and genetic approaches, and the main outcomes reported were discussed. The studies described transient receptor potential melastatin 2 activation and enhanced expression in different Parkinson’s disease models. They also evidenced protective and restorative effects when using transient receptor potential melastatin 2 antagonists, knockout, or silencing. This review provides a literature overview and suggests where there is a need for more research. As a perspective point, this review shows evidence that supports transient receptor potential melastatin 2 as a pharmacological target for Parkinson’s disease in the future.  Related Articles | Metrics

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Mesenchymal stem cell-derived exosomes regulate microglia phenotypes: a promising treatment for acute central nervous system injury Yu-Yan Liu, Yun Li, Lu Wang, Yan Zhao, Rui Yuan, Meng-Meng Yang, Ying Chen, Hao Zhang, Fei-Hu Zhou, Zhi-Rong Qian, Hong-Jun Kang 2023, 18 (8):  1657-1665.  doi: 10.4103/1673-5374.363819 Abstract ( 301 )   PDF (4327KB) ( 183 )   Save There is growing evidence that long-term central nervous system (CNS) inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression. In acute CNS injury, brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration. However, microglial activation can also impede CNS repair and amplify tissue damage, and phenotypic transformation may be responsible for this dual role. Mesenchymal stem cell (MSC)-derived exosomes (Exos) are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties. MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis. MSC-Exos can be neuroprotective in several acute CNS models, including for stroke and traumatic brain injury, showing great clinical potential. This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury. Finally, this review explored the potential mechanisms and factors associated with MSC-Exos in modulating the phenotypic balance of microglia, focusing on the interplay between CNS inflammation, the brain, and injury aspects, with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury. Related Articles | Metrics

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The role of monocytes in optic nerve injury Xiangxiang Liu, Yuan Liu, Mohamed M. Khodeiry, Richard K. Lee 2023, 18 (8):  1666-1671.  doi: 10.4103/1673-5374.363825 Abstract ( 95 )   PDF (2985KB) ( 49 )   Save Monocytes, including monocyte-derived macrophages and resident microglia, mediate many phases of optic nerve injury pathogenesis. Resident microglia respond first, followed by infiltrating macrophages which regulate neuronal inflammation, cell proliferation and differentiation, scar formation and tissue remodeling following optic nerve injury. However, microglia and macrophages have distinct functions which can be either beneficial or detrimental to the optic nerve depending on the spatial context and temporal sequence of their activity. These divergent effects are attributed to pro- and anti-inflammatory cytokines expressed by monocytes, crosstalk between monocyte and glial cells and even microglia-macrophage communication. In this review, we describe the dynamics and functions of microglia and macrophages in neuronal inflammation and regeneration following optic nerve injury, and their possible role as therapeutic targets for axonal regeneration. Related Articles | Metrics

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Immortalized hippocampal astrocytes from 3xTg-AD mice, a new model to study disease-related astrocytic dysfunction: a comparative review Laura Tapella, Giulia Dematteis, Armando A Genazzani, Massimiliano De Paola, Dmitry Lim 2023, 18 (8):  1672-1678.  doi: 10.4103/1673-5374.363192 Abstract ( 115 )   PDF (2578KB) ( 127 )   Save Alzheimer’s disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD, emphasizing the urgent need for a comprehensive understanding of cell-specific pathology. Astrocytes, principal homeostatic cells of the central nervous system, are key players in the pathogenesis of neurodegenerative diseases, including AD. Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways. Tumor-derived and immortalized astrocytic cell lines, alongside the emerging technology of adult induced pluripotent stem cells, are widely used to study cellular dysfunction in AD. Surprisingly, no stable cell lines were available from genetic mouse AD models. Recently, we established immortalized hippocampal astroglial cell lines from amyloid-β precursor protein/presenilin-1/Tau triple-transgenic (3xTg)-AD mice (denominated as wild type (WT)- and 3Tg-iAstro cells) using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection, thereby maintaining natural heterogeneity of primary cultures. Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling, mitochondrial dysfunctions, disproteostasis, altered homeostatic and signaling support to neurons, and blood-brain barrier models. Here we provide a comparative overview of the most used models to study astrocytes in vitro, such as primary culture, tumor-derived cell lines, immortalized astroglial cell lines, and induced pluripotent stem cell-derived astrocytes. We conclude that immortalized WT- and 3Tg-iAstro cells provide a non-competitive but complementary, low-cost, easy-to-handle, and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery. Related Articles | Metrics

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Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials Bruno P. Imbimbo, Viviana Triaca, Camillo Imbimbo, Robert Nisticò 2023, 18 (8):  1679-1683.  doi: 10.4103/1673-5374.363185 Abstract ( 92 )   PDF (4712KB) ( 59 )   Save We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson’s disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer’s disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington’s disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson’s disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants. Related Articles | Metrics

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The role of purinergic receptors in neural repair and regeneration after spinal cord injury Rui-Dong Cheng, Wen Ren, Ben-Yan Luo, Xiang-Ming Ye 2023, 18 (8):  1684-1690.  doi: 10.4103/1673-5374.363186 Abstract ( 109 )   PDF (971KB) ( 70 )   Save Spinal cord injury is a serious injury of the central nervous system that results in neurological deficits. The pathophysiological mechanisms underlying spinal cord injury, as well as the mechanisms involved in neural repair and regeneration, are highly complex. Although there have been many studies on these mechanisms, there is no effective intervention for such injury. In spinal cord injury, neural repair and regeneration is an important part of improving neurological function after injury, although the low regenerative ability of nerve cells and the difficulty in axonal and myelin regeneration after spinal cord injury hamper functional recovery. Large amounts of ATP and its metabolites are released after spinal cord injury and participate in various aspects of functional regulation by acting on purinergic receptors which are widely expressed in the spinal cord. These processes mediate intracellular and extracellular signalling pathways to improve neural repair and regeneration after spinal cord injury. This article reviews research on the mechanistic roles of purinergic receptors in spinal cord injury, highlighting the potential role of purinergic receptors as interventional targets for neural repair and regeneration after spinal cord injury. Related Articles | Metrics

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Role of vascular endothelial growth factor as a critical neurotrophic factor for the survival and physiology of motoneurons Paula M. Calvo#, Rosendo G. Hernández#, Rosa R. de la Cruz, Angel M. Pastor 2023, 18 (8):  1691-1696.  doi: 10.4103/1673-5374.363194 Abstract ( 142 )   PDF (2274KB) ( 62 )   Save Vascular endothelial growth factor (VEGF) was discovered by its angiogenic activity. However, during evolution, it appeared earlier as a neurotrophic factor required for the development of the nervous system in invertebrates lacking a circulatory system. We aimed at reviewing recent evidence indicating that VEGF has neuroprotective effects in neurons exposed to a variety of insults. Of particular interest is the link established between VEGF and motoneurons, especially after the design of the VEGFδ/δ  mutant mice. These mice are characterized by low levels of VEGF and develop muscle weakness and motoneuron degeneration resembling amyotrophic lateral sclerosis. The administration of VEGF through several routes to animal models of amyotrophic lateral sclerosis delays motor impairment and motoneuron degeneration and increases life expectancy. There are new recent advances in the role of VEGF in the physiology of motoneurons. Our experimental aims use the extraocular (abducens) motoneurons lesioned by axotomy as a model for studying VEGF actions. Axotomized abducens motoneurons exhibit severe alterations in their discharge activity and a loss of synaptic boutons. The exogenous administration of VEGF to axotomized abducens motoneurons, either from the transected nerve or intraventricularly, fully restores the synaptic and discharge properties of abducens motoneurons, despite being axotomized. In addition, when an anti-VEGF neutralizing antibody is delivered from the muscle to intact, uninjured abducens motoneurons, these cells display alterations in their discharge pattern and a loss of synaptic boutons that resemble the state of axotomy. All these data indicate that VEGF is an essential neurotrophic factor for motoneurons. Related Articles | Metrics

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Prenatal and postnatal drug exposure: focus on persistent central effects Giulia Costa, Alexia E. Pollack 2023, 18 (8):  1697-1702.  doi: 10.4103/1673-5374.363190 Abstract ( 88 )   PDF (1032KB) ( 68 )   Save Clinical studies indicate significant use of prescription, nonprescription and social/recreational drugs by women during pregnancy; however, limited knowledge exists about the detrimental effects that this practice may have on the developing central nervous system of the fetus. Importantly, few experimental and clinical data are available on how gestational exposure could exacerbate the effects of the same or a different drug consumed by the offspring later in life. The present review summarizes recent findings on the central toxicity elicited by several classes of drugs, administered prenatally and postnatally in experimental animals and humans, focusing on prescription and nonprescription analgesics, anti-inflammatory agents, alcohol and nicotine. Related Articles | Metrics

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Overcoming axon regeneration failure and psychopathology: how may gabapentinoids help boost CNS repair? Haven I. Rodocker, Andrea Tedeschi 2023, 18 (8):  1703-1704.  doi: 10.4103/1673-5374.361668 Abstract ( 88 )   PDF (475KB) ( 69 )   Save Spinal cord injury (SCI) at the cervical level compromises the function of both upper and lower extremities, thereby impeding an individual’s ability to complete daily tasks required for independent living and profoundly affecting the overall quality of life among individuals afflicted by SCI and their families. Recovery of spinal cord functions may be attained by promoting the sprouting of non-injured axons and/or the regeneration of damaged axons. The regenerative capacity of neurons differs profoundly between animal lineages and within the mammalian central and peripheral nervous systems (Tedeschi et al., 2017). Whereas axons in the peripheral nervous system are able to mount a successful regenerative response after injury, long-distance axon regeneration fails in the adult mammalian central nervous system. To date, no therapeutic strategy that aims to restore function is currently available for SCI individuals. Related Articles | Metrics

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Neuroplastin in Ca2+ signal regulation and plasticity of glutamatergic synapses Ayse Malci, Xiao Lin, Yun Stone Shi, Rodrigo Herrera-Molina 2023, 18 (8):  1705-1706.  doi: 10.4103/1673-5374.363826 Abstract ( 84 )   PDF (2069KB) ( 53 )   Save The main function of neurons is information transmission in the form of action potentials. To fulfill this duty, neurons are connected functionally with each other via synapses, the microscopic structures where specialized molecular machinery is strategically placed to release and receive neurotransmitters and to generate and extinguish calcium (Ca2+) signals. These synaptic molecular components are highly dynamic and they influence each other to confer structural and functional adaptability (plasticity) to neuronal communication (Biederer et al., 2017). Recently, neuroplastin (Np), a cell recognition molecule, has emerged to play diverse neuronal functions including synapse formation, spine structure, Ca2+ signal regulation, excitatory/inhibitory balance, and synaptic plasticity. Evidence from different labs has converged to form a coherent picture; however, the uncovered mechanisms may represent only the tip of Np’s iceberg. Many questions remain to be answered. For example, why do neurons need two Np isoforms? How do Np isoforms contribute to Ca2+ signal regulation and synaptic plasticity? Related Articles | Metrics

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Gut microbiota neurotransmitters: influence on risk and outcome of ischemic stroke Ryszard Pluta, Sławomir Januszewski 2023, 18 (8):  1707-1708.  doi: 10.4103/1673-5374.363829 Abstract ( 105 )   PDF (339KB) ( 46 )   Save Ischemic stroke: Stroke is the second and third cause of death and disability, respectively, with an annual rate of 24.9 million cases worldwide (Chidambaram et al., 2022). Stroke is defined as the lack of blood supply to a specific area of the brain, accounting for 85% of all cases (Chidambaram et al., 2022). Changes in the gut microbiota have also been reported as risk factor for stroke (Pluta et al., 2021; Tan et al., 2021; Chidambaram et al., 2022). Post-stroke neurodegeneration is multifactorial characterized by neuronal death, amyloid plaques, neurofibrillary tangles, a neuroinflammatory response, a lack of acetylcholine, and a cognitive deficit with full-blown dementia (approximately 50% survivors) (Yuan et al., 2020; Pluta 2022). Related Articles | Metrics

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Augmentation of transforming growth factor-β signaling for the treatment of neurological disorders Jian Luo 2023, 18 (8):  1711-1712.  doi: 10.4103/1673-5374.363833 Abstract ( 136 )   PDF (1165KB) ( 36 )   Save Members of the transforming growth factor-β (TGF-β) superfamily perform a wide range of essential functions during development and in adulthood, as well as in response to injury and inflammation (Luo, 2022). In the adult central nervous system, TGF-βs and their receptors are widely expressed in all of the major neuronal, glial, and vascular cell types. Members of the TGF-β superfamily are pivotal responders to pathological insults to the brain. Dysfunction of TGF-β signaling contributes to pathogenesis of neurological disorders. Manipulation of TGF-β signaling pathway alters pathological and functional outcomes in models of neurological diseases (Luo, 2022). Therefore, the TGF-β signaling pathway has emerged as a potential therapeutic target against neurological diseases. Related Articles | Metrics

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Therapeutic potential of lysosomal cathepsins for neurodegenerative diseases Susy Prieto Huarcaya, Friederike Zunke 2023, 18 (8):  1713-1714.  doi: 10.4103/1673-5374.363181 Abstract ( 112 )   PDF (548KB) ( 54 )   Save Lysosomes are ubiquitous and dynamic organelles with a central role in degradation and recycling of damaged cell components and misfolded proteins, otherwise known as autophagy. Autophagy plays a fundamental role in the process of correcting cell homeostasis and cellular survival. Unsurprisingly, this process is essential in the central nervous system, as neurons are not able to easily eliminate altered proteins given their post-mitotic state. Thus, lysosomal function is critical in maintaining neuronal health. Interestingly, increasing evidence suggests that impaired autophagy underlies several neurodegenerative diseases. Genetic deletion of key components of the autophagy machinery results in the accumulation of protein aggregates and subsequent neuropathologies. Moreover, some genetic variants found in lysosomal storage disorders (LSDs), which can also be hallmarked by neuronal degeneration, have been implicated as risk factors for Alzheimer’s disease (AD), Parkinson’s disease (PD) and others. Specifically, deficiency in the cathepsin family of lysosomal proteases, which play a vital role in the clearance of aggregation-prone proteins, such as alpha-synuclein (αSyn), amyloid β peptide, and saposins C (SapC) and D (SapD), seems to contribute to neuropathogenesis. Hence, targeting lysosomal function represents a novel therapeutic approach for tackling neurodegeneration.  Related Articles | Metrics

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Neurovascular unit permeability in neuroinflammatory diseases: a common pathologic and therapeutic target? Molly Monsour, Cesar V. Borlongan 2023, 18 (8):  1715-1716.  doi: 10.4103/1673-5374.363197 Abstract ( 89 )   PDF (495KB) ( 34 )   Save Deleterious inflammatory cell invasion has been implicated in neurological diseases, partly manifesting as a leaky blood-central nervous system barrier (BCNSB) (Huang et al., 2021). Uncovering the perturbations of the neurovascular unit (NVU) may reveal the role of detrimental pro-inflammatory cells and signaling molecules in disrupting the central nervous system immune-privileged environment. The NVU includes the central nervous system, BCNSB, and surrounding vasculature, allowing for a tightly modulated exchange of oxygen and nutrients, while prohibiting unwanted peripheral signals (Iadecola, 2017). The protective properties of the NVU are reliant upon functional neurons, glial cells, endothelial cells, vascular smooth muscle cells, pericytes, and a basement membrane (Monsour et al., 2022). In numerous brain disease processes, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease (PD), ischemic stroke, and traumatic brain injury (TBI), the components of the NVU and their functions are impaired, resulting in a leaky BCNSB permitting inflammatory cell entry into the central nervous system (Table 1 and Figure 1).  Related Articles | Metrics

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Brain network correlates of epilepsy occurrence in multiple sclerosis and neuroinflammation Dumitru Ciolac, Gabriel Gonzalez-Escamilla, Yaroslav Winter, Vinzenz Fleischer, Matthias Grothe, Sergiu Groppa 2023, 18 (8):  1717-1718.  doi: 10.4103/1673-5374.363188 Abstract ( 84 )   PDF (1459KB) ( 40 )   Save Multiple sclerosis (MS), the most common inflammatory condition of the central nervous system in young adults, is characterized by immune-mediated demyelination and neurodegeneration that translate into heterogeneous clinical phenotypes and disease trajectories. Although focal demyelinating lesions within the white matter are the hallmark of MS pathology, a large amount of lesions has been detected in both cortical and subcortical grey matter tissue. Besides focal pathology, diffuse inflammation and axonal damage are increasingly recognized in normal appearing white matter, as well as grey matter. Among various clinical manifestations, patients with MS may experience epileptic seizures, which can emerge at any time point throughout the disease course. Several clinical factors such as earlier onset of MS, longer disease duration, and higher disability have been related to the increased prevalence of epilepsy in patients with MS (Neuß et al., 2020; Grothe et al., 2021). Acute seizures and epilepsy were also reported in other neuroinflammatory disorders of the central nervous system, e.g., in myelin oligodendrocyte glycoprotein antibody disease, acute disseminated encephalomyelitis or neuromyelitis optica spectrum disorder. A few available neuroimaging and neuropathological studies suggested that the extent of cortical grey matter damage is proportional to the risk of epilepsy occurrence in patients with MS (Calabrese et al., 2012; Nicholas et al., 2016). However, despite the significant progress achieved in elucidating the molecular and cellular basis of MS pathology, mechanisms of increased susceptibility to seizure generation in acute and chronic neuroinflammation are poorly understood, thereby, leaving many questions open. Only a few to list: what are the brain structural fingerprints of epileptic seizures in MS? Is the location of tissue damage within a particular brain region (e.g., hippocampus or thalamus) is critical for initiating epilepsy? Is there a specific “network correlate” of hyperexcitable neuronal circuits and do they render networks vulnerable to ongoing MS-mediated damage? And finally, what are the main “culprit mechanisms” responsible for ictogenesis and epileptogenesis in MS? Based on the aforementioned questions, the overarching aim of this perspective article was to portray the brain network correlates of epilepsy occurrence in MS. First, we describe structural abnormalities of brain tissue associated with a higher susceptibility of epilepsy occurrence. Afterwards, we highlight the network alterations that are linked to epileptogenesis in patients with MS and explain the candidate molecular mechanisms underlying network hyperexcitability. Finally, we provide a conceptual background for future studies.    Related Articles | Metrics

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Oxidative stress in N88S seipinopathy: novel insights into the mechanisms of neurodegeneration and therapeutic avenues Vítor Costa, Vitor Teixeira 2023, 18 (8):  1719-1720.  doi: 10.4103/1673-5374.363196 Abstract ( 65 )   PDF (523KB) ( 48 )   Save Lipid droplets (LDs) are ubiquitous cellular organelles that perform functions mostly dedicated to energy homeostasis and lipid metabolism. As neutral lipid depots (triacylglycerol, sterol esters), they can be rapidly mobilized through lipase-mediated hydrolysis (lipolysis) or via lipophagy, a specific form of autophagy devoted to consumption of LDs inside the lysosome. These processes usually reflect adaptation to changes in nutrient availability and membrane buildup during active growth. LDs also contribute to buffering of unsaturated fatty acids, and prevent cellular accumulation of oxidized and peroxidized lipids, thereby providing immediate protection against lipotoxicity and oxidative stress.  Related Articles | Metrics

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Is EAAT2 a potential  therapeutic intervention target for Alzheimer’s disease? Oliver WG Wood, Jason HY Yeung, Andrea Kwakowsky 2023, 18 (8):  1721-1722.  doi: 10.4103/1673-5374.363834 Abstract ( 106 )   PDF (553KB) ( 51 )   Save Alzheimer’s disease (AD) is the most common form of dementia worldwide, impairing memory and cognitive functions due to widespread neuronal death. The global incidence of this neurodegenerative disorder is predicted to increase rapidly in the near future. This growth in prevalence of AD will create a large burden for health systems worldwide. Further research into new therapeutic avenues is therefore crucial, given the extremely limited treatment options currently available for AD. The dysfunction and aggregation of two proteins, amyloid-beta (Aβ) and tau, are typically considered the main pathological hallmarks that cause neuronal death in AD. However, numerous other cellular alterations occur, one of which is extensive damage to neurotransmitter systems. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is responsible for the vast majority of excitatory neuron-to-neuron communication throughout the brain. Various receptors, enzymes, and transporters function together in a well-orchestrated manner to ensure glutamatergic homeostasis. The proper regulation of this system is critical for a normal cellular physiological state, given excess activation of glutamatergic postsynaptic receptors can cause glutamate excitotoxicity, which is heavily implicated in the pathogenesis of AD (Han et al., 2016; Yeung et al., 2021). Related Articles | Metrics

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Targeting chaperone-mediated autophagy for Parkinson’s disease therapy Yi-Ting Wang, Jia-Hong Lu 2023, 18 (8):  1723-1724.  doi: 10.4103/1673-5374.363831 Abstract ( 135 )   PDF (3087KB) ( 74 )   Save Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. Epidemiological projections for the global incidence of PD indicate that the number of people with PD might approach 12 million by 2040 (Adrissi and Fleisher, 2022). PD clinical symptoms include bradykinesia, resting tremors, rigidity, and non-motor symptoms such as depression, autonomic dysfunctions, sensory impairments, and sleep disruptions. The neuropathologies of PD are the continuous loss of dopaminergic neurons in the middle brain substantia nigra pars compacta and the accumulation of Lewy bodies which are mainly composed of fibrillar α-synuclein aggregates in neuronal somata. There is growing evidence showing that autophagy is a critical avenue for regulating PD pathogenesis. In 2004, mutant α-synuclein blocked chaperone-mediated autophagy (CMA) demonstrated the first connection between CMA malfunction and PD (Cuervo et al., 2004).   Related Articles | Metrics

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Cell senescence, loss of splicing, and lipid metabolism in TDP-43-related neurodegenerative processes Pascual Torres, Reinald Pamplona, Manuel Portero-Otin 2023, 18 (8):  1725-1726.  doi: 10.4103/1673-5374.363832 Abstract ( 106 )   PDF (317KB) ( 52 )   Save In recent work, we have shown that cell senescence of mouse fibroblasts in vitro associates with a build-up of cryptic exons in selected mRNAs, whose level is usually controlled by the activity of TAR DNA binding protein of 43 kDa (Tdp-43) (Torres et al., 2022). In vivo, we also found traits of cell senescence in the motor neuron disease model achieved by overexpressing SOD-G93A, the SOD1 gene (harboring a single amino acid substitution of glycine to alanine at codon 93). These mice express an age-related increase in the p21 and p16 mRNA levels, with enhanced protein levels of codified proteins in the cytosol of several cells present in the lumbar spinal cords of the model. Most cells showing increased p16 immunoreactivity were identified as astrocytes and microglia, with neuronal cells relatively spared from this senescence biomarker’s build-up. In addition to increased signs of replicative senescence (increased p16 and p21 expression), these mice also exhibit some characteristics related to senescence-associated secretory profile, such as increased levels of interleukin-6, and interleukin-1a, in a sex-specific manner. We qualify the cellular senescence in this model as atypical, as we were not able to significantly change the motor phenotype by treatment of anti-BCL2-BCLx antagonist, Navitoclax®, whose use has been beneficial in other preclinical models of age-related neurodegenerative diseases, such as Alzheimer’s disease. Of note, reinforcing the complexity of senolytical approaches, in vitro treatments of fibroblasts employing a quercetin-dasatinib® (but not Navitoclax®) combinations were able to abolish the senescence-associated build-up of p16 and p21 (Torres et al., 2022). These results suggest the importance of glial cell senescence in the association between aging and selective neuron demise. Disease-specific reactive astrocytosis secondary to neuron loss and astrocytopathy due to intrinsic alterations of astrocytes occur in neurodegenerative diseases, overlap each other, and, together with astrocyte senescence, contribute to disease-specific astrogliopathy in aging and neurodegenerative diseases with abnormal protein aggregates in old age, including amyotrophic lateral sclerosis (ALS). In addition to the well-known increase in glial fibrillary acidic protein and other proteins in reactive astrocytes, astrocytopathy is evidenced by the deposition of abnormal proteins and could contribute to neuronal loss, either by losing homeostatic support functions or by acting as sources of noxious agents towards neurons (Ferrer, 2017). Related Articles | Metrics

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Trick or treat? Does cancer fool Schwann cells by mimicking axons to promote metastasis into nerves? Peter Arthur-Farraj 2023, 18 (8):  1727-1727.  doi: 10.4103/1673-5374.361669 Abstract ( 84 )   PDF (1029KB) ( 72 )   Save The Schwann cell reaction to nerve injury, termed the repair program, is crucial to successful nerve regeneration. Over the last decade, substantial advances have been made in elucidating the underlying molecular mechanisms in Schwann cells that lead to functional nerve repair. Moreover, the field has identified situations, such as aging and chronic denervation where these mechanisms go awry, paving the way for the development of therapeutic interventions (Arthur-Farraj and Coleman, 2021; Cattin and Lloyd, 2016; Jessen and Mirsky, 2019). A recent article by Deborde et al. (2022) has demonstrated that unfortunately there is a downside to Schwann cells having such an efficient regeneration-promoting program; the promotion of tumor invasion of peripheral nerves. Related Articles | Metrics

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Amyotrophic lateral sclerosis disease burden: doing better at getting better Cinzia Volonté, Susanna Amadio 2023, 18 (8):  1728-1729.  doi: 10.4103/1673-5374.363193 Abstract ( 74 )   PDF (506KB) ( 44 )   Save Amyotrophic lateral sclerosis (ALS) is classified as a multigenic, multifactorial, and heterogeneous neurodegenerative/neuroinflammatory disease that slays especially upper and lower motor neurons controlling voluntary muscle activity. After the insurgence that is characterized by typical symptoms such as weakness in the limbs and muscle twitches, the disease rapidly evolves into progressive muscle atrophy, paralysis, and lastly death occurring by respiratory failure usually within 2–4 years of diagnosis. ALS is now understood as a multisystem and broad-spectrum motor neuron disease largely variable in presentation and outcomes, also showing extra-motor deficits such as extrapyramidal, thalamic, cerebellar, and sensory nerve abnormalities, in addition to comorbid cognitive-behavioral instabilities and psychiatric symptoms. Approximately 15% of ALS patients are also reported suffering from frontotemporal dementia. Concomitant immunological irregularities and gut dysbiosis are often observed. The autonomic nervous system is also involved in the disease, since patients die of sudden death when they lose their ability to compensate for cardiorespiratory arrest. It clearly emerges that a disease like ALS impacts multiple systems throughout the body, and it is not just a neurological disorder. Related Articles | Metrics

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Data and subject heterogeneity and data sharing: keys to translational success in spinal cord injury research? Karim Fouad, Olivia H. Wireman, John C. Gensel 2023, 18 (8):  1730-1731.  doi: 10.4103/1673-5374.363191 Abstract ( 102 )   PDF (2139KB) ( 52 )   Save Spinal cord injury (SCI) is a highly devastating and complex injury with many secondary consequences. Finding a treatment for SCI has been a rollercoaster ride through exciting peaks and sobering valleys. As a matter of fact, there are still no robust and reliable clinical treatments to minimize or repair spinal cord damage. The reasons are manifold and in this opinion piece, we will argue that subject heterogeneity and a lack of transparency in reporting findings are potential contributors to the challenge of finding and translating treatments from the bench to the bedside.  Related Articles | Metrics

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Novel neuron-Schwann cell co-culture models to study peripheral nerve degeneration and regeneration Kazunori Sango 2023, 18 (8):  1732-1733.  doi: 10.4103/1673-5374.363195 Abstract ( 218 )   PDF (637KB) ( 98 )   Save Schwann cells are glial cells in the peripheral nervous system that provide trophic support for the growth and maintenance of sensory, motor, and autonomic neurons and ensheath their axons in either a myelinating or an unmyelinating form. Myelinating Schwann cells wrap around large-diameter axons to form multilayered myelin structures essential for the rapid action potential propagation from one node of Ranvier to the next node (saltatory conduction). In contrast, non-myelinating Schwann cells surround several small-diameter axons to form Remak bundles. Following peripheral nerve injury, Schwann cells lose axonal contact and change their phenotype in favor of axonal regeneration and functional restoration. These “de-differentiated” Schwann cells migrate into the site distal to the injury and phagocytose axonal and myelin debris together with macrophages (Wallerian degeneration). Subsequently, they proliferate to constitute the bands of Büngner which act as guideposts for regenerating axons and provide various neurotrophic factors and chemokines that help axonal reinnervation toward target tissues and protect injured neurons from degeneration and cell death. At the final regeneration stage, the “re-differentiated” Schwann cells remyelinate growing large diameter axons or ensheath small diameter axons forming Remak bundles (Sango et al., 2017). Schwann cell abnormalities and/or their crosstalk with neurons lead to demyelinating neuropathy (myelinopathy) development and progression. These deviations are also involved in the manifestations of axons (axonopathy) and neuronal cell bodies (neuronopathy) (Niimi et al., 2019). Related Articles | Metrics

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Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage Bo-Yun Ding, Chang-Nan Xie, Jia-Yu Xie, Zhuo-Wei Gao, Xiao-Wei Fei, En-Hui Hong, Wen-Jin Chen, Yi-Zhao Chen 2023, 18 (8):  1734-1742.  doi: 10.4103/1673-5374.360249 Abstract ( 208 )   PDF (4030KB) ( 89 )   Save Intracerebral hemorrhage is often accompanied by oxidative stress induced by reactive oxygen species, which causes abnormal mitochondrial function and secondary reactive oxygen species generation. This creates a vicious cycle leading to reactive oxygen species accumulation, resulting in progression of the pathological process. Therefore, breaking the cycle to inhibit reactive oxygen species accumulation is critical for reducing neuronal death after intracerebral hemorrhage. Our previous study found that increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH oxidase 4, NOX4) led to neuronal apoptosis and damage to the blood-brain barrier after intracerebral hemorrhage. The purpose of this study was to investigate the role of NOX4 in the circle involving the neuronal tolerance to oxidative stress, mitochondrial reactive oxygen species and modes of neuronal death other than apoptosis after intracerebral hemorrhage. We found that NOX4 knockdown by adeno-associated virus (AAV-NOX4) in rats enhanced neuronal tolerance to oxidative stress, enabling them to better resist the oxidative stress caused by intracerebral hemorrhage. Knockdown of NOX4 also reduced the production of reactive oxygen species in the mitochondria, relieved mitochondrial damage, prevented secondary reactive oxygen species accumulation, reduced neuronal pyroptosis and contributed to relieving secondary brain injury after intracerebral hemorrhage in rats. Finally, we used a mitochondria-targeted superoxide dismutase mimetic to explore the relationship between reactive oxygen species and NOX4. The mitochondria-targeted superoxide dismutase mimetic inhibited the expression of NOX4 and neuronal pyroptosis, which is similar to the effect of AAV-NOX4. This indicates that NOX4 is likely to be an important target for inhibiting mitochondrial reactive oxygen species production, and NOX4 inhibitors can be used to alleviate oxidative stress response induced by intracerebral hemorrhage. Related Articles | Metrics

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Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke Xiu-De Qin, Tai-Qin Yang, Jing-Hui Zeng, Hao-Bin Cai, Shao-Hua Qi, Jian-Jun Jiang, Ying Cheng, Long-Sheng Xu, Fan Bu 2023, 18 (8):  1743-1749.  doi: 10.4103/1673-5374.363836 Abstract ( 214 )   PDF (4192KB) ( 54 )   Save Ischemic stroke can cause blood-brain barrier (BBB) injury, which worsens brain damage induced by stroke. Abnormal expression of tight junction proteins in endothelial cells (ECs) can increase intracellular space and BBB leakage. Selective inhibition of mitogen-activated protein kinase, the negative regulatory substrate of mitogen-activated protein kinase phosphatase (MKP)-1, improves tight junction protein function in ECs, and genetic deletion of MKP-1 aggravates ischemic brain injury. However, whether the latter affects BBB integrity, and the cell type-specific mechanism underlying this process, remain unclear. In this study, we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke. We found that overexpression of MKP-1 in ECs reduced infarct volume, reduced the level of inflammatory factors interleukin-1β, interleukin-6, and chemokine C-C motif ligand-2, inhibited vascular injury, and promoted the recovery of sensorimotor and memory/cognitive function. Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase (ERK) 1/2 and the downregulation of occludin expression. Finally, to investigate the mechanism by which MKP-1 exerted these functions in ECs, we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose, and pharmacologically inhibited the activity of MKP-1 and ERK1/2. Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death, cell monolayer leakage, and downregulation of occludin expression, and that inhibiting ERK1/2 can reverse these effects. In addition, co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2. These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2, thereby protecting the integrity of BBB, alleviating brain injury, and improving post-stroke prognosis.   Related Articles | Metrics

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Piezo1 suppression reduces demyelination after intracerebral hemorrhage Jie Qu, Hang-Fan Zong, Yi Shan, Shan-Chun Zhang, Wei-Ping Guan, Yang Yang, Heng-Li Zhao 2023, 18 (8):  1750-1756.  doi: 10.4103/1673-5374.361531 Abstract ( 186 )   PDF (17723KB) ( 55 )   Save Piezo1 is a mechanically-gated calcium channel. Recent studies have shown that Piezo1, a mechanically-gated calcium channel, can attenuate both psychosine- and lipopolysaccharide-induced demyelination. Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage, in this study, we investigated the role of Piezo1 in intracerebral hemorrhage. We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon (within 48 hours) after intracerebral hemorrhage, primarily in oligodendrocytes. Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema, myelin sheath loss, and degeneration in injured tissue, a substantial reduction in oligodendrocyte apoptosis, and a significant improvement in neurological function. In addition, we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway. These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage, as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath, thereby improving neuronal function after intracerebral hemorrhage.  Related Articles | Metrics

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Alzheimer’s disease with sleep insufficiency: a cross-sectional study on correlations among clinical characteristics, orexin, its receptors, and the blood-brain barrier Peng Guo, Wen-Jing Zhang, Teng-Hong Lian, Wei-Jiao Zhang, Ming-Yue He, Ya-Nan Zhang, Yue Huang, Du-Yu Ding, Hui-Ying Guan, Jing-Hui Li, Dan-Ning Li, Dong-Mei Luo, Wei-Jia Zhang, Hao Yue, Xiao-Min Wang, Wei Zhang 2023, 18 (8):  1757-1762.  doi: 10.4103/1673-5374.360250 Abstract ( 145 )   PDF (592KB) ( 34 )   Save Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimer’s disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimer’s disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer’s disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimer’s disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups: those with insufficient sleep (sleep duration ≤ 6 hours, n = 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n = 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood–brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimer’s disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimer’s disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer’s disease. Related Articles | Metrics

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Sphingosine 1-phosphate receptor 1 regulates blood-brain barrier permeability in epileptic mice Li-Xiang Yang, Yuan-Yuan Yao, Jiu-Rong Yang, Hui-Lin Cheng, Xin-Jian Zhu, Zhi-Jun Zhang 2023, 18 (8):  1763-1769.  doi: 10.4103/1673-5374.360263 Abstract ( 126 )   PDF (4682KB) ( 172 )   Save Destruction of the blood-brain barrier is a critical component of epilepsy pathology. Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity. However, its effect on blood-brain barrier permeability in epileptic mice remains unclear. In this study, we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice. S1P1 expression was increased in the hippocampus after status epilepticus, whereas tight junction protein expression was decreased in epileptic mice compared with controls. Intraperitoneal injection of SEW2871, a specific agonist of sphingosine-1-phosphate receptor 1, decreased the level of tight junction protein in the hippocampus of epileptic mice, increased blood-brain barrier leakage, and aggravated the severity of seizures compared with the control. W146, a specific antagonist of sphingosine-1-phosphate receptor 1, increased the level of tight junction protein, attenuated blood-brain barrier disruption, and reduced seizure severity compared with the control. Furthermore, sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1β and tumor necrosis factor-α and caused astrocytosis. Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline, a neuroinflammation inhibitor. Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors. Additionally, specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage, seizure severity, and epilepsy-associated depression-like behaviors. Taken together, our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.  Related Articles | Metrics

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Microglia and astrocytes mediate synapse engulfment in a MER tyrosine kinase-dependent manner after traumatic brain injury Hui Shen, Xiao-Jing Shi, Lin Qi, Cheng Wang, Muyassar Mamtilahun, Zhi-Jun Zhang, Won-Suk Chung, Guo-Yuan Yang, Yao-Hui Tang 2023, 18 (8):  1770-1776.  doi: 10.4103/1673-5374.363187 Abstract ( 112 )   PDF (32056KB) ( 32 )   Save Recent studies have shown that microglia/macrophages and astrocytes can mediate synaptic phagocytosis through the MER proto-oncokinase in developmental or stroke models, but it is unclear whether the same mechanism is also active in traumatic brain injury. In this study, we established a mouse model of traumatic brain injury and found that both microglia/macrophages and astrocytes phagocytosed synapses and expression of the MER proto-oncokinase increased 14 days after injury. Specific knockout of MER in microglia/macrophages or astrocytes markedly reduced injury volume and greatly improved neurobehavioral function. In addition, in both microglia/macrophages-specific and astrocytes-specific MER knock-out mice, the number of microglia/macrophage and astrocyte phagocytosing synapses was markedly decreased, and the total number of dendritic spines was increased. Our study suggested that MER proto-oncokinase expression in microglia/macrophages and astrocytes may play an important role in synaptic phagocytosis, and inhibiting this process could be a new strategy for treating traumatic brain injury. Related Articles | Metrics

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Inhibition of Notch 1 signaling in the subacute stage after stroke promotes striatal astrocyte-derived neurogenesis Xiao-Zhu Hao, Cheng-Feng Sun, Lu-Yi Lin, Chan-Chan Li, Xian-Jing Zhao, Min Jiang, Yan-Mei Yang, Zhen-Wei Yao 2023, 18 (8):  1777-1781.  doi: 10.4103/1673-5374.363179 Abstract ( 179 )   PDF (2646KB) ( 149 )   Save Inhibition of Notch1 signaling has been shown to promote astrocyte-derived neurogenesis after stroke. To investigate the regulatory role of Notch1 signaling in this process, in this study, we used a rat model of stroke based on middle cerebral artery occlusion and assessed the behavior of reactive astrocytes post-stroke. We used the γ-secretase inhibitor N-[N-(3,5-diuorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT) to block Notch1 signaling at 1, 4, and 7 days after injury. Our results showed that only administration of DAPT at 4 days after stroke promoted astrocyte-derived neurogenesis, as manifested by recovery of white matter fiber bundle integrity on magnetic resonance imaging, which is consistent with recovery of neurologic function. These findings suggest that inhibition of Notch1 signaling at the subacute stage post-stroke mediates neural repair by promoting astrocyte-derived neurogenesis.  Related Articles | Metrics

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Potential targets and mechanisms of photobiomodulation for spinal cord injury Cheng Ju, Yang-Guang Ma, Xiao-Shuang Zuo, Xuan-Kang Wang, Zhi-Wen Song, Zhi-Hao Zhang, Zhi-Jie Zhu, Xin Li, Zhuo-Wen Liang, Tan Ding, Zhe Wang, Xue-Yu Hu 2023, 18 (8):  1782-1788.  doi: 10.4103/1673-5374.361534 Abstract ( 170 )   PDF (4514KB) ( 70 )   Save As a classic noninvasive physiotherapy, photobiomodulation, also known as low-level laser therapy, is widely used for the treatment of many diseases and has anti-inflammatory and tissue repair effects. Photobiomodulation has been shown to promote spinal cord injury repair. In our previous study, we found that 810 nm low-level laser therapy reduced the M1 polarization of macrophages and promoted motor function recovery. However, the mechanism underlying this inhibitory effect is not clear. In recent years, transcriptome sequencing analysis has played a critical role in elucidating the progression of diseases. Therefore, in this study, we performed M1 polarization on induced mouse bone marrow macrophages and applied low-level laser therapy. Our sequencing results showed the differential gene expression profile of photobiomodulation regulating macrophage polarization. We analyzed these genes using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Networks of protein-protein interactions and competing RNA endogenous networks were constructed. We found that photobiomodulation inhibited STAT3 expression through increasing the expression of miR-330-5p, and that miR-330-5p binding to STAT3 inhibited STAT3 expression. Inducible nitric oxide synthase showed trends in changes similar to the changes in STAT3 expression. Finally, we treated a mouse model of spinal cord injury using photobiomodulation and confirmed that photobiomodulation reduced inducible nitric oxide synthase and STAT3 expression and promoted motor function recovery in spinal cord injury mice. These findings suggest that STAT3 may be a potential target of photobiomodulation, and the miR-330-5p/STAT3 pathway is a possible mechanism by which photobiomodulation has its biological effects. Related Articles | Metrics

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Splenectomy does not affect mouse behaviors Jiao-Qiong Guan, Pei-Sen Zhang, Wen-Chao Zhang, Bing-Qian Zhang, Hai-Tao Wu, Yue Lan, Ti-Fei Yuan 2023, 18 (8):  1789-1794.  doi: 10.4103/1673-5374.360247 Abstract ( 121 )   PDF (14552KB) ( 59 )   Save The spleen is critical for immunity. It is the largest immune organ and immune center in the peripheral system. While the relationship between behavior and immunity has been demonstrated in physiology and diseases, the role of the spleen in behavior is not clear. To investigate the effects of the spleen on behaviors, we performed a refined splenectomy procedure on C57BL/6J mice and performed an open field test, circadian rhythm test, elevated plus maze, sucrose preference test, and Barnes maze test. Splenectomy did not induce changes in general locomotion, circadian rhythms, learning and memory, or depression/anxiety-related behaviors. To further investigate the effects of spleen on stress susceptibility, we established mouse models of depression through chronic unpredictable mild stress. The behavioral performances of mice subjected to splenectomy showed no differences from control animals. These findings suggest that splenectomy does not cause changes in baseline behavioral performance in mice.  Related Articles | Metrics

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Death-associated protein kinase 1 is associated with cognitive dysfunction in major depressive disorder Xiao-Hui Li, Hong-Can Zhu, Xue-Min Cui, Wang Wang, Lin Yang, Li-Bo Wang, Neng-Wei Hu, Dong-Xiao Duan 2023, 18 (8):  1795-1801.  doi: 10.4103/1673-5374.361532 Abstract ( 105 )   PDF (2450KB) ( 82 )   Save We previously showed that death-associated protein kinase 1 (DAPK1) expression is increased in hippocampal tissue in a mouse model of major depressive disorde and is related to cognitive dysfunction in Alzheimer’s disease. In addition, depression is a risk factor for developing Alzheimer’s disease, as well as an early clinical manifestation of Alzheimer’s disease. Meanwhile, cognitive dysfunction is a distinctive feature of major depressive disorder. Therefore, DAPK1 may be related to cognitive dysfunction in major depressive disorder. In this study, we established a mouse model of major depressive disorder by housing mice individually and exposing them to chronic, mild, unpredictable stressors. We found that DAPK1 and tau protein levels were increased in the hippocampal CA3 area, and tau was hyperphosphorylated at Thr231, Ser262, and Ser396 in these mice. Furthermore, DAPK1 shifted from axonal expression to overexpression on the cell membrane. Exercise and treatment with the antidepressant drug citalopram decreased DAPK1 expression and tau protein phosphorylation in hippocampal tissue and improved both depressive symptoms and cognitive dysfunction. These results indicate that DAPK1 may be a potential reason and therapeutic target of cognitive dysfunction in major depressive disorder.  Related Articles | Metrics

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Macrophage migration inhibitory factor facilitates astrocytic production of the CCL2 chemokine following spinal cord injury Han Zhang, Yu-Ming Hu, Ying-Jie Wang, Yue Zhou, Zhen-Jie Zhu, Min-Hao Chen, Yong-Jun Wang, Hua Xu, You-Hua Wang 2023, 18 (8):  1802-1808.  doi: 10.4103/1673-5374.363184 Abstract ( 88 )   PDF (8222KB) ( 51 )   Save Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation. Overproduced chemokines are responsible for the migratory process of the leukocytes, but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated. We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury. The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes. Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells, and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect. Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor. Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats. Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury. Related Articles | Metrics

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Poly(ADP-ribose) polymerase family member 14 promotes functional recovery after spinal cord injury through regulating microglia M1/M2 polarization via STAT1/6 pathway Ai-Hua Xu, Yang Yang, Yang Shao, Man-Yu Jiang, Yong-Xin Sun 2023, 18 (8):  1809-1817.  doi: 10.4103/1673-5374.357909 Abstract ( 132 )   PDF (32138KB) ( 37 )   Save Poly(ADP-ribose)polymerase family member 14 (PARP14), which is an intracellular mono(ADP-ribosyl) transferase, has been reported to promote post-stroke functional recovery, but its role in spinal cord injury (SCI) remains unclear. To investigate this, a T10 spinal cord contusion model was established in C57BL/6 mice, and immediately after the injury PARP14 shRNA-carrying lentivirus was injected 1 mm from the injury site to silence PARP14 expression. We found that PARP14 was up-regulated in the injured spinal cord and that lentivirus-mediated downregulation of PARP14 aggravated functional impairment after injury, accompanied by obvious neuronal apoptosis, severe neuroinflammation, and slight bone loss. Furthermore, PARP14 levels were elevated in microglia after SCI, PARP14 knockdown activated microglia in the spinal cord and promoted a shift from M2-polarized microglia (anti-inflammatory phenotype) to M1-polarized microglia (pro-inflammatory phenotype) that may have been mediated by the signal transducers and activators of transcription (STAT) 1/6 pathway. Next, microglia M1 and M2 polarization were induced in vitro using lipopolysaccharide/interferon-γ and interleukin-4, respectively. The results showed that PARP14 knockdown promoted microglia M1 polarization, accompanied by activation of the STAT1 pathway. In addition, PARP14 overexpression made microglia more prone to M2 polarization and further activated the STAT6 pathway. In conclusion, these findings suggest that PARP14 may improve functional recovery after SCI by regulating the phenotypic transformation of microglia via the STAT1/6 pathway. Related Articles | Metrics

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Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson’s disease Hai-Yang Yu, Tong Sun, Zhen Wang, Hong Li, Duo Xu, Jing An, Lu-Lu Wen, Jia-Yi Li, Wen Li, Juan Feng 2023, 18 (8):  1818-1826.  doi: 10.4103/1673-5374.360242 Abstract ( 104 )   PDF (4780KB) ( 100 )   Save Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson’s disease in patients with diabetes mellitus. Therefore, using these two treatments may help treat Parkinson’s disease. To further investigate the mechanisms of action of these two compounds, we established a model of Parkinson’s disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin. We found that both exendin-4 and linagliptin reversed motor dysfunction, glial activation, and dopaminergic neuronal death in this model. In addition, both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion. Moreover, in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1β pathway and subsequent pyroptosis by decreasing the production of reactive oxygen species. These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1β pathway in a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore, these two drugs may serve as novel anti-inflammatory treatments for Parkinson’s disease.  Related Articles | Metrics

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A rabies virus-based toolkit for efficient retrograde labeling and monosynaptic tracing Kun-Zhang Lin, Lei Li, Wen-Yu Ma, Xin Yang, Zeng-Peng Han, Neng-Song Luo, Jie Wang, Fu-Qiang Xu 2023, 18 (8):  1827-1833.  doi: 10.4103/1673-5374.358618 Abstract ( 475 )   PDF (5331KB) ( 147 )   Save Analyzing the structure and function of the brain’s neural network is critical for identifying the working principles of the brain and the mechanisms of brain diseases. Recombinant rabies viral vectors allow for the retrograde labeling of projection neurons and cell type-specific trans-monosynaptic tracing, making these vectors powerful candidates for the dissection of synaptic inputs. Although several attenuated rabies viral vectors have been developed, their application in studies of functional networks is hindered by the long preparation cycle and low yield of these vectors. To overcome these limitations, we developed an improved production system for the rapid rescue and preparation of a high-titer CVS-N2c-ΔG virus. Our results showed that the new CVS-N2c-ΔG-based toolkit performed remarkably: (1) N2cG-coated CVS-N2c-ΔG allowed for efficient retrograde access to projection neurons that were unaddressed by rAAV9-Retro, and the efficiency was six times higher than that of rAAV9-Retro; (2) the trans-monosynaptic efficiency of oG-mediated CVS-N2c-ΔG was 2–3 times higher than that of oG-mediated SAD-B19-ΔG; (3) CVS-N2c-ΔG could delivery modified genes for neural activity monitoring, and the time window during which this was maintained was 3 weeks; and (4) CVS-N2c-ΔG could express sufficient recombinases for efficient transgene recombination. These findings demonstrate that new CVS-N2c-ΔG-based toolkit may serve as a versatile tool for structural and functional studies of neural circuits. Related Articles | Metrics

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Inhibiting tau protein improves the recovery of spinal cord injury in rats by alleviating neuroinflammation and oxidative stress Guo-Liang Chen, Kai Sun, Xi-Zhe Liu, Kui-Leung Tong, Zi-Juan Chen, Lu Yu, Ning-Ning Chen, Shao-Yu Liu 2023, 18 (8):  1834-1840.  doi: 10.4103/1673-5374.363183 Abstract ( 176 )   PDF (2620KB) ( 77 )   Save After spinal cord injury, the concentrations of total and hyperphosphorylated tau in cerebrospinal fluid increase, and levels of both correlate with injury severity. Tau inhibition is considered effective therapy for many central nervous system diseases, including traumatic brain injury and Alzheimer’s disease. However, whether it can play a role in the treatment of spinal cord injury remains unclear. In this study, the therapeutic effects of tau inhibition were investigated in a rat model of transection spinal cord injury by injecting the rats with a lentivirus encoding tau siRNA that inhibits tau expression. We found that tau inhibition after spinal cord injury down-regulated the levels of inflammatory mediators, including tumor necrosis factor-α, interleukin-6 and interleukin-1β. It also led to a shift of activated microglial polarization from the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype, and reduced the amount of reactive oxygen species in the acute phase. Furthermore, the survival of residual neural cells around the injury epicenter, and neuronal and axonal regeneration were also markedly enhanced, which promoted locomotor recovery in the model rats. Collectively, our findings support the conclusion that tau inhibition can attenuate neuroinflammation, alleviate oxidative stress, protect residual cells, facilitate neurogenesis, and improve the functional recovery after spinal cord injury, and thus suggest that tau could be a good molecular target for spinal cord injury therapy. Related Articles | Metrics

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Exercise combined with administration of adipose-derived stem cells ameliorates neuropathic pain after spinal cord injury Xing Cheng, Gu-Ping Mao, Wen-Jie Hu, Zheng-Ran Yu, Yi-Yang Xu, Wei Chen, Xiang Li, Xiao-Lin Zeng, Wen-Wu Zhang, Jie-Wen Chen, Yong Wan, Le Wang 2023, 18 (8):  1841-1846.  doi: 10.4103/1673-5374.361533 Abstract ( 111 )   PDF (3818KB) ( 52 )   Save Experimental studies have shown that exercise and human adipose-derived stem cells (ADSCs) play positive roles in spinal cord injury (SCI). However, whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear. Thus, there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI. In this study, a thoracic 11 (T11) SCI contusion model was established in adult C57BL/6 mice. Exercise was initiated from 7 days post-injury and continued to 28 days post-injury, and approximately 1 × 105 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI. Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale, von Frey filament test, Hargreaves method, and cold plate test. Histological studies (Eriochrome cyanine staining and immunohistochemistry) were performed at the end of the experiment (28 days post-injury). Exercise combined with administration of ADSCs partially improved early motor function (7, 14, and 21 days post-injury), mechanical allodynia, mechanical hypoalgesia, thermal hyperalgesia, and thermal hypoalgesia. Administration of ADSCs reduced white and gray matter loss at the lesion site. In addition, fewer microglia and astrocytes (as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, respectively) were present in the lumbar dorsal horn in the SCI + ADSCs and SCI + exercise + ADSCs groups compared with the sham group. Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCI-induced neuropathic pain.  Related Articles | Metrics

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Long noncoding RNA H19 regulates degeneration and regeneration of injured peripheral nerves Yu-Mei Feng, Jian Shao, Min Cai, Yi-Yue Zhou, Yi Yao, Jia-Xi Qian, Zi-Han Ding, Mao-Rong Jiang, Deng-Bing Yao 2023, 18 (8):  1847-1851.  doi: 10.4103/1673-5374.363182 Abstract ( 140 )   PDF (5086KB) ( 137 )   Save Our previous studies have shown that long noncoding RNA (lncRNA) H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration, and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons. However, the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear. In this study, we established a Sprague-Dawley rat model of sciatic nerve transection injury. We performed in situ hybridization and found that at 4–7 days after sciatic nerve injury, lncRNA H19 was highly expressed. At 14 days before injury, adeno-associated virus was intrathecally injected into the L4–L5 foramina to disrupt or overexpress lncRNA H19. After overexpression of lncRNA H19, the growth of newly formed axons from the sciatic nerve was inhibited, whereas myelination was enhanced. Then, we performed gait analysis and thermal pain analysis to evaluate rat behavior. We found that lncRNA H19 overexpression delayed the recovery of rat behavior function, whereas interfering with lncRNA H19 expression improved functional recovery. Finally, we examined the expression of lncRNA H19 downstream target SEMA6D, and found that after lncRNA H19 overexpression, the SEMA6D protein level was increased. These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves. This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.  Related Articles | Metrics

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Peripheral nerve regeneration through nerve conduits evokes differential expression of growth-associated protein-43 in the spinal cord Jesús Chato-Astrain, Olga Roda, David Sánchez-Porras, Esther Miralles, Miguel Alaminos, Fernando Campos 2023, 18 (8):  1852-1856.  doi: 10.4103/1673-5374.363180 Abstract ( 113 )   PDF (5488KB) ( 103 )   Save Growth-associated protein 43 plays a key role in neurite outgrowth through cytoskeleton remodeling. We have previously demonstrated that structural damage of peripheral nerves induces growth-associated protein 43 upregulation to promote growth cone formation. Conversely, the limited regenerative capacity of the central nervous system due to an inhibitory environment prevents major changes in neurite outgrowth and should be presumably associated with low levels of growth-associated protein 43 expression. However, central alterations due to peripheral nerve damage have never been assessed using the growth-associated protein 43 marker. In this study, we used the tubulization technique to repair 1 cm-long nerve gaps in the rat nerve injury/repair model and detected growth-associated protein 43 expression in the peripheral and central nervous systems. First, histological analysis of the regeneration process confirmed an active regeneration process of the nerve gaps through the conduit from 10 days onwards. The growth-associated protein 43 expression profile varied across regions and follow-up times, from a localized expression to an abundant and consistent expression throughout the regeneration tissue, confirming the presence of an active nerve regeneration process. Second, spinal cord changes were also histologically assessed, and no apparent changes in the structural and cellular organization were observed using routine staining methods. Surprisingly, remarkable differences and local changes appeared in growth-associated protein 43 expression at the spinal cord level, in particular at 20 days post-repair and beyond. Growth-associated protein 43 protein was first localized in the gracile fasciculus and was homogeneously distributed in the left posterior cord. These findings differed from the growth-associated protein 43 pattern observed in the healthy control, which did not express growth-associated protein 43 at these levels. Our results revealed a differential expression in growth-associated protein 43 protein not only in the regenerating nerve tissue but also in the spinal cord after peripheral nerve transection. These findings open the possibility of using this marker to monitor changes in the central nervous system after peripheral nerve injury. Related Articles | Metrics