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15 November 2022, Volume 17 Issue 11 Previous Issue   

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Interplay of SOX transcription factors and microRNAs in the brain under physiological and pathological conditions Milena Stevanovic, Danijela Stanisavljevic Ninkovic, Marija Mojsin, Danijela Drakulic, Marija Schwirtlich 2022, 17 (11):  2325-2334.  doi: 10.4103/1673-5374.338990 Abstract ( 161 )   PDF (4359KB) ( 164 )   Save Precise tuning of gene expression, accomplished by regulatory networks of transcription factors, epigenetic modifiers, and microRNAs, is crucial for the proper neural development and function of the brain cells. The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis, such as maintaining the cell stemness, cell proliferation, cell fate decisions, and terminal differentiation into neurons and glial cells. MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression. Together with other gene regulatory factors, microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment. The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain. Deregulated SOX/microRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies, including neurodegenerative disorders, traumatic brain injury, and cancer. Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neurorestoration. Numerous studies have confirmed complex interactions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma. Keeping in mind the crucial roles of SOX genes and microRNAs in neural development, we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions. Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies. Related Articles | Metrics

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Cerebellar pathology in motor neuron disease: neuroplasticity and neurodegeneration Rangariroyashe H. Chipika, Grainne Mulkerrin, Pierre-François Pradat, Aizuri Murad, Fabrice Ango, Cédric Raoul, Peter Bede 2022, 17 (11):  2335-2341.  doi: 10.4103/1673-5374.336139 Abstract ( 168 )   PDF (3723KB) ( 137 )   Save Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition. The clinical picture is dominated by upper and lower motor neuron degeneration, but extra-motor pathology is increasingly recognized, including cerebellar pathology. Post-mortem and neuroimaging studies primarily focus on the characterization of supratentorial disease, despite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis. Cardinal clinical features of amyotrophic lateral sclerosis, such as dysarthria, dysphagia, cognitive and behavioral deficits, saccade abnormalities, gait impairment, respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology. This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral sclerosis. Structural imaging studies consistently capture cerebellar grey matter volume reductions, diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alterations and functional imaging studies commonly report increased functional connectivity with supratentorial regions. Increased functional connectivity is commonly interpreted as evidence of neuroplasticity representing compensatory processes despite the lack of post-mortem validation. There is a scarcity of post-mortem studies focusing on cerebellar alterations, but these detect pTDP-43 in cerebellar nuclei. Cerebellar pathology is an overlooked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms, widespread connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions. Related Articles | Metrics

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Neuroinflammation as a mechanism linking hypertension with the increased risk of Alzheimer’s disease Ekta Bajwa, Andis Klegeris 2022, 17 (11):  2342-2346.  doi: 10.4103/1673-5374.336869 Abstract ( 293 )   PDF (585KB) ( 134 )   Save Alzheimer’s disease, the most common type of dementia among older adults, currently cannot be prevented or effectively treated. Only a very small percentage of Alzheimer’s disease cases have an established genetic cause. The majority of Alzheimer’s disease cases lack a clear causative event, but several modifiable factors have been associated with an increased risk of this disease. Persistent midlife hypertension is one such risk factor, which can be effectively controlled through changes in diet, lifestyle, and antihypertensive drugs. Identifying molecular mechanisms linking modifiable risk factors with the increased risk of Alzheimer’s disease could enhance our understanding of this disease and lead to identification of novel targets and therapeutic approaches for effective treatments. Glial cell-driven neuroinflammation is one of the key pathological features of Alzheimer’s disease. In this review, we illustrate that neuroinflammation could also be one of the possible mechanisms linking hypertension and Alzheimer’s disease. Animal studies have demonstrated that chronically elevated blood pressure leads to adverse glial activation and increased brain inflammatory mediators. We highlight damage to cerebral microvasculature and locally activated renin-angiotensin system as the key pathogenetic mechanisms linking hypertension to neuroinflammation and the accompanying neurodegeneration. The role of tumor necrosis factor-α and interleukin-1β as pro-inflammatory signaling molecules providing this link is discussed. We also summarize the available experimental data indicating that neuroinflammatory changes and glial activation can be reversed by several different classes of antihypertensive medicines. These studies suggest antihypertensives could be beneficial in Alzheimer’s disease not only due to their ability to control the blood pressure, but also due to their anti-neuroinflammatory effects. Confirmation of these observations in human subjects is required and recent advances in the brain imaging techniques allowing visualization of both microglia and astrocyte activation will be essential for this research. Related Articles | Metrics

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An atypical ubiquitin ligase at the heart of neural development and programmed axon degeneration Satpal Virdee 2022, 17 (11):  2347-2350.  doi: 10.4103/1673-5374.338992 Abstract ( 125 )   PDF (534KB) ( 54 )   Save The degeneration of nerve fibres following injury was first described by Augustus Waller over 170 years ago. Initially assumed to be a passive process, it is now evident that axons respond to insult via regulated cellular signaling events resulting in their programmed degeneration. Pro-survival and pro-degenerative factors have been identified and their regulatory mechanisms are beginning to emerge. The ubiquitin system has been implicated in the pro-degenerative process and a key component is the ubiquitin E3 ligase MYCBP2 (also known as PHR1). Ubiquitin E3 ligases are tasked with the transfer of the small protein modifier ubiquitin to substrates and consist of hundreds of members. They can be classified as single subunit systems or as multi-subunit complexes. Their catalytic domains can also be assigned to three general architectures. Hints that MYCBP2 might not conform to these established formats came to light and it is now clear from biochemical and structural studies that MYCBP2 is indeed an outlier in terms of its modus operandi. Furthermore, the unconventional way in which MYCBP2 transfers ubiquitin to substrates has been linked to neurodevelopmental and pro-degenerative function. Herein, we will summarize these research developments relating to the unusual features of MYCBP2 and postulate therapeutic strategies that prevent Wallerian degeneration. These have exciting potential for providing relief from pathological neuropathies and neurodegenerative diseases. Related Articles | Metrics

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The endogenous progenitor response following traumatic brain injury: a target for cell therapy paradigms Anna Badner, Brian J. Cummings 2022, 17 (11):  2351-2354.  doi: 10.4103/1673-5374.335833 Abstract ( 156 )   PDF (489KB) ( 106 )   Save Although there is ample evidence that central nervous system progenitor pools respond to traumatic brain injury, the reported effects are variable and likely contribute to both recovery as well as pathophysiology. Through a better understanding of the diverse progenitor populations in the adult brain and their niche-specific reactions to traumatic insult, treatments can be tailored to enhance the benefits and dampen the deleterious effects of this response. This review provides an overview of endogenous precursors, the associated effects on cognitive recovery, and the potential of exogenous cell therapeutics to modulate these endogenous repair mechanisms. Beyond the hippocampal dentate gyrus and subventricular zone of the lateral ventricles, more recently identified sites of adult neurogenesis, the meninges, as well as circumventricular organs, are also discussed as targets for endogenous repair. Importantly, this review highlights that progenitor proliferation alone is no longer a meaningful outcome and studies must strive to better characterize precursor spatial localization, transcriptional profile, morphology, and functional synaptic integration. With improved insight and a more targeted approach, the stimulation of endogenous neurogenesis remains a promising strategy for recovery following traumatic brain injury. Related Articles | Metrics

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The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer’s disease Yan-Li Zhang, Juan Wang, Zhi-Na Zhang, Qiang Su, Jun-Hong Guo 2022, 17 (11):  2355-2363.  doi: 10.4103/1673-5374.335829 Abstract ( 184 )   PDF (1551KB) ( 255 )   Save Neurovascular dysfunction, as an integral part of Alzheimer’s disease, may have an important influence on the onset and progression of chronic neurodegenerative processes. The blood-brain barrier (BBB) pathway is one of the main pathways that mediates the clearance of amyloid-beta (Aβ) in the brain parenchyma. A large number of studies have shown that receptors and ATP-binding cassette transporters expressed on endothelial cells play an important role in Aβ transport across the BBB, but the specific mechanism is not clear. In this review, we summarize the possible mechanisms of Aβ production and clearance, and in particular the relationship between Aβ and brain capillary endothelial cells. Aβ is produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions. Dysregulation of Aβ clearance is considered to be the main reason for the massive accumulation of Aβ in the brain parenchyma. Several pathways mediating Aβ clearance from the brain into the periphery have been identified, including the BBB pathway, the blood-cerebrospinal fluid barrier and arachnoid granule pathway, and the lymphoid-related pathway. Brain capillary endothelial cells are the key components of Aβ clearance mediated by BBB. Receptors (such as LRP1, RAGE, and FcRn) and ATP-binding cassette transporters (such as P-gp, ABCA1, and ABCC1) expressed on endothelial cells play a critical role in Aβ transcytosis across the BBB. The toxic effects of Aβ can induce dysregulation of receptor and transporter expression on endothelial cells. Excessive Aβ exerts potent detrimental cerebrovascular effects by promoting oxidative stress, inducing chronic inflammation, and impairing endothelial structure and functions. All of these are main causes for the reduction in Aβ clearance across the BBB and the accumulation of Aβ in the brain parenchyma. Therefore, studies on the interactions between Aβ and brain capillary endothelial cells, including their receptors and transporters, studies on inhibition of the toxic effects of Aβ on endothelial cells, and studies on promoting the ability of endothelial cells to mediate Aβ clearance may provide new therapeutic strategies for Aβ clearance in Alzheimer’s disease. Related Articles | Metrics

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Telomerase and neurons: an unusual relationship Gabriele Saretzki 2022, 17 (11):  2364-2367.  doi: 10.4103/1673-5374.336133 Abstract ( 209 )   PDF (1795KB) ( 130 )   Save Most people associate the enzyme telomerase with its role in maintaining telomeres, which is its best-known canonical role. For this important function, two main components are required: the protein telomerase reverse transcriptase (TERT) and the telomerase RNA component. In addition, over the last decades, an ever-growing number of other, non-telomeric, non-canonical functions for the telomerase protein TERT has been established. These reach from tumor promotion to decreasing oxidative stress and apoptosis as well as activating autophagy. These functions are more and more recognized as being important in many tissues and physiological as well as pathological conditions. The role of telomerase in brain development and neuronal cells has been investigated for more than 20 years. However, the non-telomeric role in non-dividing neurons of the brain for telomerase and the TERT-protein has only recently been highlighted by extensive research. Moreover, these developments promoted the suggestion of a beneficial and protective role of TERT against neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This review summarizes the most important findings in the field of telomerase in neurons and gives an outlook onto possible therapeutic applications of boosting telomerase/TERT levels with telomerase activators to prevent or ameliorate various neurodegenerative diseases. Related Articles | Metrics

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MicroRNAs as biomarkers in glaucoma and potential therapeutic targets Bridget Martinez, Philip V. Peplow 2022, 17 (11):  2368-2375.  doi: 10.4103/1673-5374.338989 Abstract ( 293 )   PDF (596KB) ( 175 )   Save Glaucoma is a neurodegenerative disease in which optic nerve damage and visual field defects occur. It is a leading cause of irreversible blindness. Its pathogenesis is largely unknown although several risk factors have been identified, with an increase in intraocular pressure being the main one. Lowering of intraocular pressure is the only treatment available. Open-angle glaucoma is the most common form of the condition, accounting for ~90% of all cases of glaucoma, with primary open-angle glaucoma and exfoliation glaucoma being the most frequent types. There are strong indications that microRNAs play important roles in the pathogenesis of primary open-angle glaucoma. Most of the recent studies reviewed had performed microRNA profiling in aqueous humor from glaucoma patients compared to controls who were chiefly cataract patients. A very large number of microRNAs were dysregulated but with limited overlap between individual studies. MiRNAs in aqueous humor that could be possible targets for therapeutic intervention are miR-143-3p, miR-125b-5p, and miR-1260b. No overlap of findings occurred within the dysregulated miRNAs for blood plasma, blood serum, peripheral blood mononuclear cells, and tears of primary open-angle glaucoma patients. Several important limitations were identified in these studies. Further studies are warranted of microRNA expression in aqueous humor and blood samples of primary open-angle glaucoma patients in the early stages of the disease so that validated biomarkers can be identified and treatment initiated. In addition, whether modifying the levels of specific microRNAs in aqueous humor or tears has a beneficial effect on intraocular pressure and ophthalmic examination of the eyes should be investigated using suitable animal models of glaucoma. Related Articles | Metrics

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Neuroprotection and neuroregeneration: roles for the white matter Vito Antonio Baldassarro, Agnese Stanzani, Luciana Giardino, Laura Calzà, Luca Lorenzini 2022, 17 (11):  2376-2380.  doi: 10.4103/1673-5374.335834 Abstract ( 117 )   PDF (3644KB) ( 84 )   Save Efficient strategies for neuroprotection and repair are still an unmet medical need for neurodegenerative diseases and lesions of the central nervous system. Over the last few decades, a great deal of attention has been focused on white matter as a potential therapeutic target, mainly due to the discovery of the oligodendrocyte precursor cells in the adult central nervous system, a cell type able to fully repair myelin damage, and to the development of advanced imaging techniques to visualize and measure white matter lesions. The combination of these two events has greatly increased the body of research into white matter alterations in central nervous system lesions and neurodegenerative diseases and has identified the oligodendrocyte precursor cell as a putative target for white matter lesion repair, thus indirectly contributing to neuroprotection. This review aims to discuss the potential of white matter as a therapeutic target for neuroprotection in lesions and diseases of the central nervous system. Pivot conditions are discussed, specifically multiple sclerosis as a white matter disease; spinal cord injury, the acute lesion of a central nervous system component where white matter prevails over the gray matter, and Alzheimer’s disease, where the white matter was considered an ancillary component until recently. We first describe oligodendrocyte precursor cell biology and developmental myelination, and its regulation by thyroid hormones, then briefly describe white matter imaging techniques, which are providing information on white matter involvement in central nervous system lesions and degenerative diseases. Finally, we discuss pathological mechanisms which interfere with myelin repair in adulthood. Related Articles | Metrics

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Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer’s disease: a meta-analysis and systematic review Wei-Lin Liu, Hua-Wei Lin, Miao-Ran Lin, Yan Yu, Huan-Huan Liu, Ya-Ling Dai, Le-Wen Chen, Wei-Wei Jia, Xiao-Jun He, Xiao-Ling Li, Jing-Fang Zhu, Xie-Hua Xue, Jing Tao, Li-Dian Chen 2022, 17 (11):  2381-2390.  doi: 10.4103/1673-5374.335832 Abstract ( 506 )   PDF (3379KB) ( 1265 )   Save Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer’s disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer’s disease, mild cognitive impairment, and Alzheimer’s disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer’s disease, mild cognitive impairment, and preclinical Alzheimer’s disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aβ1–42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer’s disease, mild cognitive impairment, and Alzheimer’s disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer’s disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer’s disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020). Related Articles | Metrics

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Purinergic signaling systems across comparative models of spinal cord injury Eva E. Stefanova, Angela L. Scott 2022, 17 (11):  2391-2398.  doi: 10.4103/1673-5374.338993 Abstract ( 131 )   PDF (2011KB) ( 145 )   Save Within the last several decades, the scientific community has made substantial progress in elucidating the complex pathophysiology underlying spinal cord injury. However, despite the many advances using conventional mammalian models, both cellular and axonal regeneration following spinal cord injury have remained out of reach. In this sense, turning to non-mammalian, regenerative species presents a unique opportunity to identify pro-regenerative cues and characterize a spinal cord microenvironment permissive to re-growth. Among the signaling pathways hypothesized to be dysregulated during spinal cord injury is the purinergic signaling system. In addition to its well-known role as energy currency in cells, ATP and its metabolites are small molecule neurotransmitters that mediate many diverse cellular processes within the central nervous system. While our understanding of the roles of the purinergic system following spinal cord injury is limited, this signaling pathway has been implicated in all injury-induced secondary processes, including cellular death, inflammation, reactive gliosis, and neural regeneration. Given that the purinergic system is also evolutionarily conserved between mammalian and non-mammalian species, comparisons of these roles may provide important insights into conditions responsible for recovery success. Here, we compare the secondary processes between key model species and the influence of purinergic signaling in each context. As our understanding of this signaling system and pro-regenerative conditions continues to evolve, so does the potential for the development of novel therapeutic interventions for spinal cord injury.  Related Articles | Metrics

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Advancements in our understanding of circular and long non-coding RNAs in spinal cord injury Yan Zhang, Ho Jun Yun, Yu Ji, Eric Cosky, Wen-Xiu Zhang, Wei Han, Yu-Chuan Ding 2022, 17 (11):  2399-2403.  doi: 10.4103/1673-5374.335835 Abstract ( 148 )   PDF (3557KB) ( 154 )   Save Spinal cord injury (SCI), either from trauma or degenerative changes, can result in severe disability and impaired quality of life. Understanding the cellular processes and molecular mechanisms that underlie SCI is imperative to identifying molecular targets for potential therapy. Recent studies have shown that non-coding RNAs, including both long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), regulate various cellular processes in SCI. In this review, we will describe the changes in lncRNA and circRNA expression that occur after SCI and how these changes may be related to SCI progression. Current evidence for the roles of lncRNAs and circRNAs in neuronal cell death and glial cell activation will also be reviewed. Finally, the possibility that lncRNAs and circRNAs are novel modulators of SCI pathogenesis will be discussed. Related Articles | Metrics

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The uPA/uPAR system in astrocytic wound healing Manuel Yepes 2022, 17 (11):  2404-2406.  doi: 10.4103/1673-5374.338991 Abstract ( 140 )   PDF (815KB) ( 77 )   Save The repair of injured tissue is a highly complex process that involves cell proliferation, differentiation, and migration. Cell migration requires the dismantling of intercellular contacts in the injured zone and their subsequent reconstitution in the wounded area. Urokinase-type plasminogen activator (uPA) is a serine proteinase found in multiple cell types including endothelial cells, smooth muscle cells, monocytes, and macrophages. A substantial body of experimental evidence with different cell types outside the central nervous system indicates that the binding of uPA to its receptor (uPAR) on the cell surface prompts cell migration by inducing plasmin-mediated degradation of the extracellular matrix. In contrast, although uPA and uPAR are abundantly found in astrocytes and uPA binding to uPAR triggers astrocytic activation, it is unknown if uPA also plays a role in astrocytic migration. Neuronal cadherin is a member of cell adhesion proteins pivotal for the formation of cell-cell contacts between astrocytes. More specifically, while the extracellular domain of neuronal cadherin interacts with the extracellular domain of neuronal cadherin in neighboring cells, its intracellular domain binds to β-catenin, which in turn links the complex to the actin cytoskeleton. Glycogen synthase kinase 3β is a serine-threonine kinase that prevents the cytoplasmic accumulation of β-catenin by inducing its phosphorylation at Ser33, Ser37, and Ser41, thus activating a sequence of events that lead to its proteasomal degradation. The data discussed in this perspective indicate that astrocytes release uPA following a mechanical injury, and that binding of this uPA to uPAR on the cell membrane induces the detachment of β-catenin from the intracellular domain of neuronal cadherin by triggering its extracellular signal-regulated kinase 1/2-mediated phosphorylation at Tyr650. Remarkably, this is followed by the cytoplasmic accumulation of β-catenin because uPA-induced extracellular signal-regulated kinase 1/2 activation also phosphorylates lipoprotein receptor-related protein 6 at Ser1490, which in turn, by recruiting glycogen synthase kinase 3β to its intracellular domain abrogates its effect on β-catenin. The cytoplasmic accumulation of β-catenin is followed by its nuclear translocation, where it induces the expression of uPAR, which is required for the migration of astrocytes from the injured edge into the wounded area. Related Articles | Metrics

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The influence of gut microbiota alteration on age-related neuroinflammation and cognitive decline Amsha S. Alsegiani, Zahoor A. Shah 2022, 17 (11):  2407-2412.  doi: 10.4103/1673-5374.335837 Abstract ( 147 )   PDF (2242KB) ( 140 )   Save Recent emerging research on intestinal microbiota and its contribution to the central nervous system during health and disease has attracted significant attention. Age-related intestinal microbiota changes initiate brain aging and age-related neurodegenerative disorders. Aging is one of the critical predisposing risk factors for the development of neurodegenerative diseases. Maintaining a healthy gut microbiota is essential for a healthy body and aging, but dysbiosis could initiate many chronic diseases. Understanding the underlying mechanisms of gut microbiota alterations/dysbiosis will help identify biomarkers for aging-related chronic conditions. This review summarizes recent advances in microbiota-neurodegenerative disease research and will enhance our understanding of gut microbiota dysbiosis and its effects on brain aging. Related Articles | Metrics

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Lipopolysaccharide mouse models for Parkinson’s disease research: a critical appraisal Isaac Deng, Larisa Bobrovskaya 2022, 17 (11):  2413-2417.  doi: 10.4103/1673-5374.331866 Abstract ( 362 )   PDF (2068KB) ( 137 )   Save Parkinson’s disease, the most common movement disorder, has a strong neuroinflammatory aspect. This is evident by increased pro-inflammatory cytokines in the serum, and the presence of activated microglial cells, and inflammatory cytokines in the substantia nigra of post-mortem brains as well as cerebrospinal fluid of Parkinson’s disease patients. The central and peripheral neuroinflammatory aspects of Parkinson’s disease can be investigated in vivo via administration of the inflammagen lipopolysaccharide, a component of the cell wall of gram-negative bacteria. In this mini-review, we will critically evaluate different routes of lipopolysaccharide administration (including intranasal systemic and stereotasic), their relevance to clinical Parkinson’s disease as well as the recent findings in lipopolysaccharide mouse models. We will also share our own experiences with systemic and intrastriatal lipopolysaccharide models in C57BL/6 mice and will discuss the usefulness of lipopolysaccharide mouse models for future research in the field. Related Articles | Metrics

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Verapamil, a possible repurposed therapeutic candidate for stroke under hyperglycemia Saifudeen Ismael, Tauheed Ishrat 2022, 17 (11):  2418-2419.  doi: 10.4103/1673-5374.335790 Abstract ( 168 )   PDF (278KB) ( 64 )   Save Admission hyperglycemia is an independent predictor, that contributes to hemorrhagic transformation (HT), and worsened functional outcome following reperfusion therapy with tissue plasminogen activator (tPA) in ischemic stroke. Clinical studies have revealed a strong association between hyperglycemia and incidence of HT independent of prior diabetes diagnosis (Alvarez-Sabín et al., 2003). Experimental studies showed that hyperglycemia reduces the efficacy of reperfusion and cerebral blood flow following ischemic stroke in rats (Kawai et al., 1997). Hyperglycemia accelerates the production of super oxides and advanced glycation end products, which contribute to blood brain barrier disruption (Won et al., 2011). Additionally, hyperglycemic reperfusion induces glucose overload to the ischemic brain, which accelerates the synthesis reactive oxygen free radicals and worsens neurovascular damage. The increased incidence of admission hyperglycemia in stroke patients along with HT, necessitates the development of novel adjunctive therapies for the management of ischemic stroke. Related Articles | Metrics

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Engineering cerebral folding in brain organoids Glen Scott, Yu Huang 2022, 17 (11):  2420-2422.  doi: 10.4103/1673-5374.335789 Abstract ( 181 )   PDF (925KB) ( 83 )   Save Neurological diseases remain the largest cause of death and disability. The discovery of effective therapies is chiefly hindered by the lack of realistic neurological models. Unlike other tissues, it is infeasible or unethical to access primary human neural samples in bulk. But animal models often fail to replicate the complex human-specific neuronal factors present in vivo. Conventional in vitro cultures lack native three-dimensional (3D) morphologies, polarity, and receptor expression, as well as tissue-level interactions (Jensen et al., 2018). Related Articles | Metrics

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Non-canonical role of the ATR pathway in axon regeneration as a mechanosensitive brake Feng Li, Yuanquan Song 2022, 17 (11):  2423-2424.  doi: 10.4103/1673-5374.335807 Abstract ( 102 )   PDF (402KB) ( 55 )   Save DNA damage has been linked to neuropathology. Diverse DNA damage response (DDR) pathways help preserve DNA integrity in the nervous system during both the developmental and mature stages. Mutations of factors in various signaling pathways responsive to different types of DNA damage have been associated with developmental syndromes with neurological symptoms (McKinnon, 2009; Araújo and Kuraoka, 2019; Khokhlova et al., 2020). For example, mutations in a single gene encoding ataxia-telangiectasia mutated (ATM), which is activated by DNA double-strand breaks for checkpoint initiation, can lead to ataxia telangiectasia (McKinnon, 2004). It is believed that neuropathology can result from cellular DNA damage, or even DNA damage within the mitochondria, as has been shown to correlate with aging and Parkinson’s disease (Bender et al., 2006). However, attributing all the mechanisms underlying neurological diseases caused by DDR gene deficiencies to the accumulation of genetic alterations is an oversimplification. In particular, non-canonical DDRs have exhibited examples of uncoupling of upstream triggers (DNA damage) and downstream events. Other than single/double-strand breaks of DNA, for instance, telomere maintenance and oxidative stress in cells can also activate DDR (Burgess and Misteli, 2015). The consequences of DDR have been typically characterized as cell-cycle arrest, expression of repair genes, apoptosis, etc. However, the specific effects of DDR pathway activation in various types of cells, especially the terminally differentiated cells, warrant further exploration. Whether the DDR machinery can function beyond its traditional role remains an open question. Related Articles | Metrics

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Beyond vertebrates: the amphioxus as a relevant model system to explore the formation, organization, and regeneration of neuromuscular synapses Esperanza Martínez, Sylvain Marcellini, Juan Pablo Henríquez 2022, 17 (11):  2425-2426.  doi: 10.4103/1673-5374.338994 Abstract ( 155 )   PDF (981KB) ( 65 )   Save The neuromuscular junction (NMJ) is the peripheral synapse controlling muscle contraction and coordinated movement in a wide variety of animals. In humans, the mature NMJ is the primary target of morphological disassembly and functional decline in several physiological and pathological conditions, such as aging and motor diseases, respectively. Different paradigms of nerve damage in murine models have revealed that the peripheral nervous system bears regenerative abilities leading to functional NMJ recovery; however, this process is often inefficient in humans, likely due to their larger size and differences in the establishment of a still elusive regenerative niche at the NMJ (Zelada et al., 2021). One way to approach this obstacle is to understand the evolution of synaptic contacts, as they can provide novel insights into the fundamental cellular and molecular requirements that were ancestrally involved in the development and regeneration of neuromuscular synapses. Indeed, relevant information on the molecular mechanisms involved in peripheral neural organization and regeneration has been obtained from flies and worms (Richardson and Shen, 2019). The cephalochordates, also known as amphioxus, are a group of non-vertebrate chordate marine animals sharing many genomic and developmental features with the vertebrates. Interestingly, they also share several, although simplified, anatomical structures with vertebrates, including nervous and muscle tissues. Here, we specifically describe the distinctive neuromuscular contacts in amphioxus and briefly discuss how these features could provide valuable information to promote efficient vertebrate NMJ repair. Related Articles | Metrics

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Targeting O-GlcNAcylation in ischemic stroke Xuan Li, Wei Yang 2022, 17 (11):  2427-2428.  doi: 10.4103/1673-5374.335806 Abstract ( 113 )   PDF (744KB) ( 46 )   Save Ischemic stroke is a common and often devastating disease that primarily affects the elderly. Treatment currently consists predominantly of acute thrombolysis and/or thrombectomy to restore blood flow. This reperfusion therapy, however, is only accessible to a small fraction of stroke patients, and even among these patients, many still suffer life-long neurologic deficits. Thus, new stroke therapeutics are urgently needed to improve the quality of life for stroke patients. Related Articles | Metrics

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Utilizing multiphoton imaging and integrative clearing to reveal sex differences in neuroimmune interactions after nerve injury Zachary W. Castillo, Michael D. Burton 2022, 17 (11):  2429-2430.  doi: 10.4103/1673-5374.335809 Abstract ( 123 )   PDF (2462KB) ( 79 )   Save With the constant development of multiphoton microscopy, our ability to observe complex and dynamic biological processes deeper within living tissue, is steadily improving. Researchers use multiphoton microscopy, because experiments can be conducted with little to no invasiveness or tissue damage over a long period of time with no photodamage (Mancuso et al., 2009). This allows for the introduction of tissue into the context of a three-dimensional (3D) environment in which visualization of cellular activation and interaction is viable. By circumventing a distorted reconstruction with limited z-stacks, multiphoton imaging provides enhanced spatiotemporal resolution. Related Articles | Metrics

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The left-right side-specific endocrine signaling: implications for neurological deficits in stroke and neurodevelopmental disorders Georgy Bakalkin, Nikolay Lukoyanov, Igor Lavrov, Mengliang Zhang 2022, 17 (11):  2431-2433.  doi: 10.4103/1673-5374.335811 Abstract ( 126 )   PDF (946KB) ( 91 )   Save Brain injury-induced neurological deficits typically develop on the contralateral side of the body and include abnormal posture, motor weakness, and spasticity. It is believed that the interruption of descending neural pathways that convey supraspinal commands to the motoneurons in the spinal cord is the main cause of these deficits. This long-standing paradigm was challenged by our recent findings: a unilateral injury of the hindlimb sensorimotor cortex of rats with prior complete transection of the spinal cord produced hindlimb postural asymmetry (HL-PA), asymmetric hindlimb withdrawal reflexes, and asymmetry in gene expression patterns in the lumbar spinal cord (Figure 1; Lukoyanov et al., 2021). Strikingly, the contralateral hindlimb was flexed as usually seen in rats with intact spinal cord after brain injury. Hypophysectomy abolished the injury-induced effects, whereas hindlimb postural asymmetry was induced by serum from animals with brain injury transfused into animals with the intact brains. Arg-vasopressin and β-endorphin, two pituitary neurohormones, induced the right side hindlimb responses in naïve animals, while their antagonists blocked HL-PA in rats with the left-brain injury. Thus, in addition to motor pathways descending from the brain to spinal circuits, the side-specific humoral signaling mediates the effects of unilateral brain injury (UBI) on hindlimb posture and reflex asymmetries. Related Articles | Metrics

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Chemically oligomerizable TDP-43: a novel chemogenetic tool for studying the pathophysiology of amyotrophic lateral sclerosis Kohsuke Kanekura, Yoshiaki Yamanaka, Tamami Miyagi, Masahiko Kuroda 2022, 17 (11):  2434-2436.  doi: 10.4103/1673-5374.335803 Abstract ( 124 )   PDF (1206KB) ( 75 )   Save Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of both upper and lower motor neurons. Most ALS cases are sporadic, but approximately 5–10% of patients have a familial background. To date, more than 30 familial ALS-causative genes have been identified (Maurel et al., 2018). The clinical manifestation and disease progression of sporadic ALS and familial ALS are similar and often clinically and pathologically indistinguishable, suggesting that they share a common pathophysiology in motor neuronal degeneration. One of the pathological hallmarks of ALS is the mislocalization of a multifunctional nuclear protein, TAR-DNA binding protein 43 (TDP-43). TDP-43 was identified as a primary component of ubiquitin-positive cytosolic inclusion bodies seen in remnant motor neurons in both sporadic and familial ALS (Neumann et al., 2006), and was later recognized as an autosomal dominant familial ALS-causative gene (ALS10) (Sreedharan et al., 2008). Since the cytosolic inclusion of TDP-43 is seen in almost all cases of ALS, regardless of the TDP-43 genotype, TDP-43 is thought to be a central hub molecule, linking both familial and sporadic ALS. Therefore, elucidation of the molecular mechanisms underlying TDP-43-related neurotoxicity would contribute to understanding the pathophysiology of this merciless disease. Related Articles | Metrics

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Perspective on automated in vivo drug screening using the chodl mutant zebrafish line Ana-Maria Oprişoreanu 2022, 17 (11):  2437-2438.  doi: 10.4103/1673-5374.335795 Abstract ( 126 )   PDF (714KB) ( 58 )   Save Since the early 2000s, the popularity of zebrafish in in vivo drug screening has shown a substantial increase. The zebrafish has become an important screening tool covering a wide range of tissue-specific pathologies and diseases/disorders. Nowadays phenotype-based screening is favoured over target-based screening approaches, because it can identify active drugs/small molecules in the absence of a known target or suspected mechanism of action. Phenotypic screens can identify not only compounds with a positive effect, but also compounds with off-target effect. Another advantage of whole-organisms screening is the bioavailability of compounds, and the fact that in vivo experiments will allow the normal metabolization of these compounds by the living organisms. Overall, this type of approach has boosted the discovery of higher quality compounds compared to in vitro target-based screens (Zhang and Peterson, 2019). Related Articles | Metrics

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Transcription factors promote neural regeneration after spinal cord injury Zachary Finkel, Li Cai 2022, 17 (11):  2439-2440.  doi: 10.4103/1673-5374.335805 Abstract ( 127 )   PDF (327KB) ( 78 )   Save Human spinal cord injury (SCI) results in locomotor and sensory disabilities, which severely affect the quality of life. To restore function after SCI, it is necessary to repair and reconstruct the damaged local circuitry. Major hurdles in neural regeneration include a limited level of neurogenesis in the adult spinal cord and an inflammatory microenvironment that inhibits neurogenesis and axon regeneration. In addition, neurons lost to injury are never replaced. Neural stem/progenitor cells (NSPCs) persist in the adult spinal cord and represent a potential cell source for tissue repair/regeneration after injury, and they are heterogeneous populations with a limited capacity to replenish the lost neuronal population (Hachem et al., 2020; Llorens-Bobadilla et al., 2020). Traumatic injury activates NSPCs in the central nervous system (CNS). However, injury-induced NSPCs largely differentiate into glial cells, i.e., astrocytes and oligodendrocytes, which contribute to glial scar formation. Promoting endogenous NSPCs to differentiate into functional neurons by transcription factors for regeneration and restoration of local neural circuitry is an emerging approach to develop therapeutics for traumatic CNS injury and neurodegenerative disorders. Related Articles | Metrics

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TDP-35, a truncated fragment of TDP-43, induces dose-dependent toxicity and apoptosis in flies Deepak Chhangani, Diego E. Rincon-Limas 2022, 17 (11):  2441-2442.  doi: 10.4103/1673-5374.338997 Abstract ( 118 )   PDF (593KB) ( 50 )   Save TAR DNA-binding protein 43 (TDP-43) is an essential 414 amino acid protein that regulates multiple aspects of RNA biogenesis, processing, and transport.  It localizes primarily in the nucleus, but abnormal translocation and accumulation in the cytosol occur under pathological conditions (Tziortzouda et al., 2021). TDP-43 abnormalities are typical pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Mutations in the TDP-43-encoding gene TARDBP cause familial ALS, while wild-type TDP-43 is associated with almost all (~97%) of sporadic ALS cases and nearly half of frontotemporal lobar degeneration patients (~45%) (de Boer et al., 2020). Extensive research has identified post-translational modifications of TDP-43 such as phosphorylation, ubiquitination and truncation as major histopathological characteristics in TDP-43 proteinopathies. Substantial progress has occurred in studying protein aggregation involving phosphorylated and ubiquitinated TDP-43. However, as recently discussed by us, the relevance and pathological role of truncated TDP-43 forms are still poorly understood (Chhangani et al., 2021). Here we extend our discussion on truncation of TDP-43, present new experimental insights into the neurotoxic role of its cleaved TDP-35 fragment, and provide a perspective on new avenues of research in this field.  Related Articles | Metrics

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Can foods influence the onset and progress of neurodegenerative diseases? Luca Piemontese, Leonardo Brunetti, Rosalba Leuci 2022, 17 (11):  2443-2444.  doi: 10.4103/1673-5374.335810 Abstract ( 88 )   PDF (465KB) ( 64 )   Save Over the course of the last few years, the advertisement and marketing of commercial food products in the European market has seen an increasing focus on the beneficial effects of such products for consumer health (Regulation, 2006). These so-called “health claims”, which can be found on the label of some food products, have become a very important medium, aiming to reach the maximum amount of potential consumers possible, and the delivery of these promises has become a crucial objective for food companies or consortia. However, in most cases, the evidence backing up such claims (and their coveted acknowledgment on the product label) has often been cited as insufficient by institutions such as the European Food and Safety Authority (EFSA, Parma, Italy). Related Articles | Metrics

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Are ATXN2 variants modifying our understanding about neural pathogenesis, phenotypes, and diagnostic? Jose Miguel Laffita-Mesa, Martin Paucar, Per Svenningsson 2022, 17 (11):  2445-2447.  doi: 10.4103/1673-5374.338996 Abstract ( 153 )   PDF (5221KB) ( 86 )   Save ATXN2 gene encodes a cytosolic protein (ataxin-2) with pleiotropic functions (see below). This gene contains a number of exonic Cytosine-Adenine-Guanine (CAG)-repeats which encodes a polyglutamine tract (polyQ) in the N-terminal intrinsically disordered region (IDR) of the protein. ATXN2 CAG repeats are interrupted by CAA codons which is relevant only for DNA and RNA but not for protein since CAA also encodes glutamine (Q). Related Articles | Metrics

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Modeling Alzheimer’s disease: considerations for a better translational and replicable mouse model Joshua D. Cho, Mu Yang, Ismael Santa-Maria 2022, 17 (11):  2448-2449.  doi: 10.4103/1673-5374.335787 Abstract ( 115 )   PDF (290KB) ( 87 )   Save Alzheimer’s disease (AD) mouse models have proven to be an invaluable tool for deepening our understanding of disease mechanisms and for developing therapeutics. However, one common frustration is the lack of replicability in behavioral findings. As we have discussed in our recent publication (Cho et al., 2021), in the htau mouse model, the cognitive impairment reported in the original study has not been consistently replicated by different labs over the past decade. This variability in behavioral findings seems to exist in many, if not all, AD mouse models that have been behaviorally evaluated. Related Articles | Metrics

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Finding effective combinations of compounds to prevent Alzheimer’s disease Sudip Dhakal, Ian Macreadie 2022, 17 (11):  2450-2451.  doi: 10.4103/1673-5374.335812 Abstract ( 112 )   PDF (410KB) ( 68 )   Save Alzheimer’s disease (AD) remains one of the significant causes of death and morbidity in the older population (2021). The cause of AD remains unclear despite there being numerous hypotheses. Perhaps the most widely accepted hypothesis is the amyloid cascade hypothesis which is based on the accumulation of amyloid beta (Aβ) in neurons (Dhakal et al., 2019). Aβ is produced from amyloid precursor protein (APP) after its processing via beta-secretase and gamma-secretase enzymes, while the processing of APP by alpha-secretase instead of β-secretase forms a non-amyloidogenic amyloid-α protein. The increased processing of APP via β-secretase and not by the α-secretase resulting in Aβ formation is an important aspect of AD. Recent studies suggest iron overloading as one of the major contributors of APP processing by β-secretase, proposing it as a major cause (Gleason and Bush, 2021). Insights from genomic studies in Iceland revealed mutations on amyloid precursor protein restricting Aβ formation protect people from AD (Jonsson et al., 2012). It has been reported that people having the Icelandic variant are at least five times less likely to develop AD as compared to the people without it. Considering this evidence, Aβ’s cruciality in AD progression has been undisputed. The Aβ protein comprises two major isoforms: 40 amino acids (Aβ40) and 42 amino acids (Aβ42) (Nair et al., 2014). While Aβ40 is soluble and readily cleared from cells, Aβ42 is toxic and aggregate-prone that can cause proteotoxic stress. In young individuals, the amyloid aggregates are efficiently cleared from neurons. But with aging the ability of the cells to clear these aggregates is reduced and soon develops to become part of the amyloid plaques (Dhakal et al., 2019). Although Aβ42 aggregates to form fibrils and plaques in affected brains, only the soluble oligomeric forms of Aβ42 are reported to cause oxidative damage and mitochondrial dysfunction aiding in the cascade of pathological events ultimately progressing towards AD pathology. Although it is still unclear what causes the initial Aβ accumulation and impairment in cellular defense systems, the combined effect of aging, mitochondrial dysfunction, impairment of mitochondrial turnover, iron overloading, loss of cellular ability to clear aggregated proteins, and accumulation of oxidative damage are some of the most important aspects of AD pathogenesis (Dhakal and Macreadie, 2020). Related Articles | Metrics

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Genetic dissection of glutathione S-transferase omega-1: identification of novel downstream targets and Alzheimer’s disease pathways Yue Jia, Meng-Die Gao, Yun-Fang Liu, Lu Lu, Gang Chen, Ying Chen 2022, 17 (11):  2452-2458.  doi: 10.4103/1673-5374.339004 Abstract ( 202 )   PDF (1846KB) ( 98 )   Save Alzheimer’s disease (AD) is affected by genetic factors. Polymorphisms in the glutathione S-transferase omega-1 (Gsto1) gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD. Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to characterize the mechanisms underlying regulation of Gsto1 variation regulation and to identify network members that may contribute to AD risk or progression. Allele-specific assays confirmed that variation in Gsto1 expression is controlled by cis-expression quantitative trait loci. We found that Gsto1 mRNA levels were related to several central nervous system traits, such as glial acidic fibrillary protein levels in the caudate putamen, cortical gray matter volume, and hippocampus mossy fiber pathway volume. We identified 2168 genes whose expression was highly correlated with that of Gsto1. Some genes were enriched for the most common neurodegenerative diseases. Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD, such as APP, Grin2b, Ide, and Psenen. To evaluate the relationships between Gsto1 and candidate network members, we transfected astrocytes with Gsto1 siRNA and assessed the effect on putative downstream effectors. We confirmed that knockdown of Gsto1 had a significant influence on Pa2g4 expression, suggesting that Pa2g4 may be a downstream effector of Gsto1, and that both genes interact with other genes in a network during AD pathogenesis. Related Articles | Metrics

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Effects of paired associative magnetic stimulation between nerve root and cortex on motor function of lower limbs after spinal cord injury: study protocol for a randomized controlled trial Ting-Ting Sun, Guang-Yue Zhu, Ya Zheng, Ye-Ran Mao, Qi-Long Hu, Gong-Ming Song , Rong Xu, Qi Yang, Dan Zhao, Xu-Yun Hua, Dong-Sheng Xu 2022, 17 (11):  2459-2464.  doi: 10.4103/1673-5374.339012 Abstract ( 147 )   PDF (788KB) ( 90 )   Save Classic paired associative stimulation can improve synaptic plasticity, as demonstrated by animal experiments and human clinical trials in spinal cord injury patients. Paired associative magnetic stimulation (dual-target peripheral and central magnetic stimulation) has been shown to promote neurologic recovery after stroke. However, it remains unclear whether paired associative magnetic stimulation can promote recovery of lower limb motor dysfunction after spinal cord injury. We hypothesize that the current caused by central and peripheral magnetic stimulation will converge at the synapse, which will promote synapse function and improve the motor function of the relevant muscles. Therefore, this study aimed to examine the effects of paired associative magnetic stimulation on neural circuit activation by measuring changes in motor evoked and somatosensory evoked potentials, motor and sensory function of the lower limbs, functional health and activities of daily living, and depression in patients with spinal cord injury. We will recruit 110 thoracic spinal trauma patients treated in the Department of Spinal Cord Injury, China Rehabilitation Hospital and randomly assign them to experimental and control groups in a 1:1 ratio. The trial group (n = 55) will be treated with paired associative magnetic stimulation and conventional rehabilitation treatment. The control group (n = 55) will be treated with sham stimulation and conventional rehabilitation treatment. Outcomes will be measured at four time points: baseline and 4, 12, and 24 weeks after the start of intervention (active or sham paired associative magnetic stimulation). The primary outcome measure of this trial is change in lower limb American Spinal Injury Association Impairment Scale motor function score from baseline to last follow-up. Secondary outcome measures include changes in lower limb American Spinal Injury Association sensory function score, motor evoked potentials, sensory evoked potentials, modified Ashworth scale score, Maslach Burnout Inventory score, and Hamilton Depression Scale score over time. Motor evoked potential latency reflects corticospinal tract transmission time, while amplitude reflects recruitment ability; both measures can help elucidate the mechanism underlying the effect of paired associative magnetic stimulation on synaptic efficiency. Adverse events will be recorded. Findings from this trial will help to indicate whether paired associative magnetic stimulation (1) promotes recovery of lower limb sensory and motor function, reduces spasticity, and improves quality of life; (2) promotes neurologic recovery by increasing excitability of spinal cord motor neurons and stimulating synaptic plasticity; and (3) improves rehabilitation outcome in patients with spinal cord injury. Recruitment for this trial began in April 2021 and is currently ongoing. It was approved by the Ethics Committee of Yangzhi Affiliated Rehabilitation Hospital of Tongji University, China (approval No. YZ2020-018) on May 18, 2020. The study protocol was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2100044794) on March 27, 2021 (protocol version 1.0). This trial will be completed in April 2022. Related Articles | Metrics

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Effects of progesterone on T-type-Ca2+-channel expression in Purkinje cells Annika Eickhoff, Jonas Tjaden, Sarah Stahlke, Matthias Vorgerd, Verena Theis, Veronika Matschke, Carsten Theiss 2022, 17 (11):  2465-2471.  doi: 10.4103/1673-5374.339008 Abstract ( 143 )   PDF (2605KB) ( 60 )   Save Plasticity of cerebellar Purkinje cells (PC) is influenced by progesterone via the classical progesterone receptors PR-A and PR-B by stimulating dendritogenesis, spinogenesis, and synaptogenesis in these cells. Dissociated PC cultures were used to analyze progesterone effects at a molecular level on the voltage-gated T-type-Ca2+-channels Cav3.1, Cav3.2, and Cav3.3 as they helped determine neuronal plasticity by regulating Ca2+-influx in neuronal cells. The results showed direct effects of progesterone on the mRNA expression of T-type-Ca2+-channels, as well as on the protein kinases A and C being involved in downstream signaling pathways that play an important role in neuronal plasticity. For the mRNA expression studies of T-type-Ca2+-channels and protein kinases of the signaling cascade, laser microdissection and purified PC cultures of different maturation stages were used. Immunohistochemical staining was also performed to characterize the localization of T-type-Ca2+-channels in PC. Experimental progesterone treatment was performed on the purified PC culture for 24 and 48 hours. Our results show that progesterone increases the expression of Cav3.1 and Cav3.3 and associated protein kinases A and C in PC at the mRNA level within 48 hours after treatment at latest. These effects extend the current knowledge of the function of progesterone in the central nervous system and provide an explanatory approach for its influence on neuronal plasticity. Related Articles | Metrics

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ADAM10 facilitates rapid neural stem cell cycling and proper positioning within the subventricular zone niche via JAMC/RAP1Gap signaling Nadia McMillan, Gregory W. Kirschen, Sanket Desai, Emma Xia, Stella E. Tsirka, Adan Aguirre 2022, 17 (11):  2472-2483.  doi: 10.4103/1673-5374.339007 Abstract ( 166 )   PDF (10354KB) ( 29 )   Save The mechanisms that regulate neural stem cell (NSC) lineage progression and maintain NSCs within different domains of the adult neural stem cell niche, the subventricular zone are not well defined. Quiescent NSCs are arranged at the apical ventricular wall, while mitotically activated NSCs are found in the basal, vascular region of the subventricular zone. Here, we found that ADAM10 (a disintegrin and metalloproteinase 10) is essential in NSC association with the ventricular wall, and via this adhesion to the apical domain, ADAM10 regulates the switch from quiescent and undifferentiated NSC to an actively proliferative and differentiating cell state. Processing of JAMC (junctional adhesion molecule C) by ADAM10 increases Rap1GAP activity. This molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage progression. Understanding the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative properties of neural tissue. Related Articles | Metrics

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Evolution of the ErbB gene family and analysis of regulators of Egfr expression during development of the rat spinal cord Yu Zhang, Tao Zhang, Lian Xu, Ye Zhu, Li-Li Zhao, Xiao-Di Li, Wei-Wei Yang, Jing Chen, Miao Gu, Xiao-Song Gu, Jian Yang 2022, 17 (11):  2484-2490.  doi: 10.4103/1673-5374.339010 Abstract ( 148 )   PDF (7416KB) ( 26 )   Save Egfr, a member of the ErbB gene family, plays a critical role in tissue development and homeostasis, wound healing, and disease. However, expression and regulators of Egfr during spinal cord development remain poorly understood. In this study, we investigated ErbB evolution and analyzed co-expression modules, miRNAs, and transcription factors that may regulate Egfr expression in rats. We found that ErbB family members formed via Egfr duplication in the ancient vertebrates but diverged after speciation of gnathostomes. We identified a module that was co-expressed with Egfr, which involved cell proliferation and blood vessel development. We predicted 25 miRNAs and nine transcription factors that may regulate Egfr expression. Dual-luciferase reporter assays showed six out of nine transcription factors significantly affected Egfr promoter reporter activity. Two of these transcription factors (KLF1 and STAT3) inhibited the Egfr promoter reporter, whereas four transcription factors (including FOXA2) activated the Egfr promoter reporter. Real-time PCR and immunofluorescence experiments showed high expression of FOXA2 during the embryonic period and FOXA2 was expressed in the floor plate of the spinal cord, suggesting the importance of FOXA2 during embryonic spinal cord development. Considering the importance of Egfr in embryonic spinal cord development, wound healing, and disease (specifically in cancer), regulatory elements identified in this study may provide candidate targets for nerve regeneration and disease treatment in the future. Related Articles | Metrics

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Different frequencies of repetitive transcranial magnetic stimulation combined with local injection of botulinum toxin type A for post-stroke lower limb spasticity: study protocol for a prospective, single-center, non-randomized, controlled clinical trial Yang Shao, Yang Yang, Yong-Xin Sun, Ai-Hua Xu 2022, 17 (11):  2491-2496.  doi: 10.4103/1673-5374.339011 Abstract ( 157 )   PDF (551KB) ( 85 )   Save No definite consensus has currently been reached regarding the safety and efficacy of low- or high-frequency repetitive transcranial magnetic stimulation in the treatment of post-stroke muscle spasticity. The latest research indicates that when combined with local injections of botulinum toxin type A, it is more effective on post-stroke muscle spasticity than local injections of botulinum toxin type A alone. We designed a prospective, single-center, non-randomized, controlled clinical trial to investigate the safety and efficacy of different frequencies of repetitive transcranial magnetic stimulation combined with local injections of botulinum toxin type A in treating post-stroke lower limb muscle spasticity to determine an optimal therapeutic regimen. This trial will enroll 150 patients with post-stroke muscle spasticity admitted to the Department of Rehabilitation Medicine at the First Affiliated Hospital of China Medical University. All enrolled patients will undergo routine rehabilitation training and will be divided into five groups (n = 30 per group) according to the particular area of cerebral infarction and treatment methods. Group A: Patients with massive cerebral infarction will be given local injections of botulinum toxin type A and low-frequency (1 Hz) repetitive transcranial magnetic stimulation on the contralateral side; Group B: Patients with non-massive cerebral infarction will be given local injections of botulinum toxin type A and high-frequency (10–20 Hz) repetitive transcranial magnetic stimulation on the affected side; Group C: Patients with massive/non-massive cerebral infarction will be given local injections of botulinum toxin type A; Group D: Patients with massive cerebral infarction will be given low-frequency (1 Hz) repetitive transcranial magnetic stimulation on the contralateral side; and Group E: Patients with non-massive cerebral infarction will be given high-frequency (10–20 Hz) repetitive transcranial magnetic stimulation on the affected side. The primary outcome measure of this trial is a modified Ashworth scale score from 1 day before treatment to 12 months after treatment. Secondary outcome measures include Fugl-Meyer Assessment of Lower Extremity, Visual Analogue Scale, modified Barthel index, and Berg Balance Scale scores for the same time as specified for primary outcome measures. The safety indicator is the incidence of adverse events at 3–12 months after treatment. We hope to draw a definite conclusion on whether there are differences in the safety and efficacy of low- or high-frequency repetitive transcranial magnetic stimulation combined with botulinum toxin type A injections in the treatment of patients with post-stroke lower limb spasticity under strict grouping and standardized operation, thereby screening out the optimal therapeutic regimen. The study protocol was approved by the Medical Ethics Committee of the First Affiliated Hospital of China Medical University (approval No. [2021] 2021-333-3) on August 19, 2021. The trial was registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR2100052180) on October 21, 2021. The protocol version is 1.1. Related Articles | Metrics

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An enriched environment reduces hippocampal inflammatory response and improves cognitive function in a mouse model of stroke Hong-Yu Zhou, Ya-Ping Huai, Xing Jin, Ping Yan, Xiao-Jia Tang, Jun-Ya Wang, Nan Shi, Meng Niu, Zhao-Xiang Meng, Xin Wang 2022, 17 (11):  2497-2503.  doi: 10.4103/1673-5374.338999 Abstract ( 251 )   PDF (11930KB) ( 55 )   Save An enriched environment is used as a behavioral intervention therapy that applies sensory, motor, and social stimulation, and has been used in basic and clinical research of various neurological diseases. In this study, we established mouse models of photothrombotic stroke and, 24 hours later, raised them in a standard, enriched, or isolated environment for 4 weeks. Compared with the mice raised in a standard environment, the cognitive function of mice raised in an enriched environment was better and the pathological damage in the hippocampal CA1 region was remarkably alleviated. Furthermore, protein expression levels of tumor necrosis factor receptor-associated factor 6, nuclear factor κB p65, interleukin-6, and tumor necrosis factor α, and the mRNA expression level of tumor necrosis factor receptor-associated factor 6 were greatly lower, while the expression level of miR-146a-5p was higher. Compared with the mice raised in a standard environment, changes in these indices in mice raised in an isolated environment were opposite to mice raised in an enriched environment. These findings suggest that different living environments affect the hippocampal inflammatory response and cognitive function in a mouse model of stroke. An enriched environment can improve cognitive function following stroke through up-regulation of miR-146a-5p expression and a reduction in the inflammatory response. Related Articles | Metrics

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Silencing miRNA-324-3p protects against cerebral ischemic injury via regulation of the GATA2/A1R axis An-Qi Zhang, Lu Wang, Yi-Xiu Wang, Shan-Shan Hong, Yu-Shan Zhong, Ru-Yi Yu, Xin-Lu Wu, Bing-Bing Zhou, Qi-Min Yu, Hai-Feng Fu, Shuang-Dong Chen, Yun-Chang Mo, Qin-Xue Dai, Jun-Lu Wang 2022, 17 (11):  2504-2511.  doi: 10.4103/1673-5374.339009 Abstract ( 163 )   PDF (1797KB) ( 97 )   Save Previous studies have suggested that miR-324-3p is related to the pathophysiology of cerebral ischemia, but the mechanism underlying this relationship is unclear. In this study, we found that miR-324-3p expression was decreased in patients with acute ischemic stroke and in in vitro and in vivo models of ischemic stroke. miR-324-3p agomir potentiated ischemic brain damage in rats subjected to middle cerebral artery occlusion, as indicated by increased infarct volumes and cell apoptosis rates and greater neurological deficits. In a PC12 cell oxygen-glucose deprivation/reoxygenation model, a miR-324-3p mimic decreased cell viability and expression of the anti-apoptotic protein BCL2 and increased expression of the pro-apoptotic protein BAX and rates of cell apoptosis, whereas treatment with a miR-324-3p inhibitor had the opposite effects. Silencing miR-324-3p increased adenosine A1 receptor (A1R) expression through regulation of GATA binding protein 2 (GATA2). These findings suggest that silencing miR-324-3p reduces ischemic brain damage via the GATA2/A1R axis. Related Articles | Metrics

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A three-dimensional matrix system containing melatonin and neural stem cells repairs damage from traumatic brain injury in rats Xuan-Yu Fang, Da-Wei Zhao, Chao Zhang, Hong-Fei Ge, Xu-Yang Zhang, Feng-Chun Zhao, Yi-Bin Jiang, Hua Feng, Rong Hu 2022, 17 (11):  2512-2517.  doi: 10.4103/1673-5374.339001 Abstract ( 145 )   PDF (12122KB) ( 47 )   Save Brain lesions can cause neural stem cells to activate, proliferate, differentiate, and migrate to the injured area. However, after traumatic brain injury, brain tissue defects and microenvironment changes greatly affect the survival and growth of neural stem cells; the resulting reduction in the number of neural stem cells impedes effective repair of the injured area. Melatonin can promote the survival, proliferation, and differentiation of neural stem cells under adverse conditions such as oxidative stress or hypoxia that can occur after traumatic brain injury. Therefore, we investigated the therapeutic effects of melatonin combined with neural stem cells on traumatic brain injury in rats. First, in vitro studies confirmed that melatonin promoted the survival of neural stem cells deprived of oxygen and glucose. Then, we established a three-dimensional Matrigel-based transplantation system containing melatonin and neural stem cells and then used it to treat traumatic brain injury in rats. We found that treatment with the Matrigel system containing melatonin and neural stem cells decreased brain lesion volume, increased the number of surviving neurons, and improved recovery of neurological function compared with treatment with Matrigel alone, neural stem cells alone, Matrigel and neural stem cells combined, and Matrigel and melatonin combined. Our findings suggest that the three-dimensional Matrigel-based transplantation system containing melatonin and neural stem cells is a potential treatment for traumatic brain injury. Related Articles | Metrics

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Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats Yang Jiao, Yue-Tong Sun, Nai-Fei Chen, Li-Na Zhou, Xin Guan, Jia-Yi Wang, Wen-Juan Wei, Chao Han, Xiao-Lei Jiang, Ya-Chen Wang, Wei Zou, Jing Liu 2022, 17 (11):  2518-2525.  doi: 10.4103/1673-5374.339002 Abstract ( 134 )   PDF (29193KB) ( 33 )   Save Administration of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) is believed to be an effective method for treating neurodevelopmental disorders. In this study, we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism. We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy. Rat offspring were intranasally administered hUC-MSCs on postnatal day 14. We found that polypyrimidine tract-binding protein-1 (PTBP-1) participated in the regulation of lipopolysaccharide-induced maternal immune activation, which led to neonatal hypoxic/ischemic brain injury. Intranasal delivery of hUC-MSCs inhibited PTBP-1 expression, alleviated neonatal brain injury-related inflammation, and regulated the number and function of glial fibrillary acidic protein-positive astrocytes, thereby promoting plastic regeneration of neurons and improving brain function. These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation. Related Articles | Metrics

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In vivo neuronal and astrocytic activation in somatosensory cortex by acupuncture stimuli Xiao-Yue Chang, Kai Chen, Tong Cheng, Pui To Lai, Li Zhang, Kwok-Fai So, Edward S. Yang 2022, 17 (11):  2526-2529.  doi: 10.4103/1673-5374.339003 Abstract ( 195 )   PDF (1617KB) ( 90 )   Save Acupuncture is a medical treatment that has been widely practiced in China for over 3000 years, yet the neural mechanisms of acupuncture are not fully understood. We hypothesized that neurons and astrocytes act independently and synergistically under acupuncture stimulation. To investigate this, we used two-photon in vivo calcium recording to observe the effects of acupuncture stimulation at ST36 (Zusanli) in mice. Acupuncture stimulation in peripheral acupoints potentiated calcium signals of pyramidal neurons and astrocytes in the somatosensory cortex and resulted in late-onset calcium transients in astrocytes. Chemogenetic inhibition of neurons augmented the astrocytic activity. These findings suggest that acupuncture activates neuronal and astrocytic activity in the somatosensory cortex and provide evidence for the involvement of both neurons and astrocytes in acupuncture treatment. Related Articles | Metrics

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NOVA1 promotes SMN2 exon 7 splicing by binding the UCAC motif and increases SMN protein expression Li-Li Du, Jun-Jie Sun, Zhi-Heng Chen, Yi-Xiang Shao, Liu-Cheng Wu 2022, 17 (11):  2530-2536.  doi: 10.4103/1673-5374.339005 Abstract ( 101 )   PDF (5420KB) ( 73 )   Save Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disease with a high lethality rate in infants. Variants in the homologous genes survival of motor neuron (SMN)1 and SMN2 have been reported to be SMA pathogenic factors. Previous studies showed that a high inclusion rate of SMN2 exon 7 increased SMN expression, which in turn reduced the severity of SMA. The inclusion rate of SMN2 exon 7 was higher in neural tissues than in non-neural tissues. Neuro-oncological ventral antigen (NOVA) is a splicing factor that is specifically and highly expressed in neurons. It plays a key role in nervous system development and in the induction of nervous system diseases. However, it remains unclear whether this splicing factor affects SMA. In this study, we analyzed the inclusion of SMN2 exon 7 in different tissues in a mouse model of SMA (genotype smn–/–SMN22tg/0) and littermate controls (genotype smn+/–SMN22tg/0). We found that inclusion level of SMN2 exon 7 was high in the brain and spinal cord tissue, and that NOVA1 was also highly expressed in nervous system tissues. In addition, SMN2 exon 7 and NOVA1 were expressed synchronously in the central nervous system. We further investigated the effects of NOVA1 on disease and found that the number of neurons in the anterior horn of spinal cord decreased in the mouse model of SMA during postnatal days 1–7, and that NOVA1 expression levels in motor neurons decreased simultaneously as spinal muscular atrophy developed. We also found that in vitro expression of NOVA1 increased the inclusion of SMN2 exon 7 and expression of the SMN2 protein in the U87MG cell line, whereas the opposite was observed when NOVA1 was knocked down. Finally, point mutation and RNA pull-down showed that the UCAC motif in SMN2 exon 7 plays a critical role in NOVA1 binding and promoting the inclusion of exon 7. Moreover, CA was more essential for the inclusion of exon 7 than the order of Y residues in the motif. Collectively, these findings indicate that NOVA1 interacts with the UCAC motif in exon 7 of SMN2, thereby enhancing inclusion of exon 7 in SMN2, which in turn increases expression of the SMN protein. Related Articles | Metrics

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Obstructive sleep apnea aggravates neuroinflammation and pyroptosis in early brain injury following subarachnoid hemorrhage via ASC/HIF-1α pathway Jun Xu, Qian Li, Chen-Yu Xu, Shan Mao, Jia-Jia Jin, Wei Gu, Ying Shi, Chun-Fang Zou, Liang Ye 2022, 17 (11):  2537-2543.  doi: 10.4103/1673-5374.339000 Abstract ( 109 )   PDF (4255KB) ( 77 )   Save Obstructive sleep apnea can worsen the prognosis of subarachnoid hemorrhage. However, the underlying mechanism remains unclear. In this study, we established a mouse model of subarachnoid hemorrhage using the endovascular perforation method and exposed the mice to intermittent hypoxia for 8 hours daily for 2 consecutive days to simulate sleep apnea. We found that sleep apnea aggravated brain edema, increased hippocampal neuron apoptosis, and worsened neurological function in this mouse model of subarachnoid hemorrhage. Then, we established an in vitro HT-22 cell model of hemin-induced subarachnoid hemorrhage/intermittent hypoxia and found that the cells died, and lactate dehydrogenase release increased, after 48 hours. We further investigated the underlying mechanism and found that sleep apnea increased the expression of hippocampal neuroinflammatory factors interleukin-1β, interleukin-18, interleukin-6, nuclear factor κB, pyroptosis-related protein caspase-1, pro-caspase-1, and NLRP3, promoted the proliferation of astrocytes, and increased the expression of hypoxia-inducible factor 1α and apoptosis-associated speck-like protein containing a CARD, which are the key proteins in the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway. We also found that knockdown of hypoxia-inducible factor 1α expression in vitro greatly reduced the damage to HY22 cells. These findings suggest that sleep apnea aggravates early brain injury after subarachnoid hemorrhage by aggravating neuroinflammation and pyroptosis, at least in part through the hypoxia-inducible factor 1α/apoptosis-associated speck-like protein containing a CARD signaling pathway. Related Articles | Metrics

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Polydopamine-modified chitin conduits with sustained release of bioactive peptides enhance peripheral nerve regeneration in rats Ci Li, Song-Yang Liu, Li-Ping Zhou, Tian-Tian Min, Meng Zhang, Wei Pi, Yong-Qiang Wen, Pei-Xun Zhang 2022, 17 (11):  2544-2550.  doi: 10.4103/1673-5374.339006 Abstract ( 166 )   PDF (3126KB) ( 115 )   Save The introduction of neurotrophic factors into injured peripheral nerve sites is beneficial to peripheral nerve regeneration. However, neurotrophic factors are rapidly degraded in vivo and obstruct axonal regeneration when used at a supraphysiological dose, which limits their clinical benefits. Bioactive mimetic peptides have been developed to be used in place of neurotrophic factors because they have a similar mode of action to the original growth factors and can activate the equivalent receptors but have simplified sequences and structures. In this study, we created polydopamine-modified chitin conduits loaded with brain-derived neurotrophic factor mimetic peptides and vascular endothelial growth factor mimetic peptides (Chi/PDA-Ps). We found that the Chi/PDA-Ps conduits were less cytotoxic in vitro than chitin conduits alone and provided sustained release of functional peptides. In this study, we evaluated the biocompatibility of the Chi/PDA-Ps conduits. Brain-derived neurotrophic factor mimetic peptide and vascular endothelial growth factor mimetic peptide synergistically promoted proliferation of Schwann cells and secretion of neurotrophic factors by Schwann cells and attachment and migration of endothelial cells in vitro. The Chi/PDA-Ps conduits were used to bridge a 2 mm gap between the nerve stumps in rat models of sciatic nerve injury. We found that the application of Chi/PDA-Ps conduits could improve the motor function of rats and reduce gastrocnemius atrophy. The electrophysiological results and the microstructure of regenerative nerves showed that the nerve conduction function and remyelination was further restored. These findings suggest that the Chi/PDA-Ps conduits have great potential in peripheral nerve injury repair. Related Articles | Metrics

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Delayed activation of leg somatotopic fibers of an injured corticospinal tract in a patient with cerebral infarction Min Jye Cho, Sung Ho Jang 2022, 17 (11):  2551-2552.  doi: 10.4103/1673-5374.339013 Abstract ( 101 )   PDF (622KB) ( 49 )   Save Stroke is a leading cause of major adult disabilities, and motor weakness is one of the most serious disability-related sequelae of stroke. Most of the motor recovery in stroke patients is reported to occur within 6 months after stroke onset, and this period is deemed critical for motor recovery in stroke (Grefkes and Fink, 2020; Olafson et al., 2021). Therefore, active rehabilitation within 6 months after stroke onset is strongly recommended for hemiparetic stroke patients (Grefkes and Fink, 2020; Olafson et al., 2021). Research on delayed motor recovery after the critical period is important in stroke rehabilitation because it could provide a basis for rehabilitation strategies for chronic patients who failed to show good recovery during the critical period, even though they had a potential for good motor recovery. However, little is known about delayed motor recovery occurring more than 6 months after stroke onset (Jang et al., 2019). Related Articles | Metrics