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15 May 2022, Volume 17 Issue 5 Previous Issue   

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From regenerative strategies to pharmacological approaches: can we fine-tune treatment for Parkinson’s disease? Rita Caridade Silva, Helena Sofia Domingues, António J. Salgado, Fábio G. Teixeira 2022, 17 (5):  933-936.  doi: 10.4103/1673-5374.324827 Abstract ( 308 )   PDF (2816KB) ( 99 )   Save Parkinson’s disease is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by severe motor complications caused by progressive degeneration of dopaminergic neurons. Current treatment is focused on mitigating the symptoms through the administration of levodopa, rather than on preventing dopaminergic neuronal damage. Therefore, the use and development of neuroprotective/disease-modifying strategies is an absolute need that can lead to promising gains on translational research of Parkinson’s disease. For instance, N-acetylcysteine, a natural compound with strong antioxidant effects, has been shown to modulate oxidative stress, preventing dopamine-induced cell death. Despite the evidence of neuroprotective and modulatory effects of this drug, as far as we know, it does not induce per se any regenerative process. Therefore, it would be of interest to combine the latter with innovative therapies that induce dopaminergic neurons repair or even differentiation, as stem cell-based strategies. Stem cells secretome has been proposed as a promising therapeutic approach for Parkinson’s disease, given its ability to modulate cell viability/preservation of dopaminergic neurons. Such approach represents a shift in the paradigm, showing that cell-transplantation free therapies based on the use of stem cells secretome may represent a potential alternative for regenerative medicine of Parkinson’s disease. Thus, in this review, we address the current understanding of the potential combination of stem cell free-based strategies and neuroprotective/disease-modifying strategies as a new paradigm for the treatment of central nervous system neurodegenerative diseases, like Parkinson’s disease. Related Articles | Metrics

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Glymphatic imaging and modulation of the optic nerve Anisha Kasi, Crystal Liu, Muneeb A. Faiq, Kevin C. Chan 2022, 17 (5):  937-947.  doi: 10.4103/1673-5374.324829 Abstract ( 191 )   PDF (2583KB) ( 161 )   Save Optic nerve health is essential for proper function of the visual system. However, the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve, such as glaucoma, is not fully understood. Recently, it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases. The ability to clear metabolic waste is essential for tissue homeostasis in mammals, including humans. While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions, there is growing evidence of a glymphatic system in the central nervous system, which structurally includes the optic nerve. Named to acknowledge the supportive role of astroglial cells, this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system. Herein, we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve. We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents, aquaporin 4-null rodents, and humans; glymphatic imaging studies in diseases where the optic nerve is impaired; and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health. We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve. Related Articles | Metrics

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Can lithium enhance the extent of axon regeneration and neurological recovery following peripheral nerve trauma? Damien P. Kuffler 2022, 17 (5):  948-952.  doi: 10.4103/1673-5374.324830 Abstract ( 138 )   PDF (317KB) ( 51 )   Save The clinical “gold standard” technique for attempting to restore function to nerves with a gap is to bridge the gap with sensory autografts. However, autografts induce good to excellent recovery only across short nerve gaps, in young patients, and when repairs are performed a short time post nerve trauma. Even under the best of conditions, < 50% of patients recover good recovery. Although many alternative techniques have been tested, none is as effective as autografts. Therefore, alternative techniques are required that increase the percentage of patients who recover function and the extent of their recovery. This paper examines the actions of lithium, and how it appears to trigger all the cellular and molecular events required to promote axon regeneration, and how both in animal models and clinically, lithium administration enhances both the extent of axon regeneration and neurological recovery. The paper proposes more extensive clinical testing of lithium for its ability and reliability to increase the extent of axon regeneration and functional recovery.  Related Articles | Metrics

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Time-to-enrollment in clinical trials investigating neurological recovery in chronic spinal cord injury: observations from a systematic review and ClinicalTrials.gov database F M Moinuddin, Yagiz Ugur Yolcu, Waseem Wahood, Jad Zreik, Sandy Goncalves, Anthony John Windebank, Wenchun Qu, Mohamad Bydon 2022, 17 (5):  953-958.  doi: 10.4103/1673-5374.324826 Abstract ( 132 )   PDF (638KB) ( 71 )   Save Currently, large numbers of clinical trials are performed to investigate different forms of experimental therapy for patients suffering from chronic spinal cord injury (SCI). However, for the enrollment process, there are different views on how the time period between injury and interventions should be determined. Herein, we sought to evaluate the impact of time-to-enrollment in chronic SCI clinical trials. A data set comprising 957 clinical studies from clinicalTrials.gov was downloaded and analyzed focusing on the eligibility criteria for post-injury time-to-enrollment. We also aggregated individual patient data from nine clinical trials of regenerative interventions for chronic SCI selected by a systematic literature search from 1990 to 2018. Characteristics of the studies were assessed and compared by dividing into three groups based on time-to-enrollment (group 1 ≤ 12 months, group 2 = 12–23 months and group 3 ≥ 24 months). In ClinicalTrials.gov registry, 445 trials were identified for chronic SCI where 87% (385) were unrestricted in the maximum post-injury time for trial eligibility. From systematic literature search, nine studies and 156 patients (group 1 = 30, group 2 = 55 and group 3 = 71) were included. The range of time-to-enrollment was 0.5 to 321 months in those studies. We also observed various degrees of motor and sensory improvement in between three time-to-enrollment groups. Our results indicate that enrolling wide ranges of time-to-enrollment in a group may present imprecise outcomes. Clinical trial designs should consider appropriate post-injury time frames to evaluate therapeutic benefit.  Related Articles | Metrics

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Semaphorin7A: its role in the control of serotonergic circuits and functional recovery following spinal cord injury Julie Fourneau, Florence M. Bareyre 2022, 17 (5):  959-962.  doi: 10.4103/1673-5374.324828 Abstract ( 140 )   PDF (2141KB) ( 42 )   Save Serotonin is a monoamine neurotransmitter synthetized in various populations of brainstem neurons. In the spinal cord, descending serotonergic projections regulate postural muscle tone, locomotion and rhythm and coordination of movements via the Central Pattern Generator. Following a spinal cord injury, serotonergic projections to the lumbar spinal cord, where the Central Pattern Generators are located, are interrupted resulting in devastating locomotor impairments and changes in the expression and activation of serotonin and its spinal receptors. The molecular cues that control the precise patterning and targeting of serotonergic inputs onto Central Pattern Generator networks in healthy animals or after injury are still unknown. In our recent research work, we have been particularly interested in Semaphorin7A, which belongs to the Semaphorins family involved in guiding growing axons and controlling plasticity of synaptic connections. In this review, we discuss the role of Semaphorin7A signaling as an important molecular actor that instructs the patterning of serotonin inputs to spinal Central Pattern Generator networks. We show that Semaphorin7A controls the wiring of descending serotonin axons in the spinal cord. Our results reveal that mistargetting of serotonin fibers in the spinal cord is compensated in healthy uninjured Semaphorin7A deficient mice so that their gross locomotion proceeds accurately. We also demonstrate that when the system is challenged with a spinal lesion, the pattern of post-injury serotonin expression is significantly altered in Semaphorin7A deficient mice with specific ectopic targeting of serotonin fibers in the lumbar spinal cord. Compensatory mechanisms in place in uninjured Semaphorin7A deficient mice are lost and injured Semaphorin7A deficient mice exhibit a worsening of their post-injury locomotor abilities. Our findings identify Semaphorin7A as a critical determinant of serotonergic circuit formation in healthy or spinal cord injured mice. Related Articles | Metrics

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Application value of biofluid-based biomarkers for the diagnosis and treatment of spinal cord injury Hong-Da Wang, Zhi-Jian Wei, Jun-Jin Li, Shi-Qing Feng 2022, 17 (5):  963-971.  doi: 10.4103/1673-5374.324823 Abstract ( 147 )   PDF (946KB) ( 78 )   Save Recent studies in patients with spinal cord injuries (SCIs) have confirmed the diagnostic potential of biofluid-based biomarkers, as a topic of increasing interest in relation to SCI diagnosis and treatment. This paper reviews the research progress and application prospects of recently identified SCI-related biomarkers. Many structural proteins, such as glial fibrillary acidic protein, S100-β, ubiquitin carboxy-terminal hydrolase-L1, neurofilament light, and tau protein were correlated with the diagnosis, American Spinal Injury Association Impairment Scale, and prognosis of SCI to different degrees. Inflammatory factors, including interleukin-6, interleukin-8, and tumor necrosis factor α, are also good biomarkers for the diagnosis of acute and chronic SCI, while non-coding RNAs (microRNAs and long non-coding RNAs) also show diagnostic potential for SCI. Trace elements (Mg, Se, Cu, Zn) have been shown to be related to motor recovery and can predict motor function after SCI, while humoral markers can reflect the pathophysiological changes after SCI. These factors have the advantages of low cost, convenient sampling, and ease of dynamic tracking, but are also associated with disadvantages, including diverse influencing factors and complex level changes. Although various proteins have been verified as potential biomarkers for SCI, more convincing evidence from large clinical and prospective studies is thus required to identify the most valuable diagnostic and prognostic biomarkers for SCI. Related Articles | Metrics

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Potential neuroprotection by Dendrobium nobile Lindl alkaloid in Alzheimer’s disease models Dai-Di Li, Chang-Qing Zheng, Feng Zhang, Jing-Shan Shi 2022, 17 (5):  972-977.  doi: 10.4103/1673-5374.324824 Abstract ( 369 )   PDF (4133KB) ( 240 )   Save At present, treatments for Alzheimer’s disease can temporarily relieve symptoms but cannot prevent the decline of cognitive ability and other neurodegenerative changes. Dendrobium nobile Lindl alkaloid is the main active component of Dendrobium nobile Lindl. Dendrobium nobile Lindl alkaloid has been shown to resist aging, prolong life span, and exhibit immunomodulatory effects in animals. This review summarizes the mechanisms behind the neuroprotective effects reported in Alzheimer’s disease animal models. The neuroprotective effects of Dendrobium nobile Lindl alkaloid have not been studied in patients. The mechanisms by which Dendrobium nobile Lindl alkaloid has been reported to improve cognitive dysfunction in Alzheimer’s disease animal models may be associated with extracellular amyloid plaque production, regulation of tau protein hyperphosphorylation, inhibition of neuroinflammation and neuronal apoptosis, activation of autophagy, and enhanced synaptic connections.  Related Articles | Metrics

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Diffusion tensor tractography characteristics of axonal injury in concussion/mild traumatic brain injury Sung Ho Jang, You Sung Seo 2022, 17 (5):  978-982.  doi: 10.4103/1673-5374.324825 Abstract ( 236 )   PDF (1487KB) ( 57 )   Save The main advantage of diffusion tensor tractography is that it allows the entire neural tract to be evaluated. In addition, configurational analysis of reconstructed neural tracts can indicate abnormalities such as tearing, narrowing, or discontinuations, which have been used to identify axonal injury of neural tracts in concussion patients. This review focuses on the characteristic features of axonal injury in concussion or mild traumatic brain injury (mTBI) patients through the use of diffusion tensor tractography. Axonal injury in concussion (mTBI) patients is characterized by their occurrence in long neural tracts and multiple injuries, and these characteristics are common in patients with diffuse axonal injury and in concussion (mTBI) patients with axonal injury. However, the discontinuation of the corticospinal tract is mostly observed in diffuse axonal injury, and partial tearing and narrowing in the subcortical white matter are frequently observed in concussion (mTBI) patients with axonal injury. This difference appears to be attributed to the observation that axonal injury in concussion (mTBI) patients is the result of weaker forces than those producing diffuse axonal injuries. In addition, regarding the fornix, in diffuse axonal injury, discontinuation of the fornical crus has been frequently reported, but in concussion (mTBI) patients, many collateral branches form in the fornix in addition to these findings in many case studies. It is presumed that the impact on the brain in TBI is relatively weaker than that in diffuse axonal injury, and that the formation of collateral branches occurs during the fornix recovery process. Although the occurrence of axonal injury in multiple areas of the brain is an important feature of diffuse axonal injury, case studies in concussion (mTBI) have shown that axonal injury occurs in multiple neural tracts. Because axonal injury lesions in mTBI patients may persist for approximately 10 years after injury onset, the characteristics of axonal injury in concussion (mTBI) patients, which are reviewed and categorized in this review, are expected to serve as useful supplementary information in the diagnosis of axonal injury in concussion (mTBI) patients. Related Articles | Metrics

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Preliminary examination of early neuroconnectivity features in the R6/1 mouse model of Huntington’s disease by ultra-high field diffusion MRI Rodolfo G. Gatto, Carina Weissmann 2022, 17 (5):  983-986.  doi: 10.4103/1673-5374.324831 Abstract ( 151 )   PDF (1396KB) ( 39 )   Save During the last decades, advances in the understanding of genetic, cellular, and microstructural alterations associated to Huntington’s disease (HD) have improved the understanding of this progressive and fatal illness. However, events related to early neuropathological events, neuroinflammation, deterioration of neuronal connectivity and compensatory mechanisms still remain vastly unknown. Ultra-high field diffusion MRI (UHFD-MRI) techniques can contribute to a more comprehensive analysis of the early microstructural changes observed in HD. In addition, it is possible to evaluate if early imaging microstructural parameters might be linked to histological biomarkers. Moreover, qualitative studies analyzing histological complexity in brain areas susceptible to neurodegeneration could provide information on inflammatory events, compensatory increase of neuroconnectivity and mechanisms of brain repair and regeneration. The application of ultra-high field diffusion-MRI technology in animal models, particularly the R6/1 mice (a common preclinical mammalian model of HD), provide the opportunity to analyze alterations in a physiologically intact model of the disease. Although some disparities in volumetric changes across different brain structures between preclinical and clinical models has been documented, further application of different diffusion MRI techniques used in combination like diffusion tensor imaging, and neurite orientation dispersion and density imaging  have proved effective in characterizing early parameters associated to alteration in water diffusion exchange within intracellular and extracellular compartments in brain white and grey matter. Thus, the combination of diffusion MRI imaging techniques and more complex neuropathological analysis could accelerate the discovery of new imaging biomarkers and the early diagnosis and neuromonitoring of patients affected with HD. Related Articles | Metrics

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Axonal protein synthesis in central nervous system regeneration: is building an axon a local matter? Julia Schaeffer, Stephane Belin 2022, 17 (5):  987-988.  doi: 10.4103/1673-5374.324835 Abstract ( 165 )   PDF (690KB) ( 91 )   Save Neurons of the mature central nervous system (CNS, mainly the brain and spinal cord) are unable to regenerate spontaneously after a lesion, in contrast to neurons of the peripheral nervous system (PNS). While the extraneuronal environment was long thought to be limiting, evidence was given less than 15 years ago that neurons themselves are critical players of their own regeneration (Park et al., 2008). Indeed, CNS neurons show a decline of axon growth capacity as they mature and after an injury. Today, the role of axonal translation is actively explored in the paradigm of embryonic neuronal growth and in peripheral nerve injury and regeneration, but less is known about the role of local protein synthesis in regrowth of adult CNS axons. Here we discuss how the current understanding of axonal translation in the CNS may contribute to the development of novel strategies to enhance axon regeneration in the injured CNS. Related Articles | Metrics

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Axon regeneration: membrane expansion and lipidomics Sean Meehan, Sanjoy K. Bhattacharya 2022, 17 (5):  989-990.  doi: 10.4103/1673-5374.324832 Abstract ( 170 )   PDF (457KB) ( 69 )   Save Axon regeneration requires protein synthesis and membrane expansion. The presence of granular material was discovered in the perikaryon of neurons but not axons using Nissl staining (Gomes, 2019). This is one of the characteristic features of neurons and we now know that RNA content of the granular material stains with Nissl stain. Although no Nissl granules are present in axons, mRNA can be shuttled to distal axons for local protein synthesis. Axonal protein synthesis only makes up a small portion as the majority occurs in the perikaryon. The required membrane expansion and protein synthesis machinery are still present in the adult central nervous system (CNS) axon. It is conceivable that regeneration of severed or dysfunctional axons, such as those present after traumatic optic nerve or spinal cord injury and due to elevated intraocular pressure in glaucoma, occurs with possible membrane sealing, growth cone formation, and membrane expansion (Meehan et al., 2021). Axon sealing after injury as well as growth are likely to be mediated by membrane expansion (Pfenninger et al., 2003). The majority of membrane biogenesis and de novo lipid synthesis occurs in the neuron’s perikaryon. Vesicles are formed through the native secretory pathway and subsequently transported anterogradely to the distal axon for insertion. Vesicles can be seen accumulating at the growth cone’s transitional zone, likely waiting for a regulatory signal to begin membrane fusion. Related Articles | Metrics

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Activity-dependent remodeling of genome architecture in engram cells facilitates memory formation and recall Asaf Marco 2022, 17 (5):  991-993.  doi: 10.4103/1673-5374.324834 Abstract ( 191 )   PDF (255KB) ( 49 )   Save The formation and preservation of long-term memories critically depend upon coordinated activity of neuronal circuits, intracellular signaling cascades and synaptic remodeling (Josselyn et al., 2015). These essential processes occur in specific cell populations known as  the engram ensemble (Josselyn et al., 2015). The current model for engram formation suggests that an experience activates a sub-population of neurons that can be measured by the expression of immediate early genes (IEG), such as Arc (activity regulated cytoskeleton associated protein, Arg3.1) or cFos (Fos Proto-Oncogene, AP-1 transcription factor subunit). Activated engram cells are then physically or chemically modified during memory consolidation, where labile memory is transformed into a more stable and long-lasting state. Notably, the memory consolidation process occurs predominantly long after the initial stimulus had ceased and the engram cells are in a dormant or a quiescent state. Reactivation of the engram ensemble by subsequent presentation of the original stimuli results in memory retrieval. Therefore, temporal progressions of memory formation from learning to retrieval require several waves of delayed transcriptional and translational alterations (Josselyn et al., 2015). Nonetheless, the molecular mechanisms that enable this temporal and spatial synchronization remain elusive.   Related Articles | Metrics

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Is it possible to develop a cerebellar reserve? Francesca Gelfo, Laura Petrosini 2022, 17 (5):  994-996.  doi: 10.4103/1673-5374.324836 Abstract ( 144 )   PDF (393KB) ( 46 )   Save The concept of neural plasticity accounts for the now well clarified brain ability to react to internal and external stimuli by transforming its structure and function. The translation of whatever experience in specific electrical signals that run through our neural networks induces a number of plastic changes at both functional and structural levels. In the last seventy year, a large amount of evidence demonstrated that plastic changes are the basis of the brain successful responding to the experience during developmental phases, in learning and memory processes throughout life, and even in the case of damage occurrence, in both neuroprotective and therapeutic ways. Indeed, plastic changes allow brain structure to reorganize in the presence of lesion, in order to completely or at least partially recover damaged functions (Gelfo et al., 2016; 2018; Gelfo, 2019).  Related Articles | Metrics

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Metabolic reprogramming of glial cells as a new target for central nervous system axon regeneration Erin L. Walden, Shuxin Li 2022, 17 (5):  997-998.  doi: 10.4103/1673-5374.324833 Abstract ( 274 )   PDF (653KB) ( 148 )   Save After central nervous system (CNS) injury, severed axons fail to regenerate and their disconnections to the original targets result in permanent functional deficits in patients (Mahar and Cavalli, 2018). Both the diminished intrinsic regenerative capacity of mature neurons and the inhibitory CNS milieu contribute to the regenerative failure following CNS injury. Glial cells have important physiological functions, including maintaining homeostasis, supporting and protecting neurons, regulating neuronal activities, and forming myelin (Gaudet and Fonken, 2018). In response to CNS injury, reactive glial cells shift their phenotype and activities and contribute to scar formation. Gliosis is a defense response of the CNS to diminish primary damage and to repair injured tissues and has numerous beneficial effects, such as preventing the spread of damage from injury site. Various glia present around the lesion, including astrocytes, may express multiple positive molecules that promote axon regrowth, such as laminins, syndecans, glypicans, and decorin. Accordingly, preventing scar formation after injury or removing chronic astrocytic scars failed to promote axon regeneration (Anderson et al., 2016). However, reactive glial cells and scar tissues ultimately produce detrimental effects by upregulating numerous molecules that suppress neuronal elongation and form potent barriers to axon regeneration. Shortly after CNS injury, chondroitin sulfate proteoglycans (CSPGs) are upregulated dramatically and form part of the extracellular matrix components. CSPGs remain around the lesion epicenter for at least months, form an inhibitory milieu around the lesion, and suppress regrowth of injured axons into and beyond the lesion area (Hara et al., 2017). Two transmembrane protein tyrosine phosphatases (LAR and PTP σ) are important for mediating inhibition by CSPGs.  Related Articles | Metrics

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Self-renewal of peripheral nerve resident macrophage: does it represent a unique activation status? Maricris Bautista, Anand Krishnan 2022, 17 (5):  999-1000.  doi: 10.4103/1673-5374.324845 Abstract ( 130 )   PDF (602KB) ( 51 )   Save Macrophages are immune cells of myeloid origin and are present in almost all tissues. They perform a wide variety of functions contributing to tissue development, homeostasis, pathogenesis, and repair (Wynn et al., 2013). Strikingly, macrophages residing at different tissues, and at different compartments of an individual tissue, demonstrate enormously diverse molecular characteristics (Gordon and Taylor, 2005). Querying this exceptional molecular heterogeneity challenged the long-standing theory that adult tissue macrophages derive solely from circulating monocytes. Indeed, lineage tracing and fate mapping studies using chimeric and cre-floxed animal models, followed by RNA-sequencing, convincingly demonstrated that tissue resident macrophages also consist of a pool that originates from yolk-sac progenitor cells (YPC) (Ginhoux and Guilliams, 2016; De Schepper et al., 2018). For example, initial macrophages arise from primitive progenitor cells in the yolk-sac at embryonic day (E) 8.5. These macrophages migrate into developing tissues to generate long-term resident tissue macrophages. At E10.5, erythromyeloid progenitor cells from the yolk-sac enter the fetal liver giving rise to hematopoietic stem cells (HSCs), which will eventually generate fetal liver monocytes. The fetal liver monocytes then migrate into developing peripheral tissues to establish another pool of long-term resident tissue macrophages. In addition, the erythromyeloid progenitor cells seed bone marrow, and the resulting bone marrow HSCs then maintain the uninterrupted supply of circulating monocyte-derived macrophages in adult tissues (Ginhoux and Guilliams, 2016; Goldmann et al., 2016). Overall, adult tissues encompass a mix of YPC-derived and circulating monocyte-derived macrophages and they are molecularly distinct. Some examples of YPC derived macrophages include microglia, alveolar macrophages, Langerhans cells, Kupffer cells, peritoneal macrophages, cardiac macrophages, and a subset of macrophages in the peripheral nervous system (PNS) (Wynn et al., 2013; Wang et al., 2020; Ydens et al., 2020). Related Articles | Metrics

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Investigating the role of Ca2+/calmodulin-dependent protein kinase II in the survival of retinal ganglion cells Xinzheng Guo, Bo Chen 2022, 17 (5):  1001-1002.  doi: 10.4103/1673-5374.324844 Abstract ( 135 )   PDF (1901KB) ( 55 )   Save Retinal ganglion cells (RGCs) are the sole output neurons of the retina that project long axons and transmit visual information to the brain. The degeneration of RGCs leads to irreversible vision loss in a variety of pathological states, including excitotoxicity, traumatic nerve injury, and glaucoma. However, an unmet clinical challenge is the lack of effective neuroprotective approaches to protect RGCs and thus preserve their function, necessitating extensive investigation of pro-survival genes in basic and translational research. Here, we first briefly describe widely used experimental models of RGC degeneration and methods for evaluating gene function in RGC survival, and then share our thoughts on the role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in regulating the survival of RGCs after excitotoxic injury.    Related Articles | Metrics

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Iron, the endolysosomal system and neuroinflammation: a matter of balance Daniel A. Bórquez, Pamela J. Urrutia, Marco T. Núñez 2022, 17 (5):  1003-1004.  doi: 10.4103/1673-5374.324847 Abstract ( 158 )   PDF (2028KB) ( 48 )   Save Iron accumulation and neuroinflammation are cardinal features of many neurodegenerative diseases (Urrutia et al., 2021). However, the hierarchy in the pathogenic mechanisms and the molecular connections between these processes are still obscure. In this perspective, we will discuss current evidence showing that aging, the main risk factor for neurodegenerative diseases, negatively impacts lysosomal function by triggering a paradoxical condition of iron accumulation accompanied by functional iron deficiency. This condition is self-sustaining in the neuroinflammatory process. Related Articles | Metrics

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Embolic stroke of undetermined source: identification of patient subgroups for oral anticoagulation treatment Isabell Greeve, Wolf-Rüdiger Schäbitz 2022, 17 (5):  1005-1006.  doi: 10.4103/1673-5374.324837 Abstract ( 170 )   PDF (267KB) ( 758 )   Save Background: Embolic stroke of undetermined source (ESUS), a subtype of cryptogenic stroke, was defined as acute ischemic stroke displaying an embolic or non-lacunar brain infarct pattern on imaging without significant extra or intracranial ipsilateral vessel stenosis or without an identifiable cardioembolic source such as atrial fibrillation (AF) or left ventricular thrombi (Hart et al., 2014). ESUS patients tend to be younger than other stroke patients and have a lower incidence of traditional risk factors such as hypertension, diabetes and hypercholesterolemia, that are key contributors for the development of atherosclerosis, the substrate for small and large vessel disease. Two large clinical trials of embolic stroke of unknown source comparing the direct acting oral anticoagulants rivaroxaban and dabigatran to antiplatelet therapy for secondary stroke prevention, the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) (Hart et al., 2018) and Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RESPECT-ESUS) (Diener et al., 2019), showed not only no benefit for ESUS patients treated with oral anticoagulation to prevent recurrent strokes, but showed even higher risk of bleeding while treated with rivaroxaban. Consequently, the study hypothesis of prevention of recurrent stroke by oral anticoagulation with dabigatran and rivaroxaban in patients diagnosed with ESUS had to be rejected, keeping aspirin as primary secondary prevention treatment for this stroke subtype. Although the reasons for the negative study results are probably multifactorial, posthoc analysis and recent cardiac monitoring studies in ESUS patients suggested that AF may not account for the majority of stroke events in ESUS patients (for example see expert review on ESUS concept, etiology and diagnostic: Schäbitz et al., 2020). In addition to aspects of diagnosis and etiology of ESUS, this topical review will discuss recent evidence from prespecified subgroups of the NAVIGATE- and RESPECT-ESUS trials suggesting a benefit for patients treated with oral anticoagulation with regard to secondary stroke prevention.  Related Articles | Metrics

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Gut-brain axis in traumatic brain injury: impact on neuroinflammation Marta Celorrio, Stuart H. Friess 2022, 17 (5):  1007-1008.  doi: 10.4103/1673-5374.324839 Abstract ( 230 )   PDF (1573KB) ( 129 )   Save The gastrointestinal track is inhabited by tens of trillions of microorganisms. The gut microbiota is involved in gut motility, nutrient absorption and synthesis of metabolites that influence homeostasis, metabolism and immune function. Given the influence gut microbiota has on health, there is a growing body of literature describing the gut microbiota’s impact on brain and behavior. The bidirectional nature of the gut-brain axis involves neurological, immunological and hormonal mechanisms that can induce perturbations in gut or brain homeostasis. Studies using different but complementary approaches, such as germ free mice, antibiotics, probiotics, gastrointestinal infection, and fecal microbiota transplant, have shown that the gut microbiota acting via the gut-brain axis contribute to the regulation of brain and behavior, impacting depression, stress and cognition. Moreover, gut microbiota disruption has been associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and implicated in modulating disease severity in stroke. Traumatic brain injury (TBI) is a complex, acute neurological insult that can lead to chronic neurodegeneration. Understanding the influence of the gut-brain axis in the setting of TBI may create new avenues of therapeutic approaches for TBI survivors.   Related Articles | Metrics

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Forge AHEAD with stricter criteria in future trials of embolic stroke of undetermined source David Z. Rose, Scott E. Kasner 2022, 17 (5):  1009-1010.  doi: 10.4103/1673-5374.324838 Abstract ( 105 )   PDF (369KB) ( 22 )   Save What lurks within the crypt? With more than 200 known causes of ischemic stroke (Saver, 2016), what should be the minimum workup? Many centers offer high-resolution brain imaging and vessel studies, telemetry monitoring for atrial fibrillation (AF), trans-thoracic and trans-esophageal echocardiography, and a panoply of laboratory tests. Nevertheless, the proportion of strokes that are cryptogenic still ranges from 10–40% (Saver, 2016) which, problematically, includes not only those with an unknown etiology after diagnostic evaluation, but also those with an incomplete workup, as well as those with multiple possible causes (i.e., ipsilateral carotid stenosis with concurrent AF). Such heterogeneity is suboptimal for clinical practice as well as for research, which intends to generate blanket recommendations.   Related Articles | Metrics

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Amyotrophic lateral sclerosis, a neurodegenerative motor neuron disease with retinal involvement Ana I. Ramírez, Rosa de Hoz, Pilar Rojas, Juan J. Salazar 2022, 17 (5):  1011-1012.  doi: 10.4103/1673-5374.324841 Abstract ( 152 )   PDF (445KB) ( 51 )   Save Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that damages the motor neurons, the spinal cord, the cerebellum, and some areas of the brain. However, more recent studies show that it can also affect the visual system, for example, through oculomotor and visual pathways. ALS patients do not usually complain of visual problems, so studies focusing on the visual pathway are scarce. Early work on ALS and the eye was related to oculomotor function and visual pathway analysis, with visually evoked potentials being used to study the disease. Subsequently, some works have appeared that analyze visual function, with tests such as visual acuity, visual field, and contrast sensitivity. Furthermore, in neurodegenerative diseases, it is observed that the changes that occur in the brain also occur in the retina, with this nervous tissue being considered as a “window to the brain” (MacCormick et al., 2015). The changes in the retina can be detected by a widely used diagnostic test in ophthalmology, namely optical coherence tomography (OCT). Recently, this technique has been used for the analysis of the retinal and optic nerve changes that occur in various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and even ALS, and can serve to help in their diagnosis and follow-up (Salobrar-García et al., 2016; Rojas et al., 2019). In the retina of ALS patients, OCT has demonstrated retinal thinning in the peripapillary retinal nerve fiber layer, inner nuclear layer, and outer nuclear layer, which may be related to neurodegenerative processes (Volpe et al., 2015; Rohani et al., 2018; Rojas et al., 2019). This fact has been confirmed by histopathological studies performed by Volpe et al. on retinas of ALS patients and they observed a loss of retinal ganglion cell axons, which would explain the macular thinning observed by OCT (Volpe et al., 2015). In addition, a study in early spinal-onset ALS patients without ocular disease demonstrated retinal thickening, through significant increases in the macular thickness in the temporal and inferior areas of the inner macular ring, suggesting that the thickening may be due to microglial activation during the neuroinflammatory process (Rojas et al., 2019). Related Articles | Metrics

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Deuterated dextromethorphan/quinidine for agitation in Alzheimer’s disease Rita Khoury 2022, 17 (5):  1013-1014.  doi: 10.4103/1673-5374.324842 Abstract ( 168 )   PDF (306KB) ( 166 )   Save Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder; it affects around 47 million individuals worldwide (Prince et al., 2013). AD rose from the 12th most burdensome disease in the United States in 1990 to the sixth in 2016 in terms of disability-adjusted life years (Alzheimer’s Disease, Facts and Figures 2021). The burden carried by patients and their caregivers is substantially related to neuropsychiatric symptoms, notably agitation as the disease progresses. To date, there is no Food and Drug Administration (FDA)-approved treatment for agitation in AD. The American Psychiatric Association recommends pharmacotherapy in case of failure of non-pharmacological options. While antidepressants such as trazodone or citalopram can be used as first line agents, antipsychotics may be warranted in case of severe agitation. Antipsychotics carry however a black box warning regarding the increased risk of cerebrovascular events and mortality in patients with dementia. Hence, their use needs to be limited. Several agents are currently being investigated to fill the gap of finding a treatment for agitation in AD. Compounds in the pipeline include pimavanserin and brexpiprazole, both of which are antipsychotics. Newer “safer” compounds that are being studied include cannabinoid derivatives, and dextromethorphan/quinidine. Drug design is a long and expensive process. It is often associated with unexpected unfavorable tolerability and safety profile halting the development of a new product. Deuteration recently emerged as a new and cost-effective technique that aims at repurposing old medications and advancing their development in clinical trials to garner quick FDA approval. It consists of the selective replacement of hydrogen (protium) with deuterium, naturally occurring and stable isotope of hydrogen. This structural substitution increases the metabolic stability of the molecule and extends the metabolic half-life of the drug, improving its safety and tolerability (Schmidt, 2017). AVP-786 is the deuterated form of dextromethorphan/quinidine that emerges as a promising well-tolerated treatment option for agitation in AD. With two completed phase III trials investigating this compound, there is still insufficient evidence to obtain FDA approval of the deuterated form. The latest clinical evidence on dextromethorphan/quinidine and its deuterated form for this indication will be discussed herein. Related Articles | Metrics

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Significance of intercellular communication for neurodegenerative diseases Hilal Cihankaya, Carsten Theiss, Veronika Matschke 2022, 17 (5):  1015-1017.  doi: 10.4103/1673-5374.324840 Abstract ( 235 )   PDF (974KB) ( 70 )   Save The nervous system is a highly complex organization composed of its basic unit, the neuronal cells, and specialized supporting cells, the glial cells. The main glial cells in the central nervous system (CNS) are astrocytes, microglia and oligodendrocytes. Astrocytes are the most abundant glial cell type in the CNS, and they are mainly responsible for the maintenance of neurons. Microglial cells are the most important immune cells in the nervous system and are activated in response to damage and inflammation. Oligodendrocytes produce myelin sheaths wrapping the axons of neurons in the CNS, thus isolating them from the environment and allowing more efficient propagation of action potentials. Normally, neurons and glial cells work together in a balanced and controlled way to maintain a homeostasis. However, under pathological conditions of the nervous system, this coherence between neurons and glial cells can be destroyed, leading to impairments in its function. Related Articles | Metrics

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Repurposing verapamil for prevention of cognitive decline in sporadic Alzheimer’s disease Heba A. Ahmed, Tauheed Ishrat 2022, 17 (5):  1018-1019.  doi: 10.4103/1673-5374.324843 Abstract ( 117 )   PDF (589KB) ( 59 )   Save Dementia is currently the only leading cause of death that is still on the rise, with its overall costs already surpassing those of cancer and heart disease combined, it has developed into a worldwide crisis. In response to its serious and far-reaching effects, the US government has established the “National Alzheimer’s Project Act” (Public Law 111-375), which aims to prevent and successfully manage Alzheimer’s disease (AD), the most common cause of dementia, by 2025. Unfortunately, the incidence of this rapidly progressive, irreversible neurodegenerative cerebral disorder is expected to increase further in coming years, given its close connection with advanced age, yet there are no satisfactory therapies. All the available agents, currently approved by the Food and Drug Administration (FDA) for managing AD are merely palliative, their efficacy decreases over time and they are frequently associated with undesirable side effects. Moreover, efforts to develop new and more efficacious treatments have been futile, despite all the time taken (nearly 20 years) and billions of dollars spent in the rigorous process of drug design, research, development, formulation, and testing.  Related Articles | Metrics

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The emerging world of subcellular biological medicine: extracellular vesicles as novel biomarkers, targets, and therapeutics Leon G. Coleman, Jr 2022, 17 (5):  1020-1022.  doi: 10.4103/1673-5374.324846 Abstract ( 110 )   PDF (392KB) ( 37 )   Save The COVID-19 pandemic, with all its tragedy, has also ushered in a new era of biological medicine. This global crisis has brought along with it an opportunity that had not been foreseen by many – it brought the therapeutic use of subcellular biological material to the forefront of medicine. Though clinical trials for certain biological therapeutics began more than 15 years ago, in many nations there has been public hesitation to these approaches. With this shift of public thought, there will likely be many more similar therapeutic efforts in days ahead. In the case of the pioneering COVID-19 vaccines, mRNA was used as medicine for this inflammatory pathology. Further, the use of lipid delivery systems for these mRNA vaccines has opened the eyes of many regarding new possibilities for biological therapeutics and delivery systems. Within the body during normal physiology, such endogenous delivery systems are continuously operating. These extracellular vesicles (EVs) are lipid-enclosed transport systems that allow continuous communication between cells and organ systems. EVs transport diverse biological cargo such mRNAs, miRNAs, DNA, histones, long non-coding RNAs, proteins, bio-active lipids, and more. Previously considered to be inactive, not physiological, EVs have now emerged as critical mediators in a variety of biological processes and disease states (Jeppesen et al., 2019). As such, much interest has emerged for using EVs not only as disease biomarkers, but also as biological drug delivery systems or even as direct treatments themselves. Disease states with inflammatory components in particular have been studied for the involvement of EVs. Like the COVID-19 mRNA vaccines, EVs represent a new dimension of subcellular biological medicine.  Related Articles | Metrics

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Nerve bundle formation during the promotion of peripheral nerve regeneration: collagen VI-neural cell adhesion molecule 1 interaction Jia-Hui Sun, Ming Huang, Zhou Fang, Tian-Xiao Li, Ting-Ting Wu, Yi Chen, Da-Ping Quan, Ying-Ying Xu, Yu-Ming Wang, Yi Yang, Jian-Long Zou 2022, 17 (5):  1023-1033.  doi: 10.4103/1673-5374.324861 Abstract ( 249 )   PDF (6349KB) ( 133 )   Save The formation of nerve bundles, which is partially regulated by neural cell adhesion molecule 1 (NCAM1), is important for neural network organization during peripheral nerve regeneration. However, little is known about how the extracellular matrix (ECM) microenvironment affects this process. Here, we seeded dorsal root ganglion tissue blocks on different ECM substrates of peripheral nerve ECM-derived matrix-gel, Matrigel, laminin 521, collagen I, and collagen IV, and observed well-aligned axon bundles growing in the peripheral nerve ECM-derived environment. We confirmed that NCAM1 is necessary but not sufficient to trigger this phenomenon. A protein interaction assay identified collagen VI as an extracellular partner of NCAM1 in the regulation of axonal fasciculation. Collagen VI interacted with NCAM1 by directly binding to the FNIII domain, thereby increasing the stability of NCAM1 at the axolemma. Our in vivo experiments on a rat sciatic nerve defect model also demonstrated orderly nerve bundle regeneration with improved projection accuracy and functional recovery after treatment with 10 mg/mL Matrigel and 20 μg/mL collagen VI. These findings suggest that the collagen VI-NCAM1 pathway plays a regulatory role in nerve bundle formation. This study was approved by the Animal Ethics Committee of Guangzhou Medical University (approval No. GY2019048) on April 30, 2019.  Related Articles | Metrics

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Growth associated protein 43 and neurofilament immunolabeling in the transected lumbar spinal cord of lizard indicates limited axonal regeneration Lorenzo Alibardi 2022, 17 (5):  1034-1041.  doi: 10.4103/1673-5374.324850 Abstract ( 142 )   PDF (22543KB) ( 25 )   Save Previous cytological studies on the transected lumbar spinal cord of lizards have shown the presence of differentiating glial cells, few neurons and axons in the bridge region between the proximal and distal stumps of the spinal cord in some cases. A limited number of axons (20–50) can cross the bridge and re-connect the caudal stump of the spinal cord with small neurons located in the rostral stump of the spinal cord. This axonal regeneration appears to be related to the recovery of hind-limb movements after initial paralysis. The present study extends previous studies and shows that after transection of the lumbar spinal cord in lizards, a glial-connective tissue bridge that reconnects the rostral and caudal stumps of the interrupted spinal cord is formed at 11–34 days post-injury. Following an initial paralysis some recovery of hindlimb movements occurs within 1–3 months post-injury. Immunohistochemical and ultrastructural analysis for a growth associated protein 43 (GAP-43) of 48–50 kDa shows that sparse GAP-43 positive axons are present in the proximal stump of the spinal cord but their number decreased in the bridge at 11–34 days post-transection. Few immunolabeled axons with a neurofilament protein of 200–220 kDa were seen in the bridge at 11–22 days post-transection but their number increased at 34 days and 3 months post-amputation in lizards that have recovered some hindlimb movements. Numerous neurons in the rostral and caudal stumps of the spinal cord were also labeled for GAP43, a cytoplasmic protein that is trans-located into their axonal growth cones. This indicates that GAP-43 biosynthesis is related to axonal regeneration and sprouting from neurons that were damaged by the transection. Taken together, previous studies that utilized tract-tracing technique to label the present observations confirm that a limited axonal re-connection of the transected spinal cord occurs 1–3 months post-injury in lizards. The few regenerating-sprouting axons within the bridge reconnect the caudal with the rostral stumps of the spinal cord, and likely contribute to activate the neural circuits that sustain the limited but important recovery of hind-limb movements after initial paralysis. The surgical procedures utilized in the study followed the regulations on animal care and experimental procedures under the Italian Guidelines (art. 5, DL 116/92). Related Articles | Metrics

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Brief electrical nerve stimulation enhances intrinsic repair capacity of the focally demyelinated central nervous system Lydia Ayanwuyi, Nataliya Tokarska, Nikki A. McLean, Jayne M. Johnston, Valerie M. K. Verge 2022, 17 (5):  1042-1050.  doi: 10.4103/1673-5374.324848 Abstract ( 175 )   PDF (8066KB) ( 54 )   Save Our lab has shown that brief electrical nerve stimulation (ES) has a dramatic impact on remyelination of lysophosphatidyl choline (LPC)-induced focally demyelinated rat peripheral nerves, while also inducing an axon-protective phenotype and shifting macrophages from a predominantly pro-inflammatory toward a pro-repair phenotype. Whether this same potential exists in the central nervous system is not known. Thus, for proof of principle studies, the peripheral nerve demyelination and ES model was adapted to the central nervous system, whereby a unilateral focal LPC-induced demyelination of the dorsal column at the lumbar enlargement where the sciatic nerve afferents enter was created, so that subsequent ipsilateral sciatic nerve ES results in increased neural activity in the demyelinated axons. Data reveal a robust focal demyelination at 7 days post-LPC injection. Delivery of 1-hour ES at 7 days post-LPC polarizes macrophages/microglia toward a pro-repair phenotype when examined at 14 days post-LPC; results in smaller LPC-associated regions of inflammation compared to non-stimulated controls; results in significantly more cells of the oligodendroglial lineage in the demyelinated region; elevates myelin basic protein levels;  and shifts the  paranodal protein Caspr along demyelinated axons to a more restricted distribution, consistent with reformation of the paranodes of the nodes of Ranvier. ES also significantly enhanced levels of phosphorylated neurofilaments detected in the zones of demyelination, which has been shown to confer axon protection. Collectively these findings support that strategies that increase neural activity, such as brief electrical stimulation, can be beneficial for promoting intrinsic repair following focal demyelinating insults in demyelinating diseases such as multiple sclerosis. All animal procedures performed were approved by the University of Saskatchewan’s Animal Research Ethics Board (protocol# 20090087; last approval date: November 5, 2020).  Related Articles | Metrics

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Increased activation of the caudate nucleus and parahippocampal gyrus in Parkinson’s disease patients with dysphagia after repetitive transcranial magnetic stimulation: a case-control study Pei-Ling Huang, Song-Jian Wang, Rui-Feng Sun, Zi-Man Zhu, Xiao-Ling Li, Wen-Shan Li, Meng-Yue Wang, Meng Lin, Wei-Jun Gong 2022, 17 (5):  1051-1058.  doi: 10.4103/1673-5374.324863 Abstract ( 161 )   PDF (1784KB) ( 94 )   Save Repetitive transcranial magnetic stimulation (rTMS) has been shown to effectively improve impaired swallowing in Parkinson’s disease (PD) patients with dysphagia. However, little is known about how rTMS affects the corresponding brain regions in this patient group. In this case-control study, we examined data from 38 PD patients with dysphagia who received treatment at Beijing Rehabilitation Medicine Academy, Capital Medical University. The patients received high-frequency rTMS of the motor cortex once per day for 10 successive days. Changes in brain activation were compared via functional magnetic resonance imaging in PD patients with dysphagia and healthy controls. The results revealed that before treatment, PD patients with dysphagia showed greater activation in the precentral gyrus, supplementary motor area, and cerebellum compared with healthy controls, and this enhanced activation was weakened after treatment. Furthermore, before treatment, PD patients with dysphagia exhibited decreased activation in the parahippocampal gyrus, caudate nucleus, and left thalamus compared with healthy controls, and this activation increased after treatment. In addition, PD patients with dysphagia reported improved subjective swallowing sensations after rTMS. These findings suggest that swallowing function in PD patients with dysphagia improved after rTMS of the motor cortex. This may have been due to enhanced activation of the caudate nucleus and parahippocampal gyrus. The study protocol was approved by the Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University (approval No. 2018bkky017) on March 6, 2018 and was registered with Chinese Clinical Trial Registry (registration No. ChiCTR 1800017207) on July 18, 2018. Related Articles | Metrics

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Effects of acupuncture stimulation on brain activation induced by cue-elicited alcohol craving Hyeok Gyu Kwon, Seong Hun Choi, Joon Ho Seo, Chae Ha Yang, Mi Young Lee 2022, 17 (5):  1059-1064.  doi: 10.4103/1673-5374.324849 Abstract ( 187 )   PDF (3788KB) ( 87 )   Save Acupuncture has been shown to be effective on alcohol use disorder. However, the underlying mechanism remains poorly understood. To investigate the effects of Shenmen (HT7) acupoint on brain activation induced by cue-elicited alcohol craving, 30 right-handed healthy light to moderate alcohol drinkers were recruited from the community. They were randomly assigned to undergo acupuncture either at HT7 (experimental acupoint, n = 15) or Jingqu (LU8, control acupoint, n = 15) acupoints. This randomized controlled study was performed in Daegu Haany University and Daegu-Gyeongbuk Medical Innovation Foundation, Republic of Korea. Recruitment and data collection were conducted from December 2018 to May 2019. The results showed that after acupuncture at HT7 acupoint, the activation of orbitofrontal cortex and dorsolateral prefrontal cortex was greatly increased, while the activation of dorsolateral prefrontal cortex was obviously reduced, and subject’s craving for alcohol was reduced when he/she seeing alcohol-related video clips involving various alcohols (beer, wine, or soju) or drinking scenarios. Acupuncture at HT7 more greatly reduced subject’s alcohol cravings than acupuncture at LU8 acupoint. These findings suggest that acupuncture can improve the self-control of mild to moderate social drinkers through the activation of the orbitofrontal cortex and dorsolateral prefrontal cortex, thereby reducing the craving for alcohol. The study protocol was approved by the Institutional Review Board of Daegu Haany University Korean Medicine Hospital, Republic of Korea (approval No. DHUMC-D-18026-PRO-02) on November 30, 2018. Related Articles | Metrics

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Effect of vocal respiratory training on respiratory function and respiratory neural plasticity in patients with cervical spinal cord injury: a randomized controlled trial Xiao-Ying Zhang, Wei-Yong Yu, Wen-Jia Teng, Yi-Chuan Song, De-Gang Yang, Hong-Wei Liu, Song-Huai Liu, Xiao-Bing Li, Wen-Zhu Wang, Jian-Jun Li 2022, 17 (5):  1065-1071.  doi: 10.4103/1673-5374.324856 Abstract ( 143 )   PDF (2187KB) ( 251 )   Save In previous studies, researchers have used singing to treat respiratory function in patients with spinal cord injury. However, few studies have examined the way in which vocal training affects respiratory neural plasticity in patients with spinal cord injury. Vocal respiratory training (VRT) is a type of vocal muscle-related treatment that is often a component of music therapy (MT) and focuses on strengthening respiratory muscles and improving lung function. In this randomized controlled study, we analyzed the therapeutic effects of VRT on respiratory dysfunction at 3 months after cervical spinal cord injury. Of an initial group of 37 patients, 26 completed the music therapy intervention, which comprised five 30-minute sessions per week for 12 weeks. The intervention group (n = 13) received VRT training delivered by professional certified music therapists. The control group (n = 13) received respiratory physical therapy delivered by professional physical therapists. Compared with the control group, we observed a substantial increase in respiratory function in the intervention group after the 12-week intervention. Further, the nerve fiber bundles in the respiratory center in the medulla exhibited a trend towards increased diversification, with an increased number, path length, thickness, and density of nerve fiber bundles. These findings provide strong evidence for the effect of music therapeutic VRT on neural plasticity. This study was approved by the Ethics Committee of China Rehabilitation Research Center (approval No. 2020-013-1) on April 1, 2020, and was registered with the Chinese Clinical Trial Registry (registration No. ChiCTR2000037871) on September 2, 2020.  Related Articles | Metrics

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M1-type microglia can induce astrocytes to deposit chondroitin sulfate proteoglycan after spinal cord injury Shui-Sheng Yu, Zi-Yu Li#, Xin-Zhong Xu, Fei Yao, Yang Luo, Yan-Chang Liu, Li Cheng, Mei-Ge Zheng, Jue-Hua Jing 2022, 17 (5):  1072-1079.  doi: 10.4103/1673-5374.324858 Abstract ( 243 )   PDF (7389KB) ( 64 )   Save After spinal cord injury (SCI), astrocytes gradually migrate to and surround the lesion, depositing chondroitin sulfate proteoglycan-rich extracellular matrix and forming astrocytic scar, which limits the spread of inflammation but hinders axon regeneration. Meanwhile, microglia gradually accumulate at the lesion border to form microglial scar and can polarize to generate a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype. However, the effect of microglia polarization on astrocytes is unclear. Here, we found that both microglia (CX3CR1+) and astrocytes (GFAP+) gathered at the lesion border at 14 days post-injury (dpi). The microglia accumulated along the inner border of and in direct contact with the astrocytes. M1-type microglia (iNOS+CX3CR1+) were primarily observed at 3 and 7 dpi, while M2-type microglia (Arg1+CX3CR1+) were present at larger numbers at 7 and 14 dpi. Transforming growth factor-β1 (TGFβ1) was highly expressed in M1 microglia in vitro, consistent with strong expression of TGFβ1 by microglia in vivo at 3 and 7 dpi, when they primarily exhibited an M1 phenotype. Furthermore, conditioned media from M1-type microglia induced astrocytes to secrete chondroitin sulfate proteoglycan in vitro. This effect was eliminated by knocking down sex-determining region Y-box 9 (SOX9) in astrocytes and could not be reversed by treatment with TGFβ1. Taken together, our results suggest that microglia undergo M1 polarization and express high levels of TGFβ1 at 3 and 7 dpi, and that M1-type microglia induce astrocytes to deposit chondroitin sulfate proteoglycan via the TGFβ1/SOX9 pathway. The study was approved by the Institutional Animal Care and Use Committee of Anhui Medical University, China (approval No. LLSC20160052) on March 1, 2016. Related Articles | Metrics

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Baicalin attenuates blood-spinal cord barrier disruption and apoptosis through PI3K/Akt signaling pathway after spinal cord injury Rui Zhao, Xue Wu, Xue-Yuan Bi, Hao Yang, Qian Zhang 2022, 17 (5):  1080-1087.  doi: 10.4103/1673-5374.324857 Abstract ( 239 )   PDF (9140KB) ( 78 )   Save Baicalin  is a natural active ingredient isolated from Scutellariae Radix that can cross the blood-brain barrier and exhibits neuroprotective effects on multiple central nervous system diseases. However, the mechanism behind the neuroprotective effects remains unclear. In this study, rat models of spinal cord injury were established using a modified Allen’s impact method and then treated with intraperitoneal injection of Baicalin. The results revealed that Baicalin greatly increased the Basso, Beattie, Bresnahan Locomotor Rating Scale score, reduced blood-spinal cord barrier permeability, decreased the expression of Bax, Caspase-3, and nuclear factor κB, increased the expression of Bcl-2, and reduced neuronal apoptosis and pathological spinal cord injury. SH-SY5Y cell models of excitotoxicity were established by application of 10 mM glutamate for 12 hours and then treated with 40 µM Baicalin for 48 hours to investigate the mechanism of action of Baicalin. The results showed that Baicalin reversed tight junction protein expression tendencies (occludin and ZO-1) and apoptosis-related protein expression (Bax, Bcl-2, Caspase-3, and nuclear factor-κB), and also led to up-regulation of PI3K and Akt phosphorylation. These effects on Bax, Bcl-2, and Caspase-3 were blocked by pretreatment with the PI3K inhibitor LY294002. These findings suggest that Baicalin can inhibit blood-spinal cord barrier permeability after spinal cord injury and reduce neuronal apoptosis, possibly by activating the PI3K/Akt signaling pathway. This study was approved by Animal Ethics Committee of Xi’an Jiaotong University on March 6, 2014.  Related Articles | Metrics

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Experimental nerve transfer model in the neonatal rat Matthias E. Sporer, Martin Aman, Konstantin D. Bergmeister, Dieter Depisch, Katharina M. Scheuba, Ewald Unger, Bruno K. Podesser, Oskar C. Aszmann 2022, 17 (5):  1088-1095.  doi: 10.4103/1673-5374.324851 Abstract ( 134 )   PDF (40590KB) ( 44 )   Save Clinically, peripheral nerve reconstructions in neonates are most frequently applied in brachial plexus birth injuries. Most surgical concepts, however, have investigated nerve reconstructions in adult animal models. The immature neuromuscular system reacts differently to the effects of nerve lesion and surgery and is poorly investigated due to the lack of reliable experimental models. Here, we describe an experimental forelimb model in the neonatal rat, to study these effects on both the peripheral and central nervous systems. Within 24 hours after birth, three groups were prepared: In the nerve transfer group, a lesion of the musculocutaneous nerve was reconstructed by selectively transferring the ulnar nerve. In the negative control group, the musculocutaneous nerve was divided and not reconstructed and in the positive control group, a sham surgery was performed. The animal´s ability to adapt to nerve lesions and progressive improvement over time were depict by the Bertelli test, which observes the development of grooming. Twelve weeks postoperatively, animals were fully matured and the nerve transfer successfully reinnervated their target muscles, which was indicated by muscle force, muscle weight, and cross sectional area evaluation. On the contrary, no spontaneous regeneration was found in the negative control group. In the positive control group, reference values were established. Retrograde labeling indicated that the motoneuron pool of the ulnar nerve was reduced following nerve transfer. Due to this post-axotomy motoneuron death, a diminished amount of motoneurons reinnervated the biceps muscle in the nerve transfer group, when compared to the native motoneuron pool of the musculocutaneous nerve. These findings indicate that the immature neuromuscular system behaves profoundly different than similar lesions in adult rats and explains reduced muscle force. Ultimately, pathophysiologic adaptations are inevitable. The maturing neuromuscular system, however, utilizes neonatal capacity of regeneration and seizes a variety of compensation mechanism to restore a functional extremity. The above described neonatal rat model demonstrates a constant anatomy, suitable for nerve transfers and allows all standard neuromuscular analyses. Hence, detailed investigations on the pathophysiological changes and subsequent effects of trauma on the various levels within the neuromuscular system as well as neural reorganization of the neonatal rat may be elucidated. This study was approved by the Ethics Committee of the Medical University of Vienna and the Austrian Ministry for Research and Science (BMWF-66.009/0187-WF/V/3b/2015) on March 20, 2015. Related Articles | Metrics

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HOXA11-AS aggravates microglia-induced neuroinflammation after traumatic brain injury Xiang-Long Li, Bin Wang, Fu-Bing Yang, Li-Gang Chen, Jian You 2022, 17 (5):  1096-1105.  doi: 10.4103/1673-5374.322645 Abstract ( 170 )   PDF (3478KB) ( 71 )   Save Long noncoding RNAs (lncRNAs) participate in many pathophysiological processes after traumatic brain injury by mediating neuroinflammation and apoptosis. Homeobox A11 antisense RNA (HOXA11-AS) is a member of the lncRNA family that has been reported to participate in many inflammatory reactions; however, its role in traumatic brain injury remains unclear. In this study, we established rat models of traumatic brain injury using a weight-drop hitting device and injected LV-HOXA11-AS into the right lateral ventricle 2 weeks before modeling. The results revealed that overexpression of HOXA11-AS aggravated neurological deficits in traumatic brain injury rats, increased brain edema and apoptosis, promoted the secretion of proinflammatory factors interleukin-1β, interleukin-6, and tumor necrosis factor α, and promoted the activation of astrocytes and microglia. Microglia were treated with 100 ng/mL lipopolysaccharide for 24 hours to establish in vitro cell models, and then transfected with pcDNA-HOXA11-AS, miR-124-3p mimic, or sh-MDK. The results revealed that HOXA11-AS inhibited miR-124-3p expression and boosted MDK expression and TLR4-nuclear factor-κB pathway activation. Furthermore, lipopolysaccharide enhanced potent microglia-induced inflammatory responses in astrocytes. Forced overexpression of miR-124-3p or downregulating MDK repressed microglial activation and the inflammatory response of astrocytes. However, the miR-124-3p-mediated anti-inflammatory effects were reversed by HOXA11-AS. These findings suggest that HOXA11-AS can aggravate neuroinflammation after traumatic brain injury by modulating the miR-124-3p-MDK axis. This study was approved by the Animal Protection and Use Committee of Southwest Medical University (approval No. SMU-2019-042) on February 4, 2019.  Related Articles | Metrics

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Chitin scaffold combined with autologous small nerve repairs sciatic nerve defects Bo Wang, Chang-Feng Lu, Zhong-Yang Liu, Shuai Han, Pi Wei, Dian-Ying Zhang, Yu-Hui Kou, Bao-Guo Jiang 2022, 17 (5):  1106-1114.  doi: 10.4103/1673-5374.324859 Abstract ( 162 )   PDF (5490KB) ( 69 )   Save Although autologous nerve transplantation is the gold standard for treating peripheral nerve defects, it has many clinical limitations. As an alternative, various tissue-engineered nerve grafts have been developed to substitute for autologous nerves. In this study, a novel nerve graft composed of chitin scaffolds and a small autologous nerve was used to repair sciatic nerve defects in rats. The novel nerve graft greatly facilitated regeneration of the sciatic nerve and myelin sheath, reduced atrophy of the target muscle, and effectively restored neurological function. When the epineurium of the small autogenous nerve was removed, the degree of nerve regeneration was similar to that which occurs after autogenous nerve transplantation. These findings suggest that our novel nerve graft might eventually be a new option for the construction of tissue-engineered nerve scaffolds. The study was approved by the Research Ethics Committee of Peking University People’s Hospital (approval No. 2019PHE27) on October 18, 2019. Related Articles | Metrics

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Correlations between hippocampal functional connectivity, structural changes, and clinical data in patients with relapsing-remitting multiple sclerosis: a case-control study using multimodal magnetic resonance imaging Xin-Quan Gu, Ying Liu, Jie-Bing Gu, Lin-Fang Li, Ling-Ling Fu, Xue-Mei Han 2022, 17 (5):  1115-1124.  doi: 10.4103/1673-5374.324855 Abstract ( 139 )   PDF (2171KB) ( 56 )   Save Multiple sclerosis is associated with structural and functional brain alterations leading to cognitive impairments across multiple domains including attention, memory, and the speed of information processing. The hippocampus, which is a brain important structure involved in memory, undergoes microstructural changes in the early stage of multiple sclerosis. In this study, we analyzed hippocampal function and structure in patients with relapsing-remitting multiple sclerosis and explored correlations between the functional connectivity of the hippocampus to the whole brain, changes in local brain function and microstructure, and cognitive function at rest. We retrospectively analyzed data from 20 relapsing-remitting multiple sclerosis patients admitted to the Department of Neurology at the China-Japan Union Hospital of Jilin University, China, from April 2015 to November 2019. Sixteen healthy volunteers were recruited as the healthy control group. All participants were evaluated using a scale of extended disability status and the Montreal cognitive assessment within 1 week before and after head diffusion tensor imaging and functional magnetic resonance imaging.  Compared with the healthy control group, the patients with relapsing-remitting multiple sclerosis had lower Montreal cognitive assessment scores and regions of simultaneously enhanced and attenuated whole-brain functional connectivity and local functional connectivity in the bilateral hippocampus. Hippocampal diffusion tensor imaging data showed that, compared with the healthy control group, patients with relapsing-remitting multiple sclerosis had lower hippocampal fractional anisotropy values and higher mean diffusivity values, suggesting abnormal hippocampal structure. The left hippocampus whole-brain functional connectivity was negatively correlated with the Montreal cognitive assessment score (r = −0.698, P = 0.025), and whole-brain functional connectivity of the right hippocampus was negatively correlated with extended disability status scale score (r = −0.649, P = 0.042). The mean diffusivity value of the left hippocampus was negatively correlated with the Montreal cognitive assessment score (r = −0.729, P = 0.017) and positively correlated with the extended disability status scale score (r = 0.653, P = 0.041). The right hippocampal mean diffusivity value was positively correlated with the extended disability status scale score (r = 0.684, P = 0.029). These data suggest that the functional connectivity and presence of structural abnormalities in the hippocampus in patients with relapse-remission multiple sclerosis are correlated with the degree of cognitive function and extent of disability. This study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University, China (approval No. 201702202) on February 22, 2017.  Related Articles | Metrics

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Facial reanimation with interposition nerve graft or masseter nerve transfer: a comparative retrospective study Wen-Jin Wang, Wei-Dong Zhu, Mathias Tremp, Gang Chen, Zhao-Yan Wang, Hao Wu, Wei Wang 2022, 17 (5):  1125-1130.  doi: 10.4103/1673-5374.324862 Abstract ( 176 )   PDF (921KB) ( 628 )   Save Both interposition nerve grafts and masseter nerve transfers have been successfully used for facial reanimation after irreversible injuries to the cranial portion of the facial nerve. However, no comparative study of these two procedures has yet been reported. In this two-site, two-arm, retrospective case review study, 32 patients were included. Of these, 17 patients (eight men and nine women, mean age 42.1 years) underwent interposition nerve graft after tumor extirpation or trauma between 2003 and 2006 in the Ear Institute, School of Medicine, Shanghai Jiao Tong University, China, and 15 patients (six men and nine women, mean age 40.6 years) underwent masseter-to-facial nerve transfer after tumor extirpation or trauma between November 2010 and February 2016 in Shanghai Ninth People’s Hospital, China. More patients achieved House-Brackmann III recovery after masseter nerve repair than interposition nerve graft repair (15/15 vs. 12/17). The mean oral commissure excursion ratio was also higher in patients who underwent masseter nerve transfer than in patients subjected to an interposition nerve graft. These findings suggest that masseter nerve transfer results in strong oral commissure excursion, avoiding obvious synkinesis, while an interposition nerve graft provides better resting symmetry. This study was approved by the Institutional Ethics Committee, Shanghai Ninth People’s Hospital, China (approval No. SH9H-2019-T332-1) on December 12, 2019.  Related Articles | Metrics

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Repairing whole facial nerve defects with xenogeneic acellular nerve grafts in rhesus monkeys Guo-Chen Zhu, Da-Jiang Xiao, Bi-Wen Zhu, Yan Xiao 2022, 17 (5):  1131-1137.  doi: 10.4103/1673-5374.324853 Abstract ( 184 )   PDF (23337KB) ( 54 )   Save Acellular nerve allografts conducted via chemical extraction have achieved satisfactory results in bridging whole facial nerve defects clinically, both in terms of branching a single trunk and in connecting multiple branches of an extratemporal segment. However, in the clinical treatment of facial nerve defects, allogeneic donors are limited. In this experiment, we exposed the left trunk and multiple branches of the extratemporal segment in six rhesus monkeys and dissected a gap of 25 mm to construct a monkey model of a whole left nerve defect. Six monkeys were randomly assigned to an autograft group or a xenogeneic acellular nerve graft group. In the autograft group, the 25-mm whole facial nerve defect was immediately bridged using an autogenous ipsilateral great auricular nerve, and in the xenogeneic acellular nerve graft group, this was done using a xenogeneic acellular nerve graft with trunk-branches. Examinations of facial symmetry, nerve-muscle electrophysiology, retrograde transport of labeled neuronal tracers, and morphology of the regenerated nerve and target muscle at 8 months postoperatively showed that the faces of the monkey appeared to be symmetrical in the static state and slightly asymmetrical during facial movement, and that they could actively close their eyelids completely. The degree of recovery from facial paralysis reached House-Brackmann grade II in both groups. Compound muscle action potentials were recorded and orbicularis oris muscles responded to electro-stimuli on the surgical side in each monkey. FluoroGold-labeled neurons could be detected in the facial nuclei on the injured side. Immunohistochemical staining showed abundant neurofilament-200-positive axons and soluble protein-100-positive Schwann cells in the regenerated nerves. A large number of mid-graft myelinated axons were observed via methylene blue staining and a transmission electron microscope. Taken together, our data indicate that xenogeneic acellular nerve grafts from minipigs are safe and effective for repairing whole facial nerve defects in rhesus monkeys, with an effect similar to that of autologous nerve transplantation. Thus, a xenogeneic acellular nerve graft may be a suitable choice for bridging a whole facial nerve defect if no other method is available. The study was approved by the Laboratory Animal Management Committee and the Ethics Review Committee of the Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, China (approval No. 2018-D-1) on March 15, 2018. Related Articles | Metrics

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Angiotensin-(1–7) reduces α-synuclein aggregation by enhancing autophagic activity in Parkinson’s disease Qing Gao, Rui Chen, Liang Wu, Qing Huang, Xi-Xi Wang, You-Yong Tian, Ying-Dong Zhang 2022, 17 (5):  1138-1145.  doi: 10.4103/1673-5374.324854 Abstract ( 202 )   PDF (2148KB) ( 49 )   Save Abnormal accumulation of α-synuclein contributes to the formation of Lewy bodies in the substantia nigra, which is considered the typical pathological hallmark of Parkinson’s disease. Recent research indicates that angiotensin-(1–7) plays a crucial role in several neurodegenerative disorders, including Parkinson’s disease, but the underlying mechanisms remain elusive. In this study, we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson’s disease model. We investigated whether angiotensin-(1–7) is neuroprotective in this model by continuous administration of angiotensin-(1–7) into the right substantia nigra for 4 weeks. We found that angiotensin-(1–7) infusion relieved characteristic parkinsonian behaviors and reduced α-synuclein aggregation in the substantia nigra. Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone, angiotensin-(1–7), and/or the Mas receptor blocker A-779 for 24 hours. After binding to the Mas receptor, angiotensin-(1–7) attenuated apoptosis and α-synuclein aggregation in rotenone-treated cells. Primary dopaminergic neurons were also treated with angiotensin-(1–7) and/or the autophagy inhibitor 3-methyladenine for 24 hours. Angiotensin-(1–7) increased α-synuclein removal and increased the autophagy of rotenone-treated cells. We conclude that angiotensin-(1–7) reduces α-synuclein aggregation by alleviating autophagy dysfunction in Parkinson’s disease. Therefore, the angiotensin-(1–7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson’s disease and angiotensin-(1–7) has potential therapeutic value for Parkinson’s disease. All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital (approval No. DWSY-2000932) in January 2020. Related Articles | Metrics

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Biomimetic chitosan scaffolds with long-term controlled release of nerve growth factor repairs 20-mm-long sciatic nerve defects in rats Fa-Dong Liu, Hong-Mei Duan, Fei Hao, Wen Zhao, Yu-Dan Gao, Peng Hao, Zhao-Yang Yang, Xiao-Guang Li 2022, 17 (5):  1146-1155.  doi: 10.4103/1673-5374.324860 Abstract ( 169 )   PDF (8971KB) ( 39 )   Save Although autogenous nerve transplantation is the gold standard for treating peripheral nerve defects of considerable length, it still has some shortcomings, such as insufficient donors and secondary injury. Composite chitosan scaffolds loaded with controlled release of nerve growth factor can promote neuronal survival and axonal regeneration after short-segment sciatic nerve defects. However, the effects on extended nerve defects remain poorly understood. In this study, we used chitosan scaffolds loaded with nerve growth factor for 8 weeks to repair long-segment (20 mm) sciatic nerve defects in adult rats. The results showed that treatment markedly promoted the recovery of motor and sensory functions. The regenerated sciatic nerve not only reconnected with neurons but neural circuits with the central nervous system were also reconstructed. In addition, the regenerated sciatic nerve reconnected the motor endplate with the target muscle. Therefore, this novel biomimetic scaffold can promote the regeneration of extended sciatic nerve defects and reconstruct functional circuits. This provides a promising method for the clinical treatment of extended peripheral nerve injury. This study was approved by the Animal Ethics Committee of Capital Medical University, China (approval No. AEEI-2017-033) on March 21, 2017.  Related Articles | Metrics

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Antipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injury Gabriel B. Polho, Giancarlo M. Cardillo, Daniel S. Kerr, Thais Chile, Wagner F. Gattaz, Orestes V. Forlenza, Helena P. Brentani, Vanessa J. De-Paula 2022, 17 (5):  1156-1160.  doi: 10.4103/1673-5374.324852 Abstract ( 178 )   PDF (580KB) ( 46 )   Save Antipsychotics may prolong or retain telomere length, affect mitochondrial function, and then affect the metabolism of nerve cells. To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury, leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient. The mononuclear cells layer was resuspended in cell culture medium. Oxidative stress was induced with hydrogen peroxide in cultured leukocytes. Four days later, leukocytes were treated with aripiprazole, haloperidol or clozapine for 7 days. Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23% and 20% in peripheral blood mononuclear cells after acute oxidative stress injury. These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress. The experiment procedure was approved by the Ethics Committee of Faculty of Medicine of the University of São Paulo (FMUSP/CAAE approval No. 52622616.8.0000.0065). Related Articles | Metrics