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15 July 2019, Volume 14 Issue 7 Previous Issue    Next Issue

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Bridging larger gaps in peripheral nerves using neural prosthetics and physical therapeutic agents Muhammad Sana Ullah Sahar,Matthew Barton,Geoffrey Douglas Tansley 2019, 14 (7):  1109-1115.  doi: 10.4103/1673-5374.251186 Abstract ( 123 )   PDF (361KB) ( 113 )   Save Peripheral nerve injuries are relatively common and can be caused by a variety of traumatic events such as motor vehicle accidents. They can lead to long-term disability, pain, and financial burden, and contribute to poor quality of life. In this review, we systematically analyze the contemporary literature on peripheral nerve gap management using nerve prostheses in conjunction with physical therapeutic agents. The use of nerve prostheses to assist nerve regeneration across large gaps (> 30 mm) has revolutionized neural surgery. The materials used for nerve prostheses have been greatly refined, making them suitable for repairing large nerve gaps. However, research on peripheral nerve gap management using nerve prostheses reports inconsistent functional outcomes, especially when prostheses are integrated with physical therapeutic agents, and thus warrants careful investigation. This review explores the effectiveness of nerve prostheses for bridging large nerve gaps and then addresses their use in combination with physical therapeutic agents. Related Articles | Metrics

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Magnesium: pathophysiological mechanisms and potential therapeutic roles in intracerebral hemorrhage Jason J. Chang,Rocco Armonda,Nitin Goyal,Adam S. Arthur 2019, 14 (7):  1116-1121.  doi: 10.4103/1673-5374.251189 Abstract ( 110 )   PDF (183KB) ( 592 )   Save Intracerebral hemorrhage (ICH) remains the second-most common form of stroke with high morbidity and mortality. ICH can be divided into two pathophysiological stages: an acute primary phase, including hematoma volume expansion, and a subacute secondary phase consisting of blood-brain barrier disruption and perihematomal edema expansion. To date, all major trials for ICH have targeted the primary phase with therapies designed to reduce hematoma expansion through blood pressure control, surgical evacuation, and hemostasis. However, none of these trials has resulted in improved clinical outcomes. Magnesium is a ubiquitous element that also plays roles in vasodilation, hemostasis, and blood-brain barrier preservation. Animal models have highlighted potential therapeutic roles for magnesium in neurological diseases specifically targeting these pathophysiological mechanisms. Retrospective studies have also demonstrated inverse associations between admission magnesium levels and hematoma volume, hematoma expansion, and clinical outcome in patients with ICH. These associations, coupled with the multifactorial role of magnesium that targets both primary and secondary phases of ICH, suggest that magnesium may be a viable target of study in future ICH studies. Related Articles | Metrics

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Network-centric medicine for peripheral nerve injury: treating the whole to boost endogenous mechanisms of neuroprotection and regeneration David Romeo-Guitart, Caty Casas 2019, 14 (7):  1122-1128.  doi: 10.4103/1673-5374.251187 Abstract ( 117 )   PDF (395KB) ( 161 )   Save Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application. Related Articles | Metrics

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Exogenous neural stem cell transplantation for cerebral ischemia Ling-Yi Liao,Benson Wui-Man Lau,Dalinda Isabel Sánchez-Vidaña,Qiang Gao 2019, 14 (7):  1129-1137.  doi: 10.4103/1673-5374.251188 Abstract ( 142 )   PDF (443KB) ( 192 )   Save Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70–80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effec¬tiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment. Related Articles | Metrics

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Potential therapeutic molecular targets for bloodbrain barrier disruption after subarachnoid hemorrhage Hideki Kanamaru, Hidenori Suzuki 2019, 14 (7):  1138-1143.  doi: 10.4103/1673-5374.251190 Abstract ( 100 )   PDF (430KB) ( 158 )   Save Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage. Related Articles | Metrics

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Choroid plexus tumor necrosis factor receptor 1: a new neuroinflammatory piece of the complex Alzheimer’s disease puzzle Sophie Steeland,Roosmarijn E. Vandenbroucke 2019, 14 (7):  1144-1147.  doi: 10.4103/1673-5374.247443 Abstract ( 102 )   PDF (1090KB) ( 189 )   Save Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer’s disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline. Related Articles | Metrics

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Transcriptional dysregulation in neurodegenerative diseases: who tipped the balance of Yin Yang 1 in the brain? Zhefan Stephen Chen,Ho Yin Edwin Chan 2019, 14 (7):  1148-1151.  doi: 10.4103/1673-5374.251193 Abstract ( 122 )   PDF (329KB) ( 143 )   Save Yin Yang 1 (YY1) is a multi-functional transcription factor that regulates gene expression in a range of cell types, including neurons. It controls neuronal differentiation, as well as neuronal specification and migration during the development of the mammalian nervous system. Besides, YY1 also mediates the transcription of genes that are required for neuronal survival. An impairment of the transcriptional function of YY1 causes neuronal death. This review summarizes recent research findings that unveil the dysfunction of YY1 in multiple neurodegenerative disorders. The expression of disease proteins perturbs the function of YY1 via distinct molecular mechanisms, including recruitment to protein aggregates, protein degradation and aberrant nuclear/cytoplasmic shuttling. Understanding the pathogenic roles of YY1 will further broaden our knowledge of the disease mechanisms in distinct neurodegenerative disorders. Related Articles | Metrics

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Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment Chao Ren,Yong-Qiang Ji,Hong Liu,Zhe Wang,Jia-Hui Wang,Cai-Yi Zhang,Li-Na Guan,Pei-Yuan Yin 2019, 14 (7):  1152-1157.  doi: 10.4103/1673-5374.251191 Abstract ( 121 )   PDF (199KB) ( 228 )   Save Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differ¬entiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we re¬viewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial mi¬croenvironment for stem cell transplantation. Related Articles | Metrics

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Amelioration of Alzheimer’s disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer’s disease Bridget Martinez,Philip V. Peplow 2019, 14 (7):  1158-1176.  doi: 10.4103/1673-5374.251192 Abstract ( 99 )   PDF (597KB) ( 146 )   Save The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation. Related Articles | Metrics

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Precision medicine in pantothenate kinase-associated neurodegeneration Mónica Álvarez-Córdoba,Marina Villanueva-Paz,Irene Villalón-García,Suleva Povea-Cabello,Juan M. Suárez-Rivero,Marta Talaverón-Rey,Javier Abril-Jaramillo,Ana Belén Vintimilla-Tosi,José A. Sánchez-Alcázar 2019, 14 (7):  1177-1185.  doi: 10.4103/1673-5374.251203 Abstract ( 132 )   PDF (538KB) ( 150 )   Save Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future. Related Articles | Metrics

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Role of microglial cells in photoreceptor degeneration Johnny Di Pierdomenico, Diego García-Ayuso,Marta Agudo-Barriuso, Manuel Vidal-Sanz, María Paz Villegas-Pérez 2019, 14 (7):  1186-1190.  doi: 10.4103/1673-5374.251204 Abstract ( 103 )   PDF (3091KB) ( 143 )   Save Inherited photoreceptor degeneration in humans constitutes a major cause of irreversible blindness in the world. They comprise various diseases, but retinitis pigmentosa is the most frequently observed. Retinitis pigmentosa is commonly limited to the eye, where there is progressive photoreceptor degeneration, rods and secondarily cones. The mechanisms of cone and rod degeneration continue to be investigated, since most of the mutations causing retinitis pigmentosa affect rods and thus, the secondary death of cones is an intriguing question but, ultimately, the cause of blindness. Understanding the mechanisms of rod and cone degeneration could help us to develop therapies to stop or, at least, slow down the degeneration process. Secondary cone degeneration has been attributed to the trophic dependence between rods and cones, but microglial cell activation could also have a role. In this review, based on previous work carried out in our laboratory in early stages of photoreceptor degeneration in two animal models of retinitis pigmentosa, we show that microglial cell activation is observed prior to the the initiation of photoreceptor death. We also show that there is an increase of the retinal microglial cell densities and invasion of the outer retinal layers by microglial cells. The inhibition of the microglial cells improves photoreceptor survival and morphology, documenting a role for microglial cells in photoreceptor degeneration. Furthermore, these results indicate that the modulation of microglial cell reactivity can be used to prevent or diminish photoreceptor death in inherited photoreceptor degenerations. Related Articles | Metrics

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Mucin-like glycopolymer gels in electrosensory tissues generate cues which direct electrolocation in amphibians and neuronal activation in mammals James Melrose 2019, 14 (7):  1191-1195.  doi: 10.4103/1673-5374.251298 Abstract ( 102 )   PDF (160KB) ( 195 )   Save Mucin-like glycoproteins have established roles in epithelial boundary protection and lubricative roles in some tissues. This mini-review illustrates alternative functional roles which rely on keratan sulphate and sialic acid modifications to mucin glycopolymers which convey charge properties suggestive of novel electroconductive properties not previously ascribed to these polymers. Many tumour cells express mucin-like glycopolymers modified with highly sulphated keratan sulphate and sialic which can be detected using diagnostic biosensors. The mucin-like keratan sulphate glycopolymer present in the ampullae of lorenzini is a remarkable sensory polymer which elasmobranch fish (sharks, rays, skate) use to detect weak electrical fields emitted through muscular activity of prey-fish. Information on the proton gradients is conveyed to neuromast cells located at the base of the ampullae and mechanotransduced to neural networks. This ampullae keratan sulphate sensory gel is the most sensitive proton gradient detection polymer known in nature. This process is known as electrolocation, and allows the visualization of prey fish under conditions of low visibility. The bony fish have similar electroreceptors located along their lateral lines which consist of neuromast cells containing sensory hairs located within a cupulla which contains a sensory gel polymer which detects distortions in fluid flow in channels within the lateral lines and signals are sent back to neural networks providing information on the environment around these fish. One species of dolphin, the Guiana dolphin, has electrosensory pits in its bill with similar roles to the ampullae but which have evolved from its vibrissal system. Only two terrestrial animals can undertake electrolocation, these are the Duck-billed platypus and long and short nosed Echidna. In this case the electrosensor is a highly evolved innervated mucous gland. The platypus has 40,000 electroreceptors around its bill through which it electrolocates food species. The platypus has poor eyesight, is a nocturnal feeder and closes its eyes, nostrils and ears when it hunts, so electrolocation is an essential sensory skill. Mammals also have sensory cells containing stereocilia which are important in audition in the organ of corti of the cochlea and in olfaction in the olfactory epithelium. The rods and cones of the retina also have an internal connecting cilium with roles in the transport of phototransduced chemical signals and activation of neurotransmitter release to the optic nerve. Mucin-like glycopolymer gels surround the stereocilia of these sensory hair cells but these are relatively poorly characterized however they deserve detailed characterization since they may have important functional attributes. Related Articles | Metrics

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Toll-like receptor 4 and protease-activated receptor 2 in physiology and pathophysiology of the nervous system: more than just receptor cooperation? Darius Widera,Rocío Martínez Aguilar,Graeme S. Cottrell 2019, 14 (7):  1196-1201.  doi: 10.4103/1673-5374.251290 Abstract ( 93 )   PDF (1060KB) ( 174 )   Save Toll-like receptor 4 (TLR4) and protease-activated receptor 2 (PAR2) play pivotal roles in the mammalian innate immune response. Notably, in addition to their involvement in detection of invading pathogens, PAR2 and TLR4 modulate the levels of cell death-induced sterile inflammation by activating pro- or anti-inflammatory downstream signaling cascades. Within the central nervous system, there is emerging evidence that both receptors are involved in synaptic transmission and brain plasticity. Furthermore, due to their prominent role in mediating neuroinflammation, PAR2 and TLR4 are associated with development and progression of neurodegenerative disorders including but not limited to Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. In this article, we summarise the current knowledge on the cooperation between PAR2 and TLR4, discuss the potential cross-talk levels and highlight the impact of the cross-coupling on neuroinflammation. Related Articles | Metrics

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Neuroimaging characterization of recovery of impaired consciousness in patients with disorders of consciousness Sung Ho Jang, Young Hyeon Kwon 2019, 14 (7):  1202-1207.  doi: 10.4103/1673-5374.251299 Abstract ( 123 )   PDF (300KB) ( 196 )   Save Elucidation of critical brain areas or structures that are responsible for recovery of impaired consciousness in patients with disorders of consciousness is important because it can provide information that is useful when developing therapeutic strategies for neurorehabilitation or neurointervention in patients with disorders of consciousness. In this review, studies that have demonstrated brain changes during recovery of impaired consciousness were reviewed. These studies used positron emission tomography, electroencephalography/transcranial magnetic stimulation, diffusion tensor tractography, and diffusion tensor tractography/electroencephalography. The majority of these studies reported on the importance of supratentorial areas or structures in the recovery of impaired consciousness. The important brain areas or structures that were identified were the prefrontal cortex, basal forebrain, anterior cingulate cortex, and parietal cortex. These results have a clinically important implication that these brain areas or structures can be target areas for neurorehabilitation or neurointervention in patients with disorders of consciousness. However, most of studies were case reports; therefore, further original studies involving larger numbers of patients with disorders of consciousness are warranted. In addition, more detailed information on the brain areas or structures that are relevant to the recovery of impaired consciousness is needed. Related Articles | Metrics

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Identification of a microRNA switch in spinal commissural axon guidance. Guo-fa Liu, Tao Yang 2019, 14 (7):  1208-1209.  doi: 10.4103/1673-5374.251300 Abstract ( 98 )   PDF (560KB) ( 145 )   Save The formation of neural circuits is governed by multiple classes of highly c onserved extracellular guidance signals such as guidance cues, growth factors, and cell adhesion molecules. During embryonic development, vertebrate commissural neurons project axons toward the floor plate and cross the midline of the spinal cord, a process relying upon the coordination of attractive and repulsive guidance cues. For instance, floor plate-derived Sonic hedgehog (Shh) and Netrin-1 attract spinal cord commissural axons projecting toward the floor plate and crossing the midline, whereas Slit-mediated repulsion on precrossing commissural axons is silenced. In contrast, postcrossing commissural axons lose responsiveness to Netrin-1/Shh attraction, but acquire responsiveness to repulsion of Slits and Semaphorins. It is believed that low level of Robo1, one of the Slit receptors, in precrossing commissural axons silence the responsiveness of commissural axons to Slit repulsion before midline crossing. However, Robo1 expression increases in postcrossing commissural axons, triggering Slit repulsion and simultaneously silencing Netrin-1-mediated attraction on commissural axon projection. Although such a differential expression pattern of Robo1 acts as a molecular switch of Slit repulsion to control commissural axon guidance, the molecular mechanisms underlying the fine-tuned regulation of temporal expression of Robo1 in developing commissural axons are still not well understood. MicroRNAs (miRNAs), non-coding small RNA transcripts (~22 nucleotides), bind to the 3 ′ untranslated region (3 ′ UTR) of target mRNAs and regulate gene expression post-transcriptionally via mRNA decay and/or translational repression. Emerging evidence indicate that miRNAs are involved in axon guidance by regulation of either guidance receptors at transcriptional level or their downstream signaling components at posttranscriptional level). However, a key question that remains unanswered is whether miRNAs could directly regulate Robo1 expression in the developing vertebrate spinal cord. Recently, one study from our lab has shown that miR-92, a highly conserved miRNA, may function as a molecular switch to specifically repress Robo1 expression, which further regulates Slit repulsion on precrossing commissural axons and plays an important role in commissural axon guidance in the developing chicken spinal cord. This finding provides a working model of the regulation of Robo1 expression in Slit-mediated commissural axon guidance in the vertebrate nervous system. Related Articles | Metrics

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Vacuolar protein sorting protein 41 (VPS41) at an intersection of endosomal traffic in neurodegenerative disease Edward F. Griffin, Kim A. Caldwell, Guy A. Caldwell 2019, 14 (7):  1210-1212.  doi: 10.4103/1673-5374.251329 Abstract ( 84 )   PDF (539KB) ( 174 )   Save Alzheimer’s and Parkinson’s diseases are neurodegenerative disorders pathologically classified by the accumulation of amyloidogenic proteins into insoluble inclusions within the brain. Specifically, amyloid plaques in the brains of Alzheimer’s disease patients are comprised of amyloid-β (Aβ) peptide, the product of sequential cleavage of the amyloid precursor protein by β- and γ-secretases. Simil arly, α-synuclein is a major component of Lewy bodies associated with Parkinson’s disease. Though both diseases increase progressively with disease and age, the soluble oligomeric forms associated with each polypeptide are, arguably, the most toxic species. Both Aβ and α-synuclein form porous oligomers that permeabilize membranes. Intracellular α-synuclein obstructs endoplasmic reticulum-Golgi traffic and following internalization, Aβ rapidly aggregates in endosomes and lysosomes. Using transgenic Caenorhabditis elegans models of neurodegeneration, Griffin et al. (2018) show that the homotypic fusion protein sorting complex, HOPS, lies at an intersection between the two pathogenic proteins to functionally protect against neurodegeneration. Related Articles | Metrics

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LHX1–a multifunctional regulator in preoptic area-derived interneuron development Judit Symmank, Geraldine Zimmer-Bensch 2019, 14 (7):  1213-1214.  doi: 10.4103/1673-5374.251303 Abstract ( 118 )   PDF (737KB) ( 209 )   Save In the cerebral cortex, local inhibition is achieved by different types of gamma-aminobutyric (GABA)-expressing interneurons, representing essential key players of cortical information processing. Their development has to be highly orchestrated to ensure proper numbers and subtype composition in the adult cortex and defects in interneuron development contribute to the pathophysiology of psychiatric diseases. Different from cortical projection neurons, inhibitory interneurons have their origin in proliferative zones in the basal telencephalon from where they have to migrate over long distances up to the cortex. During this migratory process, post-mitotic interneurons have to continuously adopt their morphology and directionality following guidance cues that are expressed in spatiotemporal-specific manner (Zimmer-Bensch, 2018). Detection and integration of environmental signals are achieved by receptor and intracellular signaling proteins that are expressed in a subset-specific manner. This mediates the differential responses of interneuron subtypes to certain guidance factors and provides an explanation for the different migratory streams that appear to correlate with interneuron identity. Related Articles | Metrics

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Aberrant cell cycle induction is pivotal for mitochondrial biogenesis after traumatic brain injury Nilkantha Sen 2019, 14 (7):  1215-1216.  doi: 10.4103/1673-5374.251305 Abstract ( 99 )   PDF (246KB) ( 140 )   Save Cell cycle regulation and brain injury: Traumatic brain injury (TBI) is one of the primary causes of morbidity and mortality in patients, and it affects more than 1.7 million Americans each year. Other than direct damage resulting from TBI, the brain injury triggers several secondary mechanisms which either individually or in combination contribute to the neurological deficits after TBI. These secondary mechanisms include neuronal death and stimulate proliferation of astrocytes and microglial cells, which in turn triggers neuro-inflammation. The association between proliferation of dividing cells like astrocytes and microglia with cell cycle has already been highlighted in a recent publication. However, in this article, we will emphasize the importance of cell cycle in post-mitotic cells like mature neurons following brain injury. Related Articles | Metrics

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New neuroprotective perspectives in fighting oxidative stress and improving cellular energy metabolism by oleocanthal Cristina Angeloni,Laura Giusti,Silvana Hrelia 2019, 14 (7):  1217-1218.  doi: 10.4103/1673-5374.251327 Abstract ( 262 )   PDF (130KB) ( 141 )   Save Neurodegenerative diseases are a heterogeneous group of disorders characterized by a progressive dysfunction and death of neural cells which lead to compromised motor or cognitive function. Morphologically, the loss of neuron is associated with both gliosis and, frequently, with abnormal accumulation of extracellular and intracellular filamentous deposit in specific cell types. Related Articles | Metrics

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What good is the reserve? A translational perspective for the managing of cognitive decline Laura Serra,Francesca Gelfo 2019, 14 (7):  1219-1220.  doi: 10.4103/1673-5374.251328 Abstract ( 151 )   PDF (223KB) ( 123 )   Save The concept of reserve appears in the neurological literature in the 1940s arising from the observation that there is no linear relationship between neurological damage and severity of the clinical symptoms. Basically, this concept sustains that the experiences pursued during life-span enrich the brain by making it more resilient to neuronal damage. However, in the last three decades the reserve concept has become very popular in the scientific field, mainly associated with the pathophysiological mechanisms underlying the Alzheimer’s Disease (AD). In this time period the concept has been substantially modified, passing from a structural conceptthe brain reserve (BR)–to a more functional concept–the neural reserve (NR)–by way of a cognitive concept-the cognitive reserve (CR). The BR is related to the brain structure in terms of number of neurons, synapses, and dendrites, and postulates that individuals with larger brain cope better with the neurological damage than subjects with smaller brains. The concept of CR is related to the efficiency of cognitive functioning, and postulates that subjects with higher level of CR use more efficiently the pre-existent cognitive processes or are able to enlist alternative cognitive functions to cope better with brain damages. The NR is a sort of summa of the previous concepts. Indeed, NR is related to the efficiency of brain networks, namely subjects with higher NR are able to engage more efficiently different brain routes to use more effectively the cognitive functions withstanding the cerebral damage. Moreover, Stern (2017) introduced the concept of brain maintenance that postulates that life experiences (including cognitive, social and physical activities) reshape the brain, such increasing the ability to maintain the cognitive integrity. It is well known that several factors that may be associated with genetic background and also with environmental factors impact positively or negatively on brain resilience making subjects able or not to counteract the damages. An important part of the research on the reserves is dedicated to identify the better proxy measure to capture brain changes due to reserves’ mechanisms (BR, CR, NR). Related Articles | Metrics

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GPER agonist G1 suppresses neuronal apoptosis mediated by endoplasmic reticulum stress after cerebral ischemia/reperfusion injury Zi-Wei Han,Yue-Chen Chang,Ying Zhou,Hang Zhang,Long Chen,Yang Zhang,Jun-Qiang Si,Li Li 2019, 14 (7):  1221-1229.  doi: 10.4103/1673-5374.251571 Abstract ( 180 )   PDF (2793KB) ( 164 )   Save Studies have confirmed a strong association between activation of the endoplasmic reticulum stress pathway and cerebral ischemia/reperfu¬sion (I/R) injury. In this study, three key proteins in the endoplasmic reticulum stress pathway (glucose-regulated protein 78, caspase-12, and C/EBP homologous protein) were selected to examine the potential mechanism of endoplasmic reticulum stress in the neuroprotective effect of G protein-coupled estrogen receptor. Female Sprague-Dawley rats received ovariectomy (OVX), and then cerebral I/R rat models (OVX + I/R) were established by middle cerebral artery occlusion. Immediately after I/R, rat models were injected with 100 μg/kg E2 (OVX + I/R + E2), or 100 μg/kg G protein-coupled estrogen receptor agonist G1 (OVX + I/R + G1) in the lateral ventricle. Longa scoring was used to detect neurobehavioral changes in each group. Infarct volumes were measured by 2,3,5-triphenyltetrazolium chloride staining. Morphological changes in neurons were observed by Nissl staining. Terminal dexynucleotidyl transferase-mediated nick end-labeling staining revealed that compared with the OVX + I/R group, neurological function was remarkably improved, infarct volume was reduced, number of normal Nissl bodies was dramatically increased, and number of apoptotic neurons in the hippocampus was decreased after E2 and G1 intervention. To detect the expression and distribution of endoplasmic reticulum stress-related proteins in the endoplasmic reticulum, caspase-12 distribution and expression were detected by immunofluorescence, and mRNA and protein levels of glucose-regulated protein 78, caspase-12, and C/EBP homologous protein were determined by polymerase chain reaction and western blot assay. The results showed that compared with the OVX + I/R group, E2 and G1 treatment obviously decreased mRNA and protein expression levels of glucose-regulated protein 78, C/EBP homol¬ogous protein, and caspase-12. However, the G protein-coupled estrogen receptor antagonist G15 (OVX + I/R + E2 + G15) could eliminate the effect of E2 on cerebral I/R injury. These results confirm that E2 and G protein-coupled estrogen receptor can inhibit the expression of endoplasmic reticulum stress-related proteins and neuronal apoptosis in the hippocampus, thereby improving dysfunction caused by cere¬bral I/R injury. Every experimental protocol was approved by the Institutional Ethics Review Board at the First Affiliated Hospital of Shihezi University School of Medicine, China (approval No. SHZ A2017-171) on February 27, 2017. Related Articles | Metrics

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Early treadmill exercise increases macrophage migration inhibitory factor expression after cerebral ischemia/reperfusion Min Cheol Chang,Chae Ri Park,Seung Hwa Rhie,Woo Hyun Shim,Dae Yul Kim 2019, 14 (7):  1230-1236.  doi: 10.4103/1673-5374.251330 Abstract ( 102 )   PDF (1014KB) ( 173 )   Save The neuroprotective function of macrophage migration inhibitory factor (MIF) in ischemic stroke was rarely evaluated. This study aimed to investigate the effects of early treadmill exercise on recovery from ischemic stroke and to determine whether these effects are associated with the expression levels of MIF and brain-derived neurotrophic factor (BDNF) in the ischemic area. A total of 40 male Sprague-Dawley rats were randomly assigned to the ischemia and exercise group [middle cerebral artery occlusion (MCAO)-Ex, n = 10), ischemia and sedentary group (MCAO-St, n = 10), sham-surgery and exercise group (Sham-Ex, n = 10), or sham-surgery and sedentary group (Sham-St, n = 10). The MCAO-Ex and MCAO-St groups were subjected to MCAO for 60 minutes, whereas the Sham-Ex and Sham-St groups were subjected to an identical operation without MCAO. Rats in the MCAO-Ex and Sham-Ex groups then ran on a treadmill for 30 minutes once a day for 5 consecutive days. After reperfusion, the hanging time tested by the wire hang test was longer and the relative fractional anisotropy (rFA) determined by MRI was higher in the peri-infarct region of the MCAO-Ex group compared with the MCAO-St group. The expression levels of MIF and BDNF in the peri-infarct region were upregulated in the MCAO-Ex group. Increased MIF and BDNF levels were positively correlated with rFA changes in the peri-infarct region. There was no significant difference in the levels of MIF and BDNF in the peri-infarct region between the Sham-Ex and Sham-St groups. Our study demonstrated that early exercise (initiated 48 hours after the MCAO) could improve motor and neuronal recovery after ischemic stroke. Furthermore, the increased levels of MIF and BDNF in the peri-infarct region (penumbra) may be one of the mechanisms of enhanced neurological function recovery. Related Articles | Metrics

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Longitudinal quantitative electroencephalographic study in mono-hemispheric stroke patients Filippo Zappasodi,Franca Tecchio,Laura Marzetti,Vittorio Pizzella,Vincenzo Di Lazzaro,Giovanni Assenza 2019, 14 (7):  1237-1246.  doi: 10.4103/1673-5374.251331 Abstract ( 122 )   PDF (1384KB) ( 405 )   Save The identification of individual factors modulating clinical recovery after a stroke is fundamental to personalize the therapeutic intervention to enhance the final clinical outcome. In this framework, electrophysiological factors are promising since are more directly related to neuroplasticity, which supports recovery in stroke patients, than neurovascular factors. In this retrospective observational study, we investigated brain neuronal activity assessed via spectral features and Higuchi’s fractal dimension (HFD) of electroencephalographic signals in acute phase (2–10 days from symptom onset, T0) and sub-acute phase (2.5 months, T1) in 24 patients affected by unilateral middle cerebral artery stroke. Longitudinal assessment of the clinical deficits was performed using the National Institutes of Health Stroke Scale (NIHSS), together with the effective recovery calculated as the ratio between difference of NIHSS at T0 and T1 over the NIHSS value at T0. We observed that delta and alpha band electroencephalographic signal power changed between the two phases in both the hemispheres ipsilateral (ILH) and contralateral (CHL) to the lesion. Moreover, at T0, bilateral higher delta band power correlated with worse clinical conditions (Spearman’s rs = 0.460, P = 0.027 for ILH and rs = 0.508, P = 0.013 for CLH), whereas at T1 this occurred only for delta power in ILH (rs = 0.411, P = 0.046) and not for CHL. Inter-hemispheric difference (ILH vs. CLH) of alpha power in patients was lower at T0 than at T1 (P = 0.020). HFD at T0 was lower than at T1 (P = 0.005), and at both phases, ILH HFD was lower than CLH HFD (P = 0.020). These data suggest that inter-hemispheric low band asymmetry and fractal dimension changes from the acute to the sub-acute phase are sensitive to neuroplasticity processes which subtend clinical recovery. The study protocol was approved by the Bioethical Committee of Ospedale San Giovanni Calibita Fatebenefretelli (No. 40/2011) on July 14, 2011. Related Articles | Metrics

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A high methionine, low folate and vitamin B6/B12 containing diet can be associated with memory loss by epigenetic silencing of netrin-1 Anuradha Kalani,Pankaj Chaturvedi,Komal Kalani,Pradip K. Kamat,Poonam Chaturvedi,Neetu Tyagi 2019, 14 (7):  1247-1254.  doi: 10.4103/1673-5374.251333 Abstract ( 138 )   PDF (1414KB) ( 194 )   Save Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study. We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore, silencing the netrin-1 gene, which encodes the glycoprotein involved in neurogenesis, axonal guidance and maintenance of the synaptic plasticity. Wild type (C57BL/6J) mice were fed with a diet containing excess methionine (1.2%), low-folate (0.08 mg/kg), vitamin B6 (0.01 mg/kg), and B12 (10.4 mg/kg) for 6 weeks. Mice were examined weekly for the long-term memory function, using a passive avoidance test, which determined loss of fear-motivated long-term memory starting from the fourth week of diet. Similarly, an increase in brain %5-methyl cytosine was observed starting from the 4th week of diet in mice. Mice fed with a high methionine, low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation, as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis. The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis. Furthermore, the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory. Taken together, these results suggest that a diet rich in methionine and lacking in folate and vitamin B6/B12 can induce defects in learning and memory. Furthermore, the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss. The animal procedures were approved by the Institutional Animal Care and Use Committee, University of Louisville, USA (No. A3586-01) on February 2, 2018. Related Articles | Metrics

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Use of ebselen as a neuroprotective agent in rat spinal cord subjected to traumatic injury Wojciech Ślusarczyk,Edyta Olakowska,Magdalena Larysz-Brysz,Izabella Woszczycka-Korczyńska,Daria Gendosz de Carrillo,Władysław P. Węglarz,Joanna Lewin-Kowalik,Wiesław Marcol 2019, 14 (7):  1255-1261.  doi: 10.4103/1673-5374.251334 Abstract ( 118 )   PDF (653KB) ( 99 )   Save Spinal cord injury (SCI) causes disturbances of motor skills. Free radicals have been shown to be essential for the development of spinal cord trauma. Despite some progress, until now no effective pharmacological therapies against SCI have been verified. The purpose of our experiment was to investigate the neuroprotective effects of ebselen on experimental SCI. Twenty-two rats subjected to SCI were randomly subjected to SCI with no further treatment (n = 10) or intragastric administration of ebselen (10 mg/kg) immediately and 24 hours after SCI. Behavioral changes were assessed using the Basso, Beattie, and Bresnahan locomotor scale and footprint test during 12 weeks after SCI. Histopathological and immunohistochemical analyses of spinal cords and brains were performed at 12 weeks after SCI. Magnetic resonance imaging analysis of spinal cords was also performed at 12 weeks after SCI. Rats treated with ebselen presented only limited  neurobehavioral progress as well as reduced spinal cord injuries compared with the control group, namely length of lesions (cysts/scars) visualized histopathologically in the spinal cord sections was less but cavity area was very similar. The same pattern was found in T2-weighted magnetic resonance images (cavities) and diffusion-weighted images (scars). The number of FluoroGold retrogradely labeled neurons in brain stem and motor cortex was several-fold higher in ebselen-treated rats than in the control group. The findings suggest that ebselen has only limited neuroprotective effects on injured spinal cord. All exprimental procedures were approved by the Local Animal Ethics Committee for Experiments on Animals in Katowice (Katowice, Poland) (approval No. 19/2009). Related Articles | Metrics

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Bioinformatics analyses of differentially expressed genes associated with spinal cord injury: a microarray-based analysis in a mouse model Lei Guo,Jing Lv,Yun-Fei Huang,Ding-Jun Hao,Ji-Jun Liu 2019, 14 (7):  1262-1270.  doi: 10.4103/1673-5374.251335 Abstract ( 125 )   PDF (797KB) ( 157 )   Save Gene spectrum analysis has shown that gene expression and signaling pathways change dramatically after spinal cord injury, which may affect the microenvironment of the damaged site. Microarray analysis provides a new opportunity for investigating diagnosis, treatment, and prognosis of spinal cord injury. However, differentially expressed genes are not consistent among studies, and many key genes and signaling pathways have not yet been accurately studied. GSE5296 was retrieved from the Gene Expression Omnibus DataSet. Differ¬entially expressed genes were obtained using R/Bioconductor software (expression changed at least two-fold; P < 0.05). Database for Annotation, Visualization and Integrated Discovery was used for functional annotation of differentially expressed genes and Animal Transcription Factor Database for predicting potential transcription factors. The resulting transcription regulatory protein interaction network was mapped to screen representative genes and investigate their diagnostic and therapeutic value for disease. In total, this study identified 109 genes that were upregulated and 30 that were downregulated at 0.5, 4, and 24 hours, and 3, 7, and 28 days after spinal cord injury. The number of downregulated genes was smaller than the number of upregulated genes at each time point. Database for Annota¬tion, Visualization and Integrated Discovery analysis found that many inflammation-related pathways were upregulated in injured spinal cord. Additionally, expression levels of these inflammation-related genes were maintained for at least 28 days. Moreover, 399 regulation modes and 77 nodes were shown in the protein-protein interaction network of upregulated differentially expressed genes. Among the 10 upregulated differentially expressed genes with the highest degrees of distribution, six genes were transcription factors. Among these tran¬scription factors, ATF3 showed the greatest change. ATF3 was upregulated within 30 minutes, and its expression levels remained high at 28 days after spinal cord injury. These key genes screened by bioinformatics tools can be used as biological markers to diagnose diseases and provide a reference for identifying therapeutic targets. Related Articles | Metrics

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Effect of exogenous spastin combined with polyethylene glycol on sciatic nerve injury Yao-Fa Lin,Zheng Xie,Jun Zhou,Hui-Hao Chen,Wan-Wan Shao,Hao-Dong Lin 2019, 14 (7):  1271-1279.  doi: 10.4103/1673-5374.251336 Abstract ( 140 )   PDF (2244KB) ( 256 )   Save Polyethylene glycol can connect the distal and proximal ends of an injured nerve at the cellular level through axonal fusion to avoid Wallerian degeneration of the injured distal nerve and promote peripheral nerve regeneration. However, this method can only prevent Wallerian degeneration in 10% of axons because the cytoskeleton is not repaired in a timely fashion. Reconstruction of the cytoskeletal trunk and microtubule network has been suggested to be the key for improving the efficiency of axonal fusion. As a microtubule-severing protein, spastin has been used to enhance cytoskeletal reconstruction. Therefore, we hypothesized that spastin combined with polyeth¬ylene glycol can more effectively promote peripheral nerve regeneration. A total of 120 male Sprague-Dawley rats were randomly divided into sham, suture, polyethylene glycol, and polyethylene glycol + spastin groups. In suture group rats, only traditional nerve anastomosis of the end-to-end suture was performed after transection of the sciatic nerve. In polyethylene glycol and polyethylene glycol + spastin groups, 50 μL of polyethylene glycol or 25 μL of polyethylene glycol + 25 μL of spastin, respectively, were injected immediately under the epineurium of the distal suture. Sensory fiber regeneration distance, which was used to assess early nerve regeneration at 1 week after surgery, was shortest in the suture group, followed by polyethylene glycol group and greatest in the polyethylene glycol + spastin group. Behavioral assessment of motor function recovery in rats showed that limb function was restored in polyethylene glycol and polyethylene glycol + spastin groups at 8 weeks after surgery. At 1, 2, 4 and 8 weeks after surgery, sciatic functional index values and percentages of gas¬trocnemius muscle wet weight were highest in the sham group, followed by polyethylene glycol + spastin and polyethylene glycol groups, and lowest in the suture group. Masson staining was utilized to assess the morphology of muscle tissue. Morphological changes in skel¬etal muscle were detectable in suture, polyethylene glycol, and polyethylene glycol + spastin groups at 1, 2, 4, and 8 weeks after surgery. Among them, muscular atrophy of the suture group was most serious, followed by polyethylene glycol and polyethylene glycol + spastin groups. Ultrastructure of distal sciatic nerve tissue, as detected by transmission electron microscopy, showed a pattern of initial destruc¬tion, subsequent disintegration, and gradual repair in suture, polyethylene glycol, and polyethylene glycol + spastin groups at 1, 2, 4, and 8 weeks after surgery. As time proceeded, axonal ultrastructure gradually recovered. Indeed, the polyethylene glycol + spastin group was similar to the sham group at 8 weeks after surgery. Our findings indicate that the combination of polyethylene glycol and spastin can pro¬mote peripheral nerve regeneration. Moreover, the effect of this combination was better than that of polyethylene glycol alone, and both were superior to the traditional neurorrhaphy. This study was approved by the Animal Ethics Committee of the Second Military Medical University, China (approval No. CZ20170216) on March 16, 2017. Related Articles | Metrics

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Redistribution of nerve strain enables end-to-end repair under tension without inhibiting nerve regeneration Holly M. Howarth,Turki Alaziz,Brogan Nicolds,Shawn O’Connor,Sameer B. Shah 2019, 14 (7):  1280-1288.  doi: 10.4103/1673-5374.251338 Abstract ( 120 )   PDF (3539KB) ( 147 )   Save End-to-end repair under no or low tension leads to improved outcomes for transected nerves with short gaps, compared to repairs with a graft. However, grafts are typically used to enable a tension-free repair for moderate to large gaps, as excessive tension can cause repairs to fail and catastrophically impede recovery. In this study, we tested the hypothesis that unloading the repair interface by redistributing tension away from the site of repair is a safe and feasible strategy for end-to-end repair of larger nerve gaps. Further, we tested the hypothesis that such an approach does not adversely affect structural and functional regeneration. In this study, we used a rat sciatic nerve injury model to compare the integrity of repair and several regenerative outcomes following end-to-end repairs of nerve gaps of increasing size. In addition, we proposed the use of a novel implantable device to safely repair end-to-end repair of larger nerve gaps by redistributing tension away from the repair interface. Our data suggest that redistriubution of tension away from the site of repair enables safe end-to-end repair of larger gap sizes. In addition, structural and functional measures of regeneration were equal or enhanced in nerves repaired under tension – with or without a tension redistribution device – compared to tension-free repairs. Provided that repair integrity is maintained, end-to-end repairs under tension should be considered as a reasonable surgical strategy. All animal experiments were performed under the approval of the Institutional Animal Care and Use Committee of University of California, San Diego (Protocol S11274). Related Articles | Metrics