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  • Molecular approaches for spinal cord injury treatment

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Injuries to the spinal cord result in permanent disabilities that limit daily life activities. The main reasons for these poor outcomes are the limited regenerative capacity of central neurons and the inhibitory milieu that is established upon traumatic injuries. Despite decades of research, there is still no efficient treatment for spinal cord injury. Many strategies are tested in preclinical studies that focus on ameliorating the functional outcomes after spinal cord injury. Among these, molecular compounds are currently being used for neurological recovery, with promising results. These molecules target the axon collapsed growth cone, the inhibitory microenvironment, the survival of neurons and glial cells, and the re-establishment of lost connections. In this review we focused on molecules that are being used, either in preclinical or clinical studies, to treat spinal cord injuries, such as drugs, growth and neurotrophic factors, enzymes, and purines. The mechanisms of action of these molecules are discussed, considering traumatic spinal cord injury in rodents and humans.

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  • Diffusion tensor imaging reveals brain structure changes in dogs after spinal cord injury

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Based on the Wallerian degeneration in the spinal cord pathways, the changes in synaptic connections, and the spinal cord-related cellular responses that alter the cellular structure of the brain, we presumed that brain diffusion tensor imaging (DTI) parameters may change after spinal cord injury. However, the dynamic changes in DTI parameters remain unclear. We established a Beagle dog model of T10 spinal cord contusion and performed DTI of the injured spinal cord. We found dynamic changes in DTI parameters in the cerebral peduncle, posterior limb of the internal capsule, pre- and postcentral gyri of the brain within 12 weeks after spinal cord injury. We then performed immunohistochemistry to detect the expression of neurofilament heavy polypeptide (axonal marker), glial fibrillary acidic protein (glial cell marker), and NeuN (neuronal marker). We found that these pathological changes were consistent with DTI parameter changes. These findings suggest that DTI can display brain structure changes after spinal cord injury.

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  • Lamotrigine protects against cognitive deficits, synapse and nerve cell damage, and hallmark neuropathologies in a mouse model of Alzheimer 's disease

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Lamotrigine (LTG) is a widely used drug for the treatment of epilepsy. Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer's disease. However, the underlying molecular mechanisms remain unclear. In this study, amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice were used as a model of Alzheimer's disease. Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months. The cognitive functions of animals were assessed using Morris water maze. Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay. The cell damage in the brain was investigated using hematoxylin and eosin staining. The levels of amyloid-β and the concentrations of interleukin-1β, interleukin-6 and tumor necrosis factor-α in the brain were measured using enzyme-linked immunosorbent assay. Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction. We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice; alleviated damage to synapses and nerve cells in the brain; and reduced amyloid-β levels, tau protein hyperphosphorylation, and inflammatory responses. High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer's disease-related neuropathologies may have been mediated by the regulation of Ptgds, Cd74, Map3k1, Fosb, and Spp1 expression in the brain. These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer's disease. Furthermore, these data indicate that LTG may be a promising therapeutic drug for Alzheimer's disease.

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  • Dysregulated expression and distribution of Kif5α in neurites of wobbler motor neurons

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Impaired axonal transport has been observed in patients with amyotrophic lateral sclerosis (ALS) and in animal models, suggesting that transport proteins likely play a critical role in the pathological mechanism of ALS. Dysregulation of Kinesin-family-member 5α (Kif5α), a neuron-specific isoform of heavy chain kinesin family, has been described in several neurological disorders, in humans and animal models, including ALS. In this study, we determined Kif5α expression by gene sequencing, quantitative reverse transcription-polymerase chain reaction, and western blot assay in the cervical spinal cord of wobbler mice and immunofluorescence staining in dissociated cultures of the ventral horn. Further, we observed the distribution of Kif5α and mitochondria along motor neuronal branches by confocal imaging. Our results showed that Kif5α expression was greatly dysregulated in wobbler mice, which resulted in altered distribution of Kif5α along motor neuronal branches with an abnormal mitochondrial distribution. Thus, our results indicate that dysregulation of Kif5 and therefore abnormal transport in motor neuronal branches in this ALS model could be causative for several pathological findings at the cellular level, like misallocation of cytoskeletal proteins or organelles like mitochondria.

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  • Characterization of retinal ganglion cell damage at single axon bundle level in mice by visible-light optical coherence tomography fibergraphy

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Retinal ganglion cells (RGCs) receive synaptic inputs through their dendritic trees in the inner plexiform layer (IPL) and convey the visual information via their axons which form the optic nerve to the brain (Sanes and Masland, 2015). In glaucoma, RGCs and their axons degenerate and die, leading to irreversible vision loss and eventually blindness if left untreated (Quigley, 2016). The self-destructive programs in RGCs induced by glaucomatous insults are often spatially compartmentalized (Syc-Mazurek and Libby, 2019), which results in changes in the IPL, the ganglion cell layer, and the retinal nerve fiber layer (RNFL) before cell death in humans and rodents (Wollstein et al., 2012; Chen et al., 2015; Grannonico et al., 2021). Characterizing RGC morphological changes is thus potentially pertinent for timely intervention to preserve RGCs and vision, but much remains unknown to establish a sensitive and specific marker of RGC damage for better diagnosis and management of glaucoma.

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  • Glial regenerative response in the imaginal discs of Drosophila melanogaster

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Glial cells play a key role during nervous system development and actively participate in all the cellular processes involved in maintaining its structural robustness and functional plasticity. In response to neuronal damage, glial cells proliferate, migrate to the injured region and change their morphology, function, and behavior (Gallo and Deneen, 2014; Kato et al., 2018). This glial regenerative response is associated with the repairing function of these cells and is found across species, suggesting that it may reflect a common underlying genetic mechanism (Kato et al., 2018). In mammals, while the central nervous system has very limited capacity to regenerate after traumatic injury or disease, the peripheral nervous system (PNS) exhibits a far greater capacity for regeneration and damaged peripheral nerves can be totally restored (Brosius Lutz and Barres, 2014; Gallo and Deneen, 2014). The PNS largely owes its regenerative potential to the ability of the main glial cells present in the PNS, myelin, and non-myelin (Remak) Schwann cells, to convert to cells devoted to repairing after injury (Nocera and Jacob, 2020). During the regeneration of peripheral nerves in vertebrates, Schwann cells function as a central hub, collecting signals from neurons and other cell types and undergoing a complex process of reprogramming which converts them into a specialized cell for repair. Even though many aspects of regeneration in peripheral nerves have been studied, there is still a lack of understanding regarding the genetic network that controls the flexible differentiation state of PNS neurons and Schwann. The identification of those signals is essential for getting new insight to develop innovative regenerative therapies. In this scenario, the use of relatively simple model organisms, amenable to genetic, cellular, and molecular analysis is fundamental to study the behavior of glial cells in response to damage in their natural context.

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  • Astrocyte evolution and human specificity

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    The cerebral cortex is one of the most complex structures of the mammalian central nervous system and accounts for the extraordinary cognitive abilities in primates and humans. Since the 19th century, neur ons have been believed to be the main players in the building of the brain, yet astrocytes also play a crucial role as fundamental building blocks of the cerebral cortex complexity.

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  • DL-3-n-butylphthalide alleviates motor disturbance by suppressing ferroptosis in a rat model of Parkinson's disease

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    DL-3-n-butylphthalide (NBP)—a compound isolated from Apium graveolens seeds—is protective against brain ischemia via various mechanisms in humans and has been approved for treatment of acute ischemic stroke. NBP has shown recent potential as a treatment for Parkinson's disease. However, the underlying mechanism of action of NBP remains poorly understood. In this study, we established a rat model of Parkinson's disease by intraperitoneal injection of rotenone for 28 successive days, followed by intragastric injection of NBP for 14–28 days. We found that NBP greatly alleviated rotenone-induced motor disturbance in the rat model of Parkinson's disease, inhibited loss of dopaminergic neurons and aggregation of α-synuclein, and reduced iron deposition in the substantia nigra and iron content in serum. These changes were achieved by alterations in the expression of the iron metabolism-related proteins transferrin receptor, ferritin light chain, and transferrin 1. NBP also inhibited oxidative stress in the substantia nigra and protected mitochondria in the rat model of Parkinson's disease. Our findings suggest that NBP alleviates motor disturbance by inhibition of iron deposition, oxidative stress, and ferroptosis in the substantia nigra.

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  • Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Icariin, a major prenylated flavonoid found in Epimedium spp., is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer's disease. In this study, we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer's disease. We performed behavioral tests, pathological examination, and western blot assay, and found that memory deficits of the model mice were obviously improved, neuronal and synaptic damage in the cerebral cortex was substantially mitigated, and amyloid-β accumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day. Furthermore, deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed, including the insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3-kinase, protein kinase B, and glycogen synthase kinase 3β, and the levels of glucose transporter 1 and 3 were markedly increased. These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer's disease by regulating brain insulin signaling and glucose transporters, which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer's disease.

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  • Translation stalling and ribosome collision leading to proteostasis failure: implications for neurodegenerative diseases

    编辑人员 丨来源 : 《中国神经再生研究(英文版)》 1秒前

    来源 : 《中国神经再生研究(英文版)》

    Proteostasis denotes a cellular state in which protein synthesis, folding, and degradation are maintained at a homeostatic state such that an intact yet dynamic proteome is preserved. Cellular capacity to preserve proteostasis declines with age, which is assumed to contribute to the pathogenesis of age-related diseases. Proteostasis failure manifested as the formation of aberrant protein aggregates, including the amyloid plaques in Alzheimer's disease (AD), Lewy bodies in Parkinson's disease, and TAR DNA binging protein 43 inclusions in amyotrophic lateral sclerosis (ALS), is a defining feature of neurodegenerative diseases. The root cause of the proteostasis failure and protein aggregation is still enigmatic. Studies in various systems suggest that cellular co-factors play important roles in "seeding" the aforementioned pathogenic protein aggregation. But the molecular nature of the initial seeding activities remains poorly defined. The pathogenic role of the disease-characterizing, macroscopically visible protein aggregates is also uncertain. Several high-profile clinical trials targeting specific protein aggregates are inconclusive and there is no evidence for a clinically relevant therapeutic effect as of now (Mullane and Williams, 2018), suggesting that the key proteostasis-disruptive, disease-causing events remain to be identified. In this perspective, I will discuss recent evidence supporting that faulty translation products resulting from inadequate quality control of translational stalling and ribosome collision during the translation of certain problematic mRNAs can be the root cause of proteostasis failure and may represent novel therapeutic targets for neurodegenerative diseases.

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