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15 March 2021, Volume 16 Issue 3 Previous Issue    Next Issue

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Progress in clinical trials of cell transplantation for the treatment of spinal cord injury: how many questions remain unanswered? Xu-Chang Hu, Yu-Bao Lu, Yong-Na Yang, Xue-Wen Kang, Yong-Gang Wang, Bing Ma, Shuai Xing 2021, 16 (3):  405-413.  doi: 10.4103/1673-5374.293130 Abstract ( 103 )   PDF (560KB) ( 113 )   Save Spinal cord injury can lead to severe motor, sensory and autonomic nervous dysfunctions. However, there is currently no effective treatment for spinal cord injury. Neural stem cells and progenitor cells, bone marrow mesenchymal stem cells, olfactory ensheathing cells, umbilical cord blood stem cells, adipose stem cells, hematopoietic stem cells, oligodendrocyte precursor cells, macrophages and Schwann cells have been studied as potential treatments for spinal cord injury. These treatments were mainly performed in animals. However, subtle changes in sensory function, nerve root movement and pain cannot be fully investigated with animal studies. Although these cell types have shown excellent safety and effectiveness in various animal models, sufficient evidence of efficacy for clinical translation is still lacking. Cell transplantation should be combined with tissue engineering scaffolds, local drug delivery systems, postoperative adjuvant therapy and physical rehabilitation training as part of a comprehensive treatment plan to provide the possibility for patients with SCI to return to normal life. This review summarizes and analyzes the clinical trials of cell transplantation therapy in spinal cord injury, with the aim of providing a rational foundation for the development of clinical treatments for spinal cord injury. Related Articles | Metrics

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Postnatal therapeutic approaches in genetic neurodevelopmental disorders Gilad Levy, Boaz Barak 2021, 16 (3):  414-422.  doi: 10.4103/1673-5374.293133 Abstract ( 85 )   PDF (470KB) ( 76 )   Save Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes, affecting individuals worldwide. While the subject has been heavily researched, current treatment options relate mostly to alleviating symptoms, rather than targeting the altered genome itself. In this review, we address the neurogenetic basis of neurodevelopmental disorders, genetic tools that are enabling precision research of these disorders in animal models, and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.  Related Articles | Metrics

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Regulation of neuroimmune processes by damage- and resolution-associated molecular patterns Andis Klegeris 2021, 16 (3):  423-429.  doi: 10.4103/1673-5374.293134 Abstract ( 127 )   PDF (554KB) ( 107 )   Save Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis, but they also contribute to various neurological disorders, including neurotrauma, stroke, and demyelinating or neurodegenerative diseases. Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins, which can be broadly divided into the pro-inflammatory damage-associated molecular patterns (DAMPs) and anti-inflammatory resolution-associated molecular patterns (RAMPs), even though there is notable overlap between the DAMP- and RAMP-like activities for some of these molecules. Both groups of molecular patterns were initially described in peripheral immune processes and pathologies; however, it is now evident that at least some, if not all, of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders. The review of recent literature demonstrates that studies on DAMPs and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts. Nevertheless, this review also reveals that over the last five years, significant advances have been made in our understanding of the neuroimmune functions of several well-established DAMPs, including high-mobility group box 1 protein  and interleukin 33. Novel neuroimmune functions have been demonstrated for other DAMPs that previously were considered almost exclusively as peripheral immune regulators; they include mitochondrial transcription factor A and cytochrome C. RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions, such as multiple sclerosis and rheumatoid arthritis. The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is also supported by several of the identified studies. It can be concluded that further studies of DAMPs and RAMPs of the central nervous system will continue to be an important and productive field of neuroimmunology. Related Articles | Metrics

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Neonatal opioid exposure: public health crisis and novel neuroinflammatory disease Vikram Vasan, Yuma Kitase, Jessie C. Newville, Shenandoah Robinson, Gwendolyn Gerner, V. Joanna Burton, Lauren L. Jantzie 2021, 16 (3):  430-432.  doi: 10.4103/1673-5374.293136 Abstract ( 96 )   PDF (416KB) ( 125 )   Save Substance use, specifically the use of prescription and non-prescription opioids among pregnant women, is a major public health issue and chief contributor to the opioid crisis. The prevalence of Neonatal Opioid Withdrawal Syndrome has risen 5-fold in the past decade, and is a well-recognized consequence of perinatal opioid exposure. By contrast, the long-term damage to the developing brain from opioid medications is just beginning to be recognized as a serious concern. Published data suggest that opioid exposure commencing in utero negatively affects the maturation of the neural-immune system, and trajectory of central nervous system development. Methadone induces peripheral immune hyper-reactivity, lasting structural and microstructural brain injury, and significant deficits in executive function and cognitive control in adult animals following in utero exposure. Thus, to address the cascading public health crisis stemming from the multitude of infants with in utero opioid exposure who will grow up with altered neurodevelopmental trajectories, rigorous preclinical, mechanistic studies are required. Such studies will define the long-term sequelae of prenatal opioid exposure in an effort to develop appropriate and targeted interventions. Specifically, the development of novel fluid, neuroimaging and biobehavioral biomarkers will be the most useful to aid in early identification and treatment of opioid exposed infants with the greatest risk of poor clinical outcomes. These studies will be essential to understand how in utero insults determine brain structure and function in adulthood, and what targeted interventions will be required to improve long-term outcomes in the countless children being born exposed to opioids each year. Related Articles | Metrics

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Physiopathology of ischemic stroke and its modulation using memantine: evidence from preclinical stroke Hilda Martínez-Coria, Isabel Arrieta-Cruz, María-Esther Cruz, Héctor E. López-Valdés 2021, 16 (3):  433-439.  doi: 10.4103/1673-5374.293129 Abstract ( 87 )   PDF (1568KB) ( 380 )   Save Ischemic stroke is the most common type of cerebrovascular disease and is caused by an interruption of blood flow in the brain. In this disease, two different damage areas are identifying: the lesion core, in which cells quickly die; and the penumbra (surrounding the lesion core), in which cells are functionally weakened but may recover and restore their functions. The currently approved treatments for ischemic stroke are the recombinant tissue plasminogen activator and endovascular thrombectomy, but they have a short therapeutic window (4.5 and 6 hours after stroke onset, respectively) and a low percentage of stroke patients actually receive these treatments. Memantine is an approved drug for the treatment of Alzheimer’s disease. Memantine is a noncompetitive, low affinity and use-dependent antagonist of N-methyl-D-aspartate glutamate receptor. Memantine has several advantages over developing a new drug to treat focal ischemic stroke, but the most important is that it has sufficient safe probes in preclinical models and humans, and if the preclinical studies provide more evidence about pharmacological actions in tissue protection and repair, this could help to increase the number of clinical trials. The present review summarizes the physiopathology of isquemic stroke and the pharmacological actions in neuroprotection and neuroplasticity of memantine in the post stroke stage of preclinical stroke models, to illustrate their potential to improve functional recovery in human patients. Related Articles | Metrics

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MicroRNAs as diagnostic and prognostic biomarkers of age-related macular degeneration: advances and limitations Bridget Martinez, Philip V. Peplow 2021, 16 (3):  440-447.  doi: 10.4103/1673-5374.293131 Abstract ( 106 )   PDF (760KB) ( 51 )   Save A main cause of vision loss in the elderly is age-related macular degeneration (AMD). Among the cellular, biochemical, and molecular changes linked to this disease, inflammation and angiogenesis appear as being crucial in AMD pathogenesis and progression. There are two forms of the disease: dry AMD, accounting for 80–90% of cases, and wet AMD. The disease usually begins as dry AMD associated with retinal pigment epithelium and photoreceptor degeneration, whereas wet AMD is associated with choroidal neovascularization resulting in severe vision impairment. The new vessels are largely malformed, leading to blood and fluid leakage within the disrupted tissue, which provokes inflammation and scar formation and results in retinal damage and detachment. MicroRNAs are dysregulated in AMD and may facilitate the early detection of the disease and monitoring disease progression. Two recent reviews of microRNAs in AMD had indicated weaknesses or limitations in four earlier investigations. Studies in the last three years have shown considerable progress in overcoming some of these concerns and identifying specific microRNAs as biomarkers for AMD. Further large-scale studies are warranted using appropriate statistical methods to take into account gender and age disparity in the study populations and confounding factors such as smoking status.    Related Articles | Metrics

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Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1 Kenneth Maiese 2021, 16 (3):  448-455.  doi: 10.4103/1673-5374.291382 Abstract ( 133 )   PDF (743KB) ( 112 )   Save The global increase in lifespan noted not only in developed nations, but also in large developing countries parallels an observed increase in a significant number of non-communicable diseases, most notable neurodegenerative disorders. Neurodegenerative disorders present a number of challenges for treatment options that do not resolve disease progression. Furthermore, it is believed by the year 2030, the services required to treat cognitive disorders in the United States alone will exceed $2 trillion annually. Mammalian forkhead transcription factors, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), the mechanistic target of rapamycin, and the pathways of autophagy and apoptosis offer exciting avenues to address these challenges by focusing upon core cellular mechanisms that may significantly impact nervous system disease. These pathways are intimately linked such as through cell signaling pathways involving protein kinase B and can foster, sometimes in conjunction with trophic factors, enhanced neuronal survival, reduction in toxic intracellular accumulations, and mitochondrial stability. Feedback mechanisms among these pathways also exist that can oversee reparative processes in the nervous system. However, mammalian forkhead transcription factors, silent mating type information regulation 2 homolog 1, mechanistic target of rapamycin, and autophagy can lead to cellular demise under some scenarios that may be dependent upon the precise cellular environment, warranting future studies to effectively translate these core pathways into successful clinical treatment strategies for neurodegenerative disorders. Related Articles | Metrics

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Microglial activation and adult neurogenesis after brain stroke Ijair R.C. dos Santos, Michelle Nerissa C. Dias, Walace Gomes-Leal 2021, 16 (3):  456-459.  doi: 10.4103/1673-5374.291383 Abstract ( 83 )   PDF (467KB) ( 72 )   Save The discovery that new neurons are produced in some regions of the adult mammalian brain is a paradigm-shift in neuroscience research. These new-born cells are produced from neuroprogenitors mainly in the subventricular zone at the margin of the lateral ventricle, subgranular zone in the hippocampal dentate gyrus and in the striatum, a component of the basal ganglia, even in humans. In the human hippocampus, neuroblasts are produced even in elderlies. The regulation of adult neurogenesis is a complex phenomenon involving a multitude of molecules, neurotransmitters and soluble factors released by different sources including glial cells. Microglia, the resident macrophages of the central nervous system, are considered to play an important role on the regulation of adult neurogenesis both in physiological and pathological conditions. Following stroke and other acute neural disorders, there is an increase in the numbers of neuroblast production in the neurogenic niches. Microglial activation is believed to display both beneficial and detrimental role on adult neurogenesis after stroke, depending on the activation level and brain location. In this article, we review the scientific evidence addressing the role of microglial activation on adult neurogenesis after ischemia. A comprehensive understanding of the microglial role after stroke and other neural disorders it is an important step for development of future therapies based on manipulation of adult neurogenesis.  Related Articles | Metrics

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The therapeutic potential of targeting exchange protein directly activated by cyclic adenosine 3′,5′-monophosphate (Epac) for central nervous system trauma Alba Guijarro-Belmar, Dominik Mateusz Domanski, Xuenong Bo, Derryck Shewan, Wenlong Huang 2021, 16 (3):  460-469.  doi: 10.4103/1673-5374.293256 Abstract ( 113 )   PDF (5295KB) ( 89 )   Save Millions of people worldwide are affected by traumatic spinal cord injury, which usually results in permanent sensorimotor disability. Damage to the spinal cord leads to a series of detrimental events including ischaemia, haemorrhage and neuroinflammation, which over time result in further neural tissue loss. Eventually, at chronic stages of traumatic spinal cord injury, the formation of a glial scar, cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth. This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system. The intracellular signalling molecule, cyclic adenosine 3′,5′-monophosphate (cAMP), is known to play many important roles in the central nervous system, and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models. However, therapies directly targeting cAMP have not found their way into the clinic, as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects. A downstream effector of cAMP, exchange protein directly activated by cAMP 2 (Epac2), is mainly expressed in the adult central nervous system, and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration. Recently, using ex vivo modelling of traumatic spinal cord injury, Epac2 activation was found to profoundly modulate the post-lesion environment, such as decreasing the activation of astrocytes and microglia. Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury. Therefore, targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair, and future work is needed to fully establish its therapeutic potential.  Related Articles | Metrics

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Role of vitamin B12 deficiency in ischemic stroke risk and outcome Gyllian B. Yahn, Jamie E. Abato, Nafisa M. Jadavji 2021, 16 (3):  470-474.  doi: 10.4103/1673-5374.291381 Abstract ( 119 )   PDF (844KB) ( 769 )   Save Currently, ischemic stroke is the most prevalent form of stroke compared to hemorrhagic and there is a high incidence in older adults. Nutrition is a modifiable risk factor for stroke. B-vitamins are part of a metabolic network that integrates nutritional signals with biosynthesis, redox homeostasis, and epigenetics. These vitamins play an essential role in the regulation of cell proliferation, stress resistance, and embryo development. A deficiency in vitamin B12 is common in older adults and has been reported to be implicated in ischemic stroke. The aim of this review was to investigate whether vitamin B12 deficiencies impact the risk and outcome of ischemic stroke. Clinical data from our literature review strongly suggest that a deficiency in vitamin B12 is a risk factor for ischemic stroke and possible outcome. Our survey of the literature has identified that there is a gap in the understanding of the mechanisms through which a vitamin B12 deficiency leads to an increased risk of stroke and outcome. A vitamin B12 deficiency can increase homocysteine levels, which are a well-established risk factor for ischemic stroke. Another potential mechanism through which vitamin B12 deficient may impact neurological function and increase risk of stroke, is changes in myelination, however this link requires further investigation. Further studies are required in model systems to understand how a vitamin B12 deficiency changes the brain.  Related Articles | Metrics

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Current scenario of the genetic testing for rare neurological disorders exploiting next generation sequencing Chiara Di Resta, Giovanni Battista Pipitone, Paola Carrera, Maurizio Ferrari 2021, 16 (3):  475-481.  doi: 10.4103/1673-5374.293135 Abstract ( 99 )   PDF (474KB) ( 136 )   Save Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics, allowing for the detection of sequence variants with so far unprecedented large scale, mainly in genetically heterogenous diseases, such as neurological disorders. It is a fast-moving field, where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations. Despite the as yet undiscussed advantages, however, there are still some challenges in data analysis and the interpretation of variants. In this review, we address the current state of next generation sequencing diagnostic testing for inherited human disorders, particularly giving an overview of the available high-throughput sequencing approaches; including targeted, whole-exome and whole-genome sequencing; and discussing the main critical aspects of the bioinformatic process, from raw data analysis to molecular diagnosis.  Related Articles | Metrics

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Connexin therapeutics: blocking connexin hemichannel pores is distinct from blocking pannexin channels or gap junctions  Monica L. Acosta, Mohd N. Mat Nor, Cindy X. Guo, Odunayo O. Mugisho, Frazer P. Coutinho, Ilva D. Rupenthal, Colin R. Green 2021, 16 (3):  482-488.  doi: 10.4103/1673-5374.290097 Abstract ( 81 )   PDF (682KB) ( 161 )   Save Compounds that block the function of connexin and pannexin protein channels have been suggested to be valuable therapeutics for a range of diseases. Some of these compounds are now in clinical trials, but for many of them, the literature is inconclusive about the molecular effect on the tissue, despite evidence of functional recovery. Blocking the different channel types has distinct physiological and pathological implications and this review describes current knowledge of connexin and pannexin protein channels, their function as channels and possible mechanisms of the channel block effect for the latest therapeutic compounds. We summarize the evidence implicating pannexins and connexins in disease, considering their homeostatic versus pathological roles, their contribution to excesive ATP release linked to disease onset and progression. Related Articles | Metrics

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Saccharomyces cerevisiae in neuroscience: how unicellular organism helps to better understand prion protein? Takao Ishikawa 2021, 16 (3):  489-495.  doi: 10.4103/1673-5374.293137 Abstract ( 103 )   PDF (898KB) ( 172 )   Save The baker’s yeast Saccharomyces (S.) cerevisiae is a single-celled eukaryotic model organism widely used in research on life sciences. Being a unicellular organism, S. cerevisiae has some evident limitations in application to neuroscience. However, yeast prions are extensively studied and they are known to share some hallmarks with mammalian prion protein or other amyloidogenic proteins found in the pathogenesis of Alzheimer’s, Parkinson’s, or Huntington’s diseases. Therefore, the yeast S. cerevisiae has been widely used for basic research on aggregation properties of proteins in cellulo and on their propagation. Recently, a yeast-based study revealed that some regions of mammalian prion protein and amyloid β1–42 are capable of induction and propagation of yeast prions. It is one of the examples showing that evolutionarily distant organisms share common mechanisms underlying the structural conversion of prion proteins making yeast cells a useful system for studying mammalian prion protein. S. cerevisiae has also been used to design novel screening systems for anti-prion compounds from chemical libraries. Yeast-based assays are cheap in maintenance and safe for the researcher, making them a very good choice to perform preliminary screening before further characterization in systems engaging mammalian cells infected with prions. In this review, not only classical red/white colony assay but also yeast-based screening assays developed during last year are discussed. Computational analysis and research carried out using yeast prions force us to expect that prions are widely present in nature. Indeed, the last few years brought us several examples indicating that the mammalian prion protein is no more peculiar protein – it seems that a better understanding of prion proteins nature-wide may aid us with the treatment of prion diseases and other amyloid-related medical conditions. Related Articles | Metrics

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Neurogenesis versus neurodegeneration: the broken balance in Alzheimer’s disease Baruh Polis, Abraham O. Samson 2021, 16 (3):  496-497.  doi: 10.4103/1673-5374.293138 Abstract ( 101 )   PDF (490KB) ( 86 )   Save Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, eventually manifesting in severe cognitive dysfunction. Despite the recent proliferation of encouraging preclinical studies and clinical trials, scientific society is still far from a complete consensus regarding the AD etiology and pathogenesis. Accordingly, no approved AD‐modifying therapies are currently available. Nevertheless, novel concepts predicated upon the latest discoveries and comprehension of the disease as a multifactorial disorder are paving the road to the successful AD treatment.  Related Articles | Metrics

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Is serine racemase (SRR) a second hit target for LRRK2-G2019S induced Parkinson’s disease? Sarah Louise Nickels, Jens Christian Schwamborn 2021, 16 (3):  498-499.  doi: 10.4103/1673-5374.293140 Abstract ( 90 )   PDF (274KB) ( 69 )   Save To date, at least 7 million people are suffering from Parkinson’s disease (PD) worldwide, which is the second most prevalent, age-associated, and progressive neurodegenerative disorder (Tysnes and Storstein, 2017). Given the accelerated global pace of aging, it becomes of fundamental importance that we start understanding the origins of neurodegeneration in order to develop effective disease modifying treatments. Most PD patients suffer from a combination of motor and non-motor disabilities. The motor symptoms typically manifest in bradykinesia, tremor and rigidity (Hoehn and Yahr, 2001). The physical decline is directly linked to the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which disrupts dopamine signalling responsible for movement and mobility (Lanciego et al., 2012). The non-motor symptoms are more diverse and include depression, anxiety, loss of smell, constipation, sleep disorders, and dementia (Chaudhuri and Schapira, 2009). Some of them precede the motor-ones by decades, raising the possibility that PD might have a long-term-compensated neurodevelopmental origin, which only manifests at older age and in presence of other contributing factors (Le Grand et al., 2014).  Related Articles | Metrics

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Targeting mechanisms in cognitive training for neurodegenerative diseases Annalena Venneri, Riccardo Manca, Linford Fernandes, Oliver Bandmann, Matteo De Marco 2021, 16 (3):  500-501.  doi: 10.4103/1673-5374.293141 Abstract ( 69 )   PDF (508KB) ( 106 )   Save “Cognitive training” (CT) is a label used to describe paper-and-pen or computerized exercises designed to engage a desired set of mental skills for the purpose of enhancing neurocognitive functioning. Although the literature on the topic is considerably rich (on PubMed, for the sole 2018, the use of “cognitive training” as title keyword returns 123 results), very few studies pose the fundamental question: “How does CT work?”, or, more precisely, “Based on which computational mechanisms would engaging in CT result into meaningful changes in outcome measures?”.  The overwhelming majority of the studies focus on treatment efficacy by modelling outcome measure(s) as a function of CT (e.g., an active CT condition versus an active control condition), but do not describe in detail the exact mechanistic reason why CT should have an effect in the first place (De Marco et al., 2014). Biological frameworks have been proposed [i.e., the hypothetical role played by neurotrophic factors, synaptic connections and neuroplasticity (Castells-Sánchez et al., 2019)] but these have been introduced as an a posteriori interpretation, not as a driving principle for the design of the exercises. Related Articles | Metrics

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Targeting metabolism to treat multiple sclerosis Pavan Bhargava 2021, 16 (3):  502-503.  doi: 10.4103/1673-5374.293143 Abstract ( 70 )   PDF (540KB) ( 74 )   Save Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) that has both inflammatory and neurodegenerative components. Both genetic and environmental factors confer risk for developing the disease. Additionally, gut microbiota appears to play an important role in the risk for MS and potentially also in affecting disease severity, though our understanding of these interactions are still incomplete (Bhargava and Mowry, 2014). The circulating metabolome is at the intersection of these various factors – genome, gut microbiome and exposome and provides unique insights into the pathophysiology of the disease (Bhargava and Anthony, 2020).   Related Articles | Metrics

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Brain angiotensin II in dopaminergic imbalance-derived pathologies: neuroinflammation and vascular responses Victoria Belén Occhieppo, Osvaldo Martin Basmadjian, Claudia Bregonzio 2021, 16 (3):  504-505.  doi: 10.4103/1673-5374.293144 Abstract ( 82 )   PDF (499KB) ( 94 )   Save Mental disorders have been commonly associated with an imbalance in many neurotransmitter systems, such as dopamine, glutamate, and gamma-aminobutyric acid. Considering the complexity of brain functioning, all components of the neurovascular unit should be considered in studies for a better comprehension of the physiopathology and possible therapeutics. ANG II is present in the brain and binds to AT1 receptors (AT1-R), located in the neurovascular unit and has a close relationship with the mentioned neurotransmitter systems. In pathological conditions, AT1-R expressed in astrocytes, microglia, and brain endothelial cells are key mediators in the development of an oxidative/inflammatory microenvironment, as well as in glial activation. Therefore, pharmacological intervention targeting AT1-R provides a holistic and moderated approach to modulate neurotransmission systems in addition to the glial and vascular responses (Figure 1). This interaction is underscored by several studies that related brain ANG II to neurological disorders, such as Parkinson´s disease (PD) and attention deficit hyperactivity disorder (ADHD).   Related Articles | Metrics

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Dysfunction of axonal transport in normal-tension glaucoma: a biomarker of disease progression and a potential therapeutic target Kazuyuki Hirooka, Tohru Yamamoto, Yoshiaki Kiuchi 2021, 16 (3):  506-507.  doi: 10.4103/1673-5374.293145 Abstract ( 86 )   PDF (630KB) ( 60 )   Save One of the leading causes of irreversible blindness worldwide is glaucoma, with increased intraocular pressure (IOP) being the most common risk factor. However, in some glaucoma patients it has been shown that the IOP does not differ from that of the normal population. In Japan, normal-tension glaucoma (NTG), which accounts for 92% of primary open-angle glaucoma, has been shown to be more frequent in the population. Primarily, open-angle glaucoma treatments are almost exclusively focused on lowering the IOP through the use of drugs, laser therapy or surgery. However, glaucomatous optic nerve changes are believed by many investigators to occur not only due to increases in the IOP, but also because of other factors that are unrelated to the IOP, and which can play significant roles in some of these NTG cases. Glaucoma is a disease that causes vision loss through the degeneration and eventual apoptotic death of retinal ganglion cells (RGCs). The complex and multifactorial diseases caused by glaucoma are likely the result of the convergence of several molecular pathways that then induce RGC loss. Human glaucoma studies have demonstrated the presence of impaired axonal transport along the RGCs (Knox et al., 2007). Furthermore, since axonal transport is known to have a critical role with regard to the survival of RGCs, glaucomatous optic neuropathy may be associated with a failure of this transport. It has been clearly demonstrated that impaired axonal transport is an early, reversible, sensitive change in injured RGCs that precedes cell death (Fahy et al., 2016). Brain-derived neurotrophic factor, nerve growth factor, ciliary neurotrophic factor, and glial cell line-derived neurotrophic factor all help to both mediate the activity and ensure the survival of the RGCs. Other neurotrophic factors, such as fibroblast growth factor-2, neurotrophin 3, neurotrophin 4, and interleukin-10 have all been found to be neuroprotective in RGCs (Nafissi and Foldvari, 2016). The initial pathological events that are normally observed in neurodegenerative disorders include impairment of axonal transport, as the transduction of trophic signals requires the presence of intact axonal transport. Therefore, one of the attractive treatment areas when attempting to stop the RGC loss in glaucoma is to address the changes associated with the neurotrophic factor deprivation or adjust the insufficient levels of other essential molecules in order to prevent any axonal transport blockade. Related Articles | Metrics

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Continued development of azithromycin as a neuroprotective therapeutic for the treatment of spinal cord injury and other neurological conditions Timothy J. Kopper, John C. Gensel 2021, 16 (3):  508-509.  doi: 10.4103/1673-5374.293146 Abstract ( 131 )   PDF (452KB) ( 60 )   Save Spinal cord injury (SCI) induces a robust inflammatory response largely mediated by resident microglia and infiltrating macrophages across the blood-brain barrier. While these cell populations are capable of promoting repair and regenerative responses, in the days and weeks after SCI they predominately adopt pro-inflammatory profiles known to inhibit recovery and potentiate secondary injury pathways. Continued work is needed to develop clinically viable immunomodulatory therapeutics and promote pro-reparative macrophage responses. Recently we published on the therapeutic benefits of the macrolide antibiotic azithromycin (AZM), which improves locomotor and histological recovery after SCI in 3-month-old female mice (Kopper et al., 2019). Specifically, we initiated AZM beginning 30 minutes, 3, or 24 hours after injury and then daily for 7 days. AZM administration initiated at 30 minutes and 3 hours post-injury improved locomotor function as detected by an open field locomotor scale and significantly improved stepping frequency. The 24-hour time point, however, was ineffective suggesting the importance of early administration. Histologically we observed modest improvements with the 30-minute treatment time point with significantly reduced lesion length and evidence of slight increases in tissue sparing at the lesion epicenter. Previously, we observed that the same AZM dosing strategy after SCI reduces pro-inflammatory microglia and macrophage activation as determined by a diverse panel of inflammatory markers (Gensel et al., 2017). These neuroprotective findings are consistent with recent studies finding AZM to be therapeutically effective in multiple stroke models (Amantea et al., 2016b, 2019) a rat model of retinal ischemia/reperfusion injury (Zheng et al., 2007), and in a rat neonatal hypoxic-ischemic brain injury model (Barks et al., 2019). AZM is the most commonly prescribed antibiotic due in part to its safety profile and large therapeutic index (Durkin et al., 2018). Collectively, these studies highlight the potential for AZM to be developed into a safe, neuroprotective treatment for SCI and other neurological conditions. Here, we highlight additional areas of study that will facilitate the translation of AZM as a neuroprotective agent. Related Articles | Metrics

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Glial-derived transforming growth factor β1 (TGF-β1): a key factor in multiple sclerosis neuroinflammation Coram Guevara, Fernando C. Ortiz 2021, 16 (3):  510-511.  doi: 10.4103/1673-5374.293147 Abstract ( 52 )   PDF (526KB) ( 93 )   Save MS is an irreversible and progressive central nervous system (CNS) disease which originates in the autoimmune attack of lymphocytes against CNS myelin. This specialized membrane, synthesized by oligodendrocytes (OL) in the CNS, provides metabolic support to axons and allows for saltatory conduction in neurons. The lack of myelin (i.e., demyelination) leads to axonal degeneration, neuronal death, and the consequent neurological disabilities (Franklin and Ffrench-Constant, 2017). Although the causes of MS are still matter of active investigation, the early events preceding the demyelination onset have been characterized in deep. Evidence indicates that there is an increase in the blood-brain barrier (BBB) permeability, followed by the infiltration of CD4+ T lymphocytes, which, in turn, induces the overactivation of microglia and astrocytes present in the white matter. The latter leads to the dysregulation of the inflammatory response, being characterized by an increased concentration of proinflammatory cytokines promoting myelin loss (recently reviewed in Varas and Ortiz, 2019).  Related Articles | Metrics

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Psychosis symptoms following aberrant immunity in the brain Akitoshi Ozaki#, Yuki Yamawaki#, Gen Ohtsuki 2021, 16 (3):  512-513.  doi: 10.4103/1673-5374.293148 Abstract ( 159 )   PDF (932KB) ( 53 )   Save Neuroinflammation in the brain is thought related to the emergence of various psychoses, although the identifying regional significance, the involvement of immune-cells and lymphocytic activity, and ways for the therapeutic recovery are under the effort of researchers. We recently revealed that the cerebellar acute inflammation causes the symptoms manifested in mood disorders or developmental disorders, which were associated with hyperexcitability due to immune-triggered plasticity and the overconnectivity between the inflamed cerebellum and prefrontal cortex (Yamamoto et al., 2019). Here, we give a perspective regarding the emergence of psychoses focusing on the aberrant immunity, the relevance of dysfunctions in brain regions including the cerebellum, and potential therapeutic ways via metabolism. Related Articles | Metrics

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Temporal changes in inflammatory mitochondria-enriched microRNAs following traumatic brain injury and effects of miR-146a nanoparticle delivery Wang-Xia Wang, Paresh Prajapati, Hemendra J. Vekaria, Malinda Spry, Amber L. Cloud, Patrick G. Sullivan, Joe E. Springer 2021, 16 (3):  514-522.  doi: 10.4103/1673-5374.293149 Abstract ( 85 )   PDF (2130KB) ( 79 )   Save MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate post-transcriptional gene expression and contribute to all aspects of cellular function. We previously reported that the activities of several mitochondria-enriched miRNAs regulating inflammation (i.e., miR-142-3p, miR-142-5p, and miR-146a) are altered in the hippocampus at 3–12 hours following a severe traumatic brain injury. In the present study, we investigated the temporal expression profile of these inflammatory miRNAs in mitochondria and cytosol fractions at more chronic post-injury times following severe controlled cortical impact injury in rats. In addition, several inflammatory genes were analyzed in the cytosol fractions. The analysis showed that while elevated levels were observed in cytoplasm, the mitochondria-enriched miRNAs, miR-142-3p and miR-142-5p continued to be significantly reduced in mitochondria from injured hippocampi for at least 3 days and returned to near normal levels at 7 days post-injury. Although not statistically significant, miR-146a also remained at reduced levels for up to 3 days following controlled cortical impact injury, and recovered by 7 days. In contrast, miRNAs that are not enriched in mitochondria, including miR-124a, miR-150, miR-19b, miR-155, and miR-223 were either increased or demonstrated no change in their levels in mitochondrial fractions for 7 days. The one exception was that miR-223 levels were reduced in mitochondria at 1 day following injury. No major alterations were observed in sham operated animals. This temporal pattern was unique to mitochondria-enriched miRNAs and correlated with injury-induced changes in mitochondrial bioenergetics as well as expression levels of several inflammatory markers. These observations suggested a potential compartmental re-distribution of the mitochondria-enriched inflammatory miRNAs and may reflect an intracellular mechanism by which specific miRNAs regulate injury-induced inflammatory signaling. To test this, we utilized a novel peptide-based nanoparticle strategy for in vitro and in vivo delivery of a miR-146a mimic as a potential therapeutic strategy for targeting nuclear factor-kappaB inflammatory modulators in the injured brain. Nanoparticle delivery of miR-146a to BV-2 or SH-SY5Y cells significantly reduced expression of TNF receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1), two important modulators of the nuclear factor-kappaB (NF-κB) pro-inflammatory pathway. Moreover, injections of miR-146a containing nanoparticles into the brain immediately following controlled cortical impact injury significantly reduced hippocampal TNF receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 levels. Taken together, our studies demonstrate the subcellular alteration of inflammatory miRNAs after traumatic brain injury and establish proof of principle that nanoparticle delivery of miR-146a has therapeutic potential for modulating pro-inflammatory effectors in the injured brain. All of the studies performed were approved by the University of Kentucky Institutional Animal Care and Usage Committee (IACUC protocol # 2014-1300) on August 17, 2017. Related Articles | Metrics

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Atorvastatin combined with low-dose dexamethasone for vascular endothelial cell dysfunction induced by chronic subdural hematoma Yue-Shan Fan, Bo Wang, Dong Wang, Xin Xu, Chuang Gao, Ying Li, Shu Zhang, Gui-Li Yang, Xiao Liu, Rong-Cai Jiang, Jian-Ning Zhang 2021, 16 (3):  523-530.  doi: 10.4103/1673-5374.293152 Abstract ( 357 )   PDF (2696KB) ( 57 )   Save Atorvastatin has been shown to be a safe and effective non-surgical treatment option for patients with chronic subdural hematoma. However, treatment with atorvastatin is not effective in some patients, who must undergo further surgical treatment. Dexamethasone has anti-inflammatory and immunomodulatory effects, and low dosages are safe and effective for the treatment of many diseases, such as ankylosing spondylitis and community-acquired pneumonia. However, the effects of atorvastatin and low-dose dexamethasone for the treatment of chronic subdural hematoma remain poorly understood. Hematoma samples of patients with chronic subdural hematoma admitted to the General Hospital of Tianjin Medical University of China were collected and diluted in endothelial cell medium at 1:1 as the hematoma group. Atorvastatin, dexamethasone, or their combination was added to the culture medium. The main results were as follows: hopping probe ion conductance microscopy and permeability detection revealed that the best dosages to improve endothelial cell permeability were 0.1 μM atorvastatin and 0.1 μM dexamethasone. Atorvastatin, dexamethasone, or their combination could markedly improve the recovery of injured endothelial cells. Mice subcutaneously injected with diluted hematoma solution and then treated with atorvastatin, dexamethasone, or their combination exhibited varying levels of rescue of endothelial cell function. Hopping probe ion conductance microscopy, western blot assay, and polymerase chain reaction to evaluate the status of human cerebral endothelial cell status and expression level of tight junction protein indicated that atorvastatin, dexamethasone, or their combination could reduce subcutaneous vascular leakage caused by hematoma fluid. Moreover, the curative effect of the combined treatment was significantly better than that of either single treatment. Expression of Krüppel-like factor 2 protein in human cerebral endothelial cells was significantly increased, as was expression of the tight junction protein and vascular permeability marker vascular endothelial cadherin in each treatment group compared with the hematoma stimulation group. Hematoma fluid in patients with chronic subdural hematoma may damage vascular endothelial cells. However, atorvastatin combined with low-dose dexamethasone could rescue endothelial cell dysfunction by increasing the expression of tight junction proteins after hematoma injury. The effect of combining atorvastatin with low-dose dexamethasone was better than that of atorvastatin alone. Increased expression of Krüppel-like factor 2 may play an important role in the treatment of chronic subdural hematoma. The animal protocols were approved by the Animal Care and Use Committee of Tianjin Medical University of China on July 31, 2016 (approval No. IRB2016-YX-036). The study regarding human hematoma samples was approved by the Ethics Committee of Tianjin Medical University of China on July 31, 2018 (approval No. IRB2018-088-01). Related Articles | Metrics

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Changes in sensorimotor regions of the cerebral cortex in congenital amusia: a case-control study Jun-Jie Sun, Xue-Qun Pan, Ru Yang, Zhi-Shuai Jin, Yi-Hui Li, Jun Liu, Da-Xing Wu 2021, 16 (3):  531-536.  doi: 10.4103/1673-5374.293154 Abstract ( 124 )   PDF (1142KB) ( 95 )   Save Perceiving pitch is a central function of the human auditory system; congenital amusia is a disorder of pitch perception. The underlying neural mechanisms of congenital amusia have been actively discussed. However, little attention has been paid to the changes in the motor rain within congenital amusia. In this case-control study, 17 participants with congenital amusia and 14 healthy controls underwent functional magnetic resonance imaging while resting with their eyes closed. A voxel-based degree centrality method was used to identify abnormal functional network centrality by comparing degree centrality values between the congenital amusia group and the healthy control group. We found decreased degree centrality values in the right primary sensorimotor areas in participants with congenital amusia relative to controls, indicating potentially decreased centrality of the corresponding brain regions in the auditory-sensory motor feedback network. We found a significant positive correlation between the degree centrality values and the Montreal Battery of Evaluation of Amusia scores. In conclusion, our study identified novel, hitherto undiscussed candidate brain regions that may partly contribute to or be modulated by congenital amusia. Our evidence supports the view that sensorimotor coupling plays an important role in memory and musical discrimination. The study was approved by the Ethics Committee of the Second Xiangya Hospital, Central South University, China (No. WDX20180101GZ01) on February 9, 2019. Related Articles | Metrics

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Solid lipid nanoparticles loading with curcumin and dexanabinol to treat major depressive disorder Xiao-Lie He, Li Yang, Zhao-Jie Wang, Rui-Qi Huang, Rong-Rong Zhu, Li-Ming Cheng 2021, 16 (3):  537-542.  doi: 10.4103/1673-5374.293155 Abstract ( 186 )   PDF (2173KB) ( 130 )   Save Dexanabinol (HU-211) is an artificially synthesized cannabinoid derivative that exerts neuroprotective effects through anti-inflammatory and antioxidant effects. Curcumin exhibits antidepressant effects in the treatment of major depressive disorder. To investigate the antidepressant effects of solid lipid nanoparticles loaded with both curcumin and dexanabinol, and the underlying mechanisms associated with this combination, we established wild-type (CBR1+/+) and cannabinoid receptor 1 (CBR1) knockout (CBR1–/–) mouse models of major depressive disorder, through the intraperitoneal injection of corticosterone, for 3 successive days, followed by treatment with intraperitoneal injections of solid lipid nanoparticles loading with curcumin (20 mg/kg) and dexanabinol (0.85 mg/kg), for 2 successive days. Our results revealed that solid lipid nanoparticle loading with curcumin and dexanabinol increased the mRNA and protein expression levels of the mature neuronal markers neuronal nuclei, mitogen-activated protein 2, and neuron-specific beta-tubulin III, promoted the release of dopamine and norepinephrine, and increased the mRNA expression of CBR1 and the downstream genes Rasgef1c and Egr1, and simultaneously improved rat locomotor function. However, solid lipid nanoparticles loaded with curcumin and dexanabinol had no antidepressant effects on the CBR1–/– mouse models of major depressive disorder. This study was approved by the Institutional Ethics Committee of Tongji Hospital of Tongji University, China (approval No. 2017-DW-020) on May 24, 2017. Related Articles | Metrics

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Combination of epidural electrical stimulation with ex vivo triple gene therapy for spinal cord injury: a proof of principle study Filip Olegovich Fadeev, Farid Vagizovich Bashirov, Vahe Arshaluysovich Markosyan, Andrey Alexandrovich Izmailov, Tatyana Vyacheslavovna Povysheva, Mikhail Evgenyevich Sokolov, Maxim Sergeevich Kuznetsov, Anton Alexandrovich Eremeev, Ilnur Ildusovich Salafutdinov, Albert Anatolyevich Rizvanov, Hyun Joon Lee, Rustem Robertovich Islamov 2021, 16 (3):  550-560.  doi: 10.4103/1673-5374.293150 Abstract ( 205 )   PDF (4307KB) ( 508 )   Save Despite emerging contemporary biotechnological methods such as gene- and stem cell-based therapy, there are no clinically established therapeutic strategies for neural regeneration after spinal cord injury. Our previous studies have demonstrated that transplantation of genetically engineered human umbilical cord blood mononuclear cells producing three recombinant therapeutic molecules, including vascular endothelial growth factor (VEGF), glial cell-line derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) can improve morpho-functional recovery of injured spinal cord in rats and mini-pigs. To investigate the efficacy of human umbilical cord blood mononuclear cells-mediated triple-gene therapy combined with epidural electrical stimulation in the treatment of spinal cord injury, in this study, rats with moderate spinal cord contusion injury were intrathecally infused with human umbilical cord blood mononuclear cells expressing recombinant genes VEGF165, GDNF, NCAM1 at 4 hours after spinal cord injury. Three days after injury, epidural stimulations were given simultaneously above the lesion site at C5 (to stimulate the cervical network related to forelimb functions) and below the lesion site at L2 (to activate the central pattern generators) every other day for 4 weeks.  Rats subjected to the combined treatment showed a limited functional improvement of the knee joint, high preservation of muscle fiber area in tibialis anterior muscle and increased H/M ratio in gastrocnemius muscle 30 days after spinal cord injury. However, beneficial cellular outcomes such as reduced apoptosis and increased sparing of the gray and white matters, and enhanced expression of heat shock and synaptic proteins were found in rats with spinal cord injury subjected to the combined epidural electrical stimulation with gene therapy. This study presents the first proof of principle study of combination of the multisite epidural electrical stimulation with ex vivo triple gene therapy (VEGF, GDNF and NCAM) for treatment of spinal cord injury in rat models. The animal protocols were approved by the Kazan State Medical University Animal Care and Use Committee (approval No. 2.20.02.18) on February 20, 2018.   Related Articles | Metrics

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Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4 Bao-You Fan, Yi-Lin Pang, Wen-Xiang Li, Chen-Xi Zhao, Yan Zhang, Xu Wang, Guang-Zhi Ning, Xiao-Hong Kong, Chang Liu, Xue Yao, Shi-Qing Feng 2021, 16 (3):  561-566.  doi: 10.4103/1673-5374.293157 Abstract ( 223 )   PDF (2481KB) ( 284 )   Save Our previous studies showed that ferroptosis plays an important role in the acute and subacute stages of spinal cord injury. High intracellular iron levels and low glutathione levels make oligodendrocytes vulnerable to cell death after central nervous system trauma. In this study, we established an oligodendrocyte (OLN-93 cell line) model of ferroptosis induced by RSL-3, an inhibitor of glutathione peroxidase 4 (GPX4). RSL-3 significantly increased intracellular concentrations of reactive oxygen species and malondialdehyde. RSL-3 also inhibited the main anti-ferroptosis pathway, i.e., SLC7A11/glutathione/glutathione peroxidase 4 (xCT/GSH/GPX4), and downregulated acyl-coenzyme A synthetase long chain family member 4. Furthermore, we evaluated the ability of several compounds to rescue oligodendrocytes from ferroptosis. Liproxstatin-1 was more potent than edaravone or deferoxamine. Liproxstatin-1 not only inhibited mitochondrial lipid peroxidation, but also restored the expression of GSH, GPX4 and ferroptosis suppressor protein 1. These findings suggest that GPX4 inhibition induces ferroptosis in oligodendrocytes, and that liproxstatin-1 is a potent inhibitor of ferroptosis. Therefore, liproxstatin-1 may be a promising drug for the treatment of central nervous system diseases. Related Articles | Metrics

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Influence of spinal cord injury on core regions of motor function Xiao-Yan Shen, Chun-Ling Tao, Lei Ma, Jia-Huan Shen, Zhi-Ling Li, Zhi-Gong Wang, Xiao-Ying Lü 2021, 16 (3):  567-572.  doi: 10.4103/1673-5374.293158 Abstract ( 98 )   PDF (1869KB) ( 143 )   Save Functional electrical stimulation is an effective way to rebuild hindlimb motor function after spinal cord injury. However, no site map exists to serve as a reference for implanting stimulator electrodes. In this study, rat models of thoracic spinal nerve 9 contusion were established by a heavy-impact method and rat models of T6/8/9 spinal cord injury were established by a transection method. Intraspinal microstimulation was performed to record motion types, site coordinates, and threshold currents induced by stimulation. After transection (complete injury), the core region of hip flexion migrated from the T13 to T12 vertebral segment, and the core region of hip extension migrated from the L1 to T13 vertebral segment. Migration was affected by post-transection time, but not transection segment. Moreover, the longer the post-transection time, the longer the distance of migration. This study provides a reference for spinal electrode implantation after spinal cord injury. This study was approved by the Institutional Animal Care and Use Committee of Nantong University, China (approval No. 20190225-008) on February 26, 2019. Related Articles | Metrics

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Epidural electrical stimulation effectively restores locomotion function in rats with complete spinal cord injury Song Wang, Li-Cheng Zhang, Hai-Tao Fu, Jun-Hao Deng, Gao-Xiang Xu, Tong Li, Xin-Ran Ji, Pei-Fu Tang 2021, 16 (3):  573-579.  doi: 10.4103/1673-5374.290905 Abstract ( 227 )   PDF (3322KB) ( 152 )   Save Epidural electrical stimulation can restore limb motor function after spinal cord injury by reactivating the surviving neural circuits. In previous epidural electrical stimulation studies, single electrode sites and continuous tetanic stimulation have often been used. With this stimulation, the body is prone to declines in tolerance and locomotion coordination. In the present study, rat models of complete spinal cord injury were established by vertically cutting the spinal cord at the T8 level to eliminate disturbance from residual nerve fibers, and were then subjected to epidural electrical stimulation. The flexible extradural electrode had good anatomical topology and matched the shape of the spinal canal of the implanted segment. Simultaneously, the electrode stimulation site was able to be accurately applied to the L2–3 and S1 segments of the spinal cord. To evaluate the biocompatibility of the implanted epidural electrical stimulation electrodes, GFAP/Iba-1 double-labeled immunofluorescence staining was performed on the spinal cord below the electrodes at 7 days after the electrode implantation. Immunofluorescence results revealed no significant differences in the numbers or morphologies of microglia and astrocytes in the spinal cord after electrode implantation, and there was no activated Iba-1+ cell aggregation, indicating that the implant did not cause an inflammatory response in the spinal cord. Rat gait analysis showed that, at 3 days after surgery, gait became coordinated in rats with spinal cord injury under burst stimulation. The regained locomotion could clearly distinguish the support phase and the swing phase and dynamically adjust with the frequency of stimulus distribution. To evaluate the matching degree between the flexible epidural electrode (including three stimulation contacts), vertebral morphology, and the level of the epidural site of the stimulation electrode, micro-CT was used to scan the thoracolumbar vertebrae of rats before and after electrode implantation. Based on the experimental results of gait recovery using three-site stimulation electrodes at L2–3 and S1 combined with burst stimulation in a rat model of spinal cord injury, epidural electrical stimulation is a promising protocol that needs to be further explored. This study was approved by the Animal Ethics Committee of Chinese PLA General Hospital (approval No. 2019-X15-39) on April 19, 2019.  Related Articles | Metrics

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Effect of intensity-modulated radiation therapy on sciatic nerve injury caused by echinococcosis Wan-Long Xu, Dilimulati·Aikeremu, Jun-Gang Sun, Yan-Jun Zhang, Jiang-Bo Xu, Wen-Zheng Zhou, Xi-Bin Zhao, Hao Wang, Hong Yuan 2021, 16 (3):  580-586.  doi: 10.4103/1673-5374.293153 Abstract ( 151 )   PDF (2252KB) ( 135 )   Save Conventional radiotherapy has a good killing effect on femoral echinococcosis. However, the sciatic nerve around the lesion is irreversibly damaged owing to bystander effects. Although intensity-modulated radiation therapy shows great advantages for precise dose distribution into lesions, it is unknown whether intensity-modulated radiation therapy can perfectly protect the surrounding sciatic nerve on the basis of good killing of femoral echinococcosis foci. Therefore, this study comparatively analyzed differences between intensity-modulated radiation therapy and conventional radiotherapy on the basis of safety to peripheral nerves. Pure-breed Meriones meridiani with bilateral femoral echinococcosis were selected as the research object. Intensity-modulated radiation therapy was used to treat left femoral echinococcosis of Meriones meridianus, while conventional radiotherapy was used to treat right femoral echinococcosis of the same Meriones meridianus. The total radiation dose was 40 Gy. To understand whether intensity-modulated radiation therapy and conventional radiotherapy can kill femoral echinococcosis, trypan blue staining was used to detect pathological changes of bone Echinococcus granulosus and protoscolex death after radiotherapy. Additionally, enzyme histochemical staining was utilized to measure acid phosphatase activity in the protoscolex after radiotherapy. One week after radiotherapy, the overall structure of echinococcosis in bilateral femurs of Meriones meridiani treated by intensity-modulated radiation therapy disappeared. There was no significant difference in the mortality rate of protoscoleces of Echinococcus granulosus between the bilateral femurs of Meriones meridiani. Moreover, there was no significant difference in acid phosphatase activity in the protoscolex of Echinococcus granulosus between bilateral femurs. To understand the injury of sciatic nerve surrounding the foci of femoral echinococcosis caused by intensity-modulated radiation therapy and conventional radiotherapy, the ultrastructure of sciatic nerves after radiotherapy was observed by transmission electron microscopy. Additionally, apoptosis of neurons was examined using a terminal-deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and expression of Bcl-2 and Bax in sciatic nerve tissue was detected by immunohistochemical staining and western blot assay. Our results showed that most neurons in the left sciatic nerve of Meriones meridiani with echinococcosis treated by intensity-modulated radiation therapy had reversible injury, and there was no obvious apoptosis. Compared with conventional radiotherapy, the number of apoptotic cells and Bax expression in sciatic nerve treated by intensity-modulated radiation therapy were significantly decreased, while Bcl-2 expression was significantly increased. Our findings suggest that intensity-modulated radiation therapy has the same therapeutic effect on echinococcosis as conventional radiotherapy, and can reduce apoptosis of the sciatic nerve around foci caused by radiotherapy. Experiments were approved by the Animal Ethics Committee of People’s Hospital of Xinjiang Uygur Autonomous Region, China (Approval No. 20130301A41) on March 1, 2013.  Related Articles | Metrics

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Anxiety, depression, and quality of life in Parkinson’s disease: the implications of multidisciplinary treatment Viviana Lo Buono, Rosanna Palmeri, Simona De Salvo, Matteo Berenati, Agata Greco, Rosella Ciurleo, Chiara Sorbera, Vincenzo Cimino, Francesco Corallo, Placido Bramanti, Silvia Marino, Giuseppe Di Lorenzo, Lilla Bonanno 2021, 16 (3):  587-590.  doi: 10.4103/1673-5374.293151 Abstract ( 108 )   PDF (291KB) ( 117 )   Save Anxiety and depression in Parkinson’s disease (PD) reduce well-being of the patients. Emotional alterations influence motor skills and cognitive performance; moreover, they contribute significantly and independently to worsen rehabilitative treatment response. We investigated anxiety, depression, and quality of life in PD patients subjected to multidisciplinary rehabilitative training. The self-controlled study included 100 PD patients (49 males and 51 females with the mean age of 64.66 years) admitted to 60 days hospitalization rehabilitative program, between January 2017 and December 2018. Motor, cognitive, linguistic abilities, and functional independence were evaluated at admission (T0 baseline visit) and 60 days after (T1) the multidisciplinary rehabilitation including motor exercises, speech therapies, and cognitive intervention. The multidisciplinary rehabilitation improved functional status in PD patients and exerted its positive effects on mood, motor abilities, autonomy in the activities of daily life, perception of quality of life, cognitive performance and speech skills. Non-motor symptoms may worsen severe disability and reduce quality of life. They are often poorly recognized and inadequately treated. Nonetheless, multidisciplinary rehabilitative training represents an optimal strategy to improve disease management. The study was approved by Istituito di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro Neurolesi “Bonino-Pulejo” Ethical Committee (approval No. 6/2016) in June 2016.  Related Articles | Metrics

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Creatine kinase in the diagnosis and prognostic prediction of amyotrophic lateral sclerosis: a retrospective case-control study Xue-Ping Chen, Qian-Qian Wei, Ru-Wei Ou, Yan-Bing Hou, Ling-Yu Zhang, Xiao-Qin Yuan, Yun-Qian Yao, De-Sheng Jia, Qian Zhang, Wei-Xue Li, Hui-Fang Shang 2021, 16 (3):  591-595.  doi: 10.4103/1673-5374.293159 Abstract ( 136 )   PDF (649KB) ( 560 )   Save Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman’s correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, amyotrophic lateral sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval no. 2015(236)) on December 23, 2015. Related Articles | Metrics

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Guanosine-5′-triphosphate cyclohydrolase 1 regulated long noncoding RNAs are potential targets for microglial activation in neuropathic pain  Yan-Hu Liang, Guo-Wu Chen, Xue-Song Li, Shu Jia, Chun-Yang Meng 2021, 16 (3):  596-600.  doi: 10.4103/1673-5374.290914 Abstract ( 95 )   PDF (1489KB) ( 102 )   Save Several studies have confirmed that microglia are involved in neuropathic pain. Inhibition of guanosine-5′-triphosphate cyclohydrolase 1 (GTPCH1) can reduce the inflammation of microglia. However, the precise mechanism by which GTPCH1 regulates neuropathic pain remains unclear. In this study, BV2 microglia were transfected with adenovirus to knockdown GTPCH1 expression. High throughput sequencing analysis revealed that the mitogen-activated protein kinase (MAPK) related pathways and proteins were the most significantly down-regulated molecular function. Co-expression network analysis of Mapk14 mRNA and five long noncoding RNAs (lncRNAs) revealed their correlation. Quantitative reverse transcription-polymerase chain reaction revealed that among five lncRNAs, ENSMUST00000205634, ENSMUST00000218450 and ENSMUST00000156079 were related to the downregulation of Mapk14 mRNA expression. These provide some new potential targets for the involvement of GTPCH1 in neuropathic pain. This study is the first to note the differential expression of lncRNAs and mRNA in GTPCH1 knockdown BV2 microglia. Findings from this study reveal the mechanism by which GTPCH1 activates microglia and provide new potential targets for microglial activation in neuropathic pain.  Related Articles | Metrics