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15 January 2019, Volume 14 Issue 1 Previous Issue    Next Issue

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LETTER FROM THE EDITORS-IN-CHIEF Kwok-fai So, Xiao-Ming Xu 2019, 14 (1):  5-6.  Abstract ( 105 )   PDF (187KB) ( 222 )   Save In the past 11 years, Neural Regeneration Re-search (NRR) has evolved to become a frequent-ly cited journal in the field, receiving an impact factor that reflects the dedication and expertise of our editors and reviewers. In 2017, the jour-nal received an Impact Factor of 2.234, placing it in quartile 3 of neuroscience journals. We would like to take this opportunity to thank all contributors who have made this success possi-ble: our Editorial Board team, who always have supported and helped the journal’s maturation; our reviewers, who have provided thoughtful critiques in a timely manner; our readers, who have deemed NRR papers to be of high enough quality to be cited; and last, but most certainly not the least, our authors, who have chosen to submit their excellent articles to NRR. We would like to report to all of you on our achievements in 2018 and our expectations for the coming year of 2019. Related Articles | Metrics

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Differences in neuroplasticity after spinal cord injury in varying animal models and humans Mallory E. Filipp, Benjamin J. Travis, Stefanie S. Henry, Emma C. Idzikowski, Sarah A. Magnuson, Megan YF Loh, Daniel J. Hellenbrand, Amgad S. Hanna 2019, 14 (1):  7-19.  doi: 10.4103/1673-5374.243694 Abstract ( 177 )   PDF (1314KB) ( 655 )   Save Rats have been the primary model to study the process and underlying mechanisms of recovery after spinal cord injury. Two weeks after a severe spinal cord contusion rats can regain weight-bearing abilities without therapeutic interventions, as assessed by the Basso, Beattie and Bresnahan locomotor scale. However, many human patients suffer from permanent loss of motor function following spinal cord injury. While rats are the most understood animal model, major differences in sensorimotor pathways between quadrupeds and bipeds need to be considered. Understanding the major differences between the sensorimotor pathways of rats, non-human primates, and humans is a start to improving targets for treatments of human spinal cord injury. This review will discuss the neuroplasticity of the brain and spinal cord after spinal cord injury in rats, non-human primates, and humans. A brief overview of emerging interventions to induce plasticity in humans with spinal cord injury will also be discussed. Related Articles | Metrics

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Memory consolidation during sleep and adult hippocampal neurogenesis Iyo Koyanagi, Katherine G. Akers, Pablo Vergara, Sakthivel Srinivasan, Takeshi Sakurai, Masanori Sakaguchi 2019, 14 (1):  20-23.  doi: doi:10.4103/1673-5374.243695 Abstract ( 145 )   PDF (846KB) ( 259 )   Save In anticipation of the massive burden of neurodegenerative disease within super-aged societies, great efforts have been made to utilize neural stem and progenitor cells for regenerative medicine. The capacity of intrinsic neural stem and progenitor cells to regenerate damaged brain tissue remains unclear, due in part to the lack of knowledge about how these newly born neurons integrate into functional circuitry. As sizable integration of adult-born neurons naturally occurs in the dentate gyrus region of the hippocampus, clarifying the mechanisms of this process could provide insights for applying neural stem and progenitor cells in clinical settings. There is convincing evidence of functional correlations between adult-born neurons and memory consolidation and sleep; therefore, we describe some new advances that were left untouched in our recent review. Related Articles | Metrics

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Peripheral nerve regeneration and intraneural revascularization Martial Caillaud, Laurence Richard, Jean-Michel Vallat, Alexis Desmoulière, Fabrice Billet 2019, 14 (1):  24-33.  doi: 10.4103/1673-5374.243699 Abstract ( 180 )   PDF (2095KB) ( 309 )   Save Peripheral nerves are particularly vulnerable to injuries and are involved in numerous pathologies for which specific treatments are lacking. This review summarizes the pathophysiological features of the most common traumatic nerve injury in humans and the different animal models used in nerve regeneration studies. The current knowledge concerning Wallerian degeneration and nerve regrowth is then described. Finally, the involvement of intraneural vascularization in these processes is addressed. As intraneural vascularization has been poorly studied, histological experiments were carried out from rat sciatic nerves damaged by a glycerol injection. The results, taken together with the data from literature, suggest that revascularization plays an important role in peripheral nerve regeneration and must therefore be studied more carefully. Related Articles | Metrics

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Cortical stimulation for treatment of neurological disorders of hyperexcitability: a role of homeostatic plasticity Zhi Chai, Cungen Ma, Xiaoming Jin 2019, 14 (1):  34-38.  doi: 10.4103/1673-5374.243696 Abstract ( 154 )   PDF (259KB) ( 315 )   Save Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders. Related Articles | Metrics

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Aging gracefully: social engagement joins exercise and enrichment as a key lifestyle factor in resistance to age-related cognitive decline Tyler J. Dause, Elizabeth D. Kirby 2019, 14 (1):  39-42.  doi: 10.4103/1673-5374.243698 Abstract ( 185 )   PDF (291KB) ( 288 )   Save Cognitive impairment is a consequence of the normal aging process that effects many species, including humans and rodent models. Decline in hippocampal memory function is especially prominent with age and often reduces quality of life. As the aging population expands, the need for interventional strategies to prevent cognitive decline has become more pressing. Fortunately, several major lifestyle factors have proven effective at combating hippocampal aging, the most well-known of which are environmental enrichment and exercise. While the evidence supporting the beneficial nature of these factors is substantial, a less well-understood factor may also contribute to healthy cognitive aging: social engagement. We review the evidence supporting the role of social engagement in preserving hippocampal function in old age. In elderly humans, high levels of social engagement correlate with better hippocampal function, yet there is a dearth of work to indicate a causative role. Existing rodent literature is also limited but has begun to provide causative evidence and establish candidate mechanisms. Summed together, while many unanswered questions remain, it is clear that social engagement is a viable lifestyle factor for preserving cognitive function in old age. Social integration across the lifespan warrants more investigation and more appreciation when designing living circumstances for the elderly. Related Articles | Metrics

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An innovative approach for the treatment of Alzheimer’s disease: the role of peroxisome proliferator-activated receptors and their ligands in development of alternative therapeutic interventions Luca Piemontese 2019, 14 (1):  43-45.  doi: 10.4103/1673-5374.241043 Abstract ( 164 )   PDF (130KB) ( 277 )   Save Alzheimer’s disease is a multifactorial pathology, for which no cure is currently available. Nowadays, researchers are moving towards a new hypothesis of the onset of the illness, linking it to a metabolic impairment. This innovative approach will lead to the identification of new targets for the preparation of new effective drugs. Peroxisome proliferator-activated receptors and their ligands are the ideal candidates to reach the necessary breakthrough to defeat this complicate disease. Related Articles | Metrics

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Opportunities and challenges for developing closedloop bioelectronic medicines Patrick D. Ganzer, Gaurav Sharma 2019, 14 (1):  46-50.  doi: 10.4103/1673-5374.243697 Abstract ( 132 )   PDF (514KB) ( 286 )   Save The peripheral nervous system plays a major role in the maintenance of our physiology. Several peripheral nerves intimately regulate the state of the brain, spinal cord, and visceral systems. A new class of therapeutics, called bioelectronic medicines, are being developed to precisely regulate physiology and treat dysfunction using peripheral nerve stimulation. In this review, we first discuss new work using closed-loop bioelectronic medicine to treat upper limb paralysis. In contrast to open-loop bioelectronic medicines, closed-loop approaches trigger ‘on demand’ peripheral nerve stimulation due to a change in function (e.g., during an upper limb movement or a change in cardiopulmonary state). We also outline our perspective on timing rules for closed-loop bioelectronic stimulation, interface features for non-invasively stimulating peripheral nerves, and machine learning algorithms to recognize disease events for closed-loop stimulation control. Although there will be several challenges for this emerging field, we look forward to future bioelectronic medicines that can autonomously sense changes in the body, to provide closed-loop peripheral nerve stimulation and treat disease. Related Articles | Metrics

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Tissue engineering for the repair of peripheral nerve injury Pei-Xun Zhang, Na Han, Yu-Hui Kou, Qing-Tang Zhu, Xiao-Lin Liu, Da-Ping Quan, Jian-Guo Chen, Bao-Guo Jiang 2019, 14 (1):  51-58.  doi: 10.4103/1673-5374.243701 Abstract ( 168 )   PDF (199KB) ( 372 )   Save Peripheral nerve injury is a common clinical problem and affects the quality of life of patients. Traditional restoration methods are not satisfactory. Researchers increasingly focus on the field of tissue engineering. The three key points in establishing a tissue engineering material are the biological scaffold material, the seed cells and various growth factors. Understanding the type of nerve injury, the construction of scaffold and the process of repair are necessary to solve peripheral nerve injury and promote its regeneration. This review describes the categories of peripheral nerve injury, fundamental research of peripheral nervous tissue engineering and clinical research on peripheral nerve scaffold material, and paves a way for related research and the use of conduits in clinical practice. Related Articles | Metrics

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Sonic hedgehog signaling controls dentate gyrus patterning and adult neurogenesis in the hippocampus E Francesca Antonelli, Arianna Casciati, Simonetta Pazzaglia 2019, 14 (1):  59-61.  doi: 10.4103/1673-5374.243703 Abstract ( 146 )   PDF (1313KB) ( 292 )   Save The morphogen Sonic Hedgehog (Shh) plays a critical role in the development of different tissues, both in invertebrates and vertebrates. Shh mediates its action via a receptor com-plex associating two transmembrane proteins: Patched1 (Ptch1) and Smoothened (Smo). The repression exerted by Ptch1 on Smo is relieved when Shh, the ligand, binds to Ptch1, which leads to a complex signaling cascade involving the transcription factors of the Gli family and finally, to the activation of targeted genes including Ptch1 and Gli them-selves. Related Articles | Metrics

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Neuroprotective modulation of the unfolded protein response in Marinesco-Sjögren syndrome: PERK signaling inhibition and beyond Elena Restelli, Antonio Masone, Michele Sallese, Roberto Chiesa 2019, 14 (1):  62-64.  doi: 10.4103/1673-5374.243708 Abstract ( 136 )   PDF (959KB) ( 379 )   Save Individuals with Marinesco-Sjögren syndrome (MSS; OMIM 248800), a genetic disease of infancy, suffer var-ious disabilities, including loss of motor coordination due to cerebellar degeneration, and skeletal muscle weak-ness. After a progressive phase, symptoms stabilize and patients live to old age. Therefore, any pharmacological treatment that delays or attenuates cerebellar degenera-tion and/or muscle pathology can significantly improve their quality of life. We recently found that inhibiting the protein kinase RNA-like endoplasmic reticulum kinase (PERK) delays cerebellar degeneration, and ameliorates motor function and muscle pathology in a MSS mouse model. This is the first preclinical study of a pharmacological treatment for MSS. Here we summarize our findings, and discuss how this therapeutic strategy might be improved for effective treatment. Related Articles | Metrics

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Using organotypic hippocampal slice cultures to gain insight into mechanisms responsible for the neuroprotective effects of meloxicam: a role for gamma aminobutyric and endoplasmic reticulum stress Elisa Landucci, Irene L. Llorente, Berta Anuncibay-Soto, Domenico E. Pellegrini-Giampietro, Arsenio Fernández-López 2019, 14 (1):  65-66.  doi: 10.4103/1673-5374.243704 Abstract ( 169 )   PDF (233KB) ( 200 )   Save This perspective aims to put into context the recent article by Landuc-ci et al. (2018) on mechanisms involved in the neuroprotective effects of meloxicam on an organotypic hippocampal slice cultures (OHSCs) model. In vitro cell cultures are the main method for studying large quantities of homogeneous cells in an isolated environment. Thus, the use of primary dissociated neuron, astrocyte, oligodendrocyte, microglia, or endothelial cell cultures has become a standard method in many laboratories, contributing substantially to a reduction in the number of in vivo assays. Cell cultures allow many different types of assays to be performed in research laboratories, such as survival, proliferation, cell signaling, or studies about the influence of toxic or protective drugs. However, cell cultures do not reproduce the com-plex cell interactions that occur in the whole organ. Thus, other approaches, such as organotypic cultures, have been developed in recent decades to better align models with in vivo situa-tions, with the goal of preserving the original structural and synaptic organization as much as possible. In this regard, the first studies were conducted using hippocampal slices from neonates at 2 to 23 days old.  The slices were maintained in culture at the interface between air and a culture medium. They were then placed on a sterile, transparent, and porous membrane and stored in petri dishes in an incubator. This method yielded thin slices that remained one to four cell layers thick and were characterized by a well-preserved organotypic organization. Related Articles | Metrics

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Tipsy neural stem cells: chronic effects of alcohol on the brain Caitlin R. Schlagal, Ping Wu 2019, 14 (1):  67-68.  doi: 10.4103/1673-5374.243702 Abstract ( 221 )   PDF (188KB) ( 328 )   Save Neurogenesis occurs in the adult brain and is defined as the production of new neurons from a population of cells known as neural stem cells (NSCs). NSCs are also capable of self-renewal and differentiation into astrocytes or oligodendrocytes through processes known as astrogliogenesis and oligodendrogenesis, respectively. These properties of NSCs are crucial not only during development, where they drive the formation of neural connections and brain growth, but also throughout life to generate new neurons and glia in several key regions of the brain. The two main regions extensively studied for adult neurogenesis are the subventricular zone of the lateral ventricle and the subgranular zone of the hippocampus. NSCs have also been found in several other regions of the central ner-vous system, including a novel region recently identified as a neurogenic niche, the tanycyte layer of the hypothalamus. Due to the integral role of NSCs in brain maintenance and repair, these cells have been investigated in neurodegenerative diseases, neurotrauma, aging, and addic-tion. However, the effects of drugs of abuse, specifically alcohol, on NSCs remains largely elusive. Related Articles | Metrics

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Combinatorial therapies for spinal cord injury: strategies to induce regeneration Eduardo D. Gomes, Nuno A. Silva, António J. Salgado 2019, 14 (1):  69-71.  doi: 10.4103/1673-5374.243705 Abstract ( 178 )   PDF (693KB) ( 264 )   Save Spinal cord injury (SCI) is a condition without treatment, mainly characterized by the loss of motor and sensory function below the level of injury. This is accompaniedby several complications such as cardiac and respiratory compromise, and often patients present psychological ail-ments associated with the drastic alteration of their nor-mal lifestyle. SCI pathophysiology derives from a massive damage to the spinal cord tissue, which is propagated by secondary events such as inflammation, excitotoxicity among others, that increase neuronal loss. In a later stage, a glial scar composed by reactive astrocytes and a cystic cavity are formed, creating a physical and chemical bar-rier for axonal regrowth. Strategies capable of inducing neuronal regeneration are therefore a fundamental part for a successful recovery of function for these patients. Related Articles | Metrics

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Blood exosomes as a tool for monitoring treatment efficacy and progression of neurodegenerative diseases Hanin Abdel-Haq 2019, 14 (1):  72-74.  Abstract ( 125 )   PDF (298KB) ( 315 )   Save Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion disease are representative neurodegenerative diseases that share common sub-cellular features, the most obvious of which is a strong association with the accumulation of misfolded, aggregated, and insoluble forms of proteins in the brain, as evidenced in post-mortem brain tissues of patients. Related Articles | Metrics

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Pharmacogenomics in Parkinson’s disease: which perspective for developing a personalized medicine? Cinzia Ciccacci, Paola Borgiani 2019, 14 (1):  75-76.  doi: 10.4103/1673-5374.243706 Abstract ( 136 )   PDF (109KB) ( 288 )   Save Every disease treatment is ideally finalized to prevent symptom occurrence, to stop or slow down the pro-gression of disease, to alleviate complications already present and consequently to improve the quality of life for each patient. Unfortunately, in Parkinson’s disease (PD) a treatment able to completely cure the disease is not so far available. Indeed, until now, the current therapies only allow to control the disease symptoms, without ensuring a long term efficacy and without reducing the risk to develop adverse drug reactions. The actual gold standard therapy consists in levodo-pa treatment, often used in combination with dopa-mine receptor agonists, catechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase inhibitors. While the treatment with levodopa ameliorates the motor function of the patients, not all patients reach the therapeutic effect and many develop motor compli-cations after using the drug for a prolonged time. On the other side, the dopamine receptor agonist drugs can cause psychosis, visual hallucinations, excessive daytime sleepiness, compulsive behavior and impulse control disorders, while the COMT inhibitors can in-duce hepatotoxicity. Variability in drug response is a multifactorial character that depends on clinical, envi-ronmental and genetic factors. In the last decades, the increasing knowledge in the human genome inter-in-dividual variability led genetics and pharmacogenom-ics to assume a central role for the study and develop-ment of personalized and stratified medicine, with the claimed aim to decrease the number of adverse drug reactions and to increase the efficacy of drug therapy. Although in some fields, such as oncology and psychi-atry, pharmacogenomics studies have already allowed the identification and validation of genomic biomark-ers able to stratify groups of patients and to guarantee a personalized and precision medicine, in PD this is unfortunately still far to reach. Related Articles | Metrics

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Finding a way to preserve mitochondria: new pathogenic pathways in experimental multiple sclerosis Andrea Mancini, Lorenzo Gaetani, Lucia Gentili, Massimiliano Di Filippo 2019, 14 (1):  77-78.  doi: 10.4103/1673-5374.243707 Abstract ( 121 )   PDF (487KB) ( 251 )   Save Multiple sclerosis (MS) is a chronic disorder affecting central ner-vous system (CNS) in which inflammatory and neuro-degenerative features coexist since the earlier phases of the disease. During last years, attention has been directed toward the possible pathogenic pathways linking these two different features characterizing MS, in order to acquire a better understanding of the disease pathogenesis and to design new disease modifying therapies. Currently available therapies for MS are primarily aimed at modulating the immune system and are successfully used to reduce the risk of new inflammatory CNS lesions but show little or no efficacy in counteracting irreversible disease progression over time. Among the possible mechanism linking neuroinflamma-tion and neuronal loss, attention has been focused on the possible dysfunction of neuronal mitochondria during inflammatory CNS processes, since an impaired neuronal energetic support seems to represent a key event in the pathogenesis of neuro-axonal degener-ation. Related Articles | Metrics

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Do neuronal microvascular activation and resultant dysfunction in rheumatoid arthritis contribute to chronic pain? Nicholas Beazley-Long 2019, 14 (1):  79-81.  doi: 10.4103/1673-5374.243710 Abstract ( 139 )   PDF (669KB) ( 317 )   Save Microvascular dysfunction and rheumatoid arthritis (RA):Across the UK severe osteoarthritis affects ~5–7% and RA affects ~1% of the population. These are the most common causes of disabling chronic pain and are major burdens on in-dividuals and society. Consequently, the annual financial cost to the UK economy for arthritis is in the billions of pounds. People living with painful inflammatory conditions and in particular RA are at an increased risk of mortality caused by cardiovascular disease which is of a magnitude similar to that caused by diabetes. The endothelial dysfunction underlying cardio-vascular disease in RA also affects endothelia throughout the body causing a diverse range of diseases including those that are metabolic and renal in nature, and the pathogenesis and worsening of these diseases are intricately linked to dysfunc-tional endothelia. Endothelial dysfunction and cardiovascular risk are also linked to cognitive deficits in RA. Depression is another co-morbidity of RA and has been linked to increased levels of interleukin (IL)-6, IL-1 and tumour necrosis factor-α (TNFα). All three of these cytokines are associated with endothelial activation and endothelial dysfunction. For example TNFα, which is a potent endothelial activator, also causes endothelial cell apoptosis and this can be inhibited by endothelial cytoprotectants such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor-a (VEGF-A). Tar-geting endothelial activation is able to prevent the spread of pain in rodent models of inflammatory arthritis indicating that the spread of neuronal sensitiza-tion is dependent on the action of the microvasculature. This has led to the hypothesis that neuronal microvascular acti-vation and ensuing dysfunction could drive the chronic pain experienced by people living with RA. This invited perspec-tive discusses the main research that has led to the formation of this hypothesis and the caveats of targeting endothelial activation via vascular endothelial growth factor receptor-2 (VEGFR2). In doing so, I hope to shine the spotlight on the potential role of neurovasculatur e as a driver of chronic pain in inflammatory conditions. Related Articles | Metrics

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Adenosine triphosphate maintenance by branched chain amino acids as a novel neuroprotective strategy for retinal neurodegenerative diseases Tomoko Hasegawa, Hanako Ohashi Ikeda 2019, 14 (1):  82-84.  doi: 10.4103/1673-5374.244788 Abstract ( 181 )   PDF (557KB) ( 268 )   Save Retinal neuronal cell death is caused in many incurable eye diseases such as retinitis pigmentosa (RP) and glau-coma, which are leading causes of adult blindness. In RP, progressive loss of photoreceptor cells leads to visual dis-turbance. No established treatments are available to date for this condition, although potential treatments, includ-ing regenerative medicine, gene therapy, and neurotropic factor therapy are being investigated. In glaucoma, retinal ganglion cell death leads to visual disturbance. Although intraocular pressure reduction is the only established treatment to slow the loss of visual function in glaucoma, there are a fair number of cases where visual impairment progresses despite intraocular pressure being maintained within the normal range. Therapeutic strategies to pre-vent neuronal cell death are being pursued. Related Articles | Metrics

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The potential of small molecule brain-derived neurotrophic factor: mimetics to treat inherited retinal degeneration Andrea Cerquone Perpetuini, Justine Mathoux, Breandán N. Kennedy 2019, 14 (1):  85-86.  doi: 10.4103/1673-5374.243711 Abstract ( 133 )   PDF (583KB) ( 269 )   Save Is there a need for small molecule neuroprotectants in inherited retinal degeneration (iRDs)? iRDs are a heterogeneous cluster of diseases which lead to blindness in 1 in every 2–3000 people. A plethora of causative genetic defects were revealed in the last 30 years. Current research focuses on development of pharmacolog-ical, biological or mechanical implant treatments. Gene therapy demonstrated success in patients with specific genetic mutations and Luxturna, recently approved by the FDA for RPE65 related disease, entered the market at a cost of $425,000 per eye. Given over 250 genes link to iRDs, gene-specific therapy for each gene is challenging and limits widespread applicability. Cell-based approaches aim to replace defective photoreceptor or retinal pigment epithelium (RPE) cells, however concerns remain over long-term benefit, safety and integration of transplanted pho-toreceptor cells. Human embryonic stem cell (hESC) derived RPE patches appear more promising when transplanted into an initial cohort of patients affected by age-related macular degeneration (AMD). An alternative to replacing defective cells or genes is to identify neuroprotective factors preventing vision loss. Drug treatment has several advantages including: i) bypass permanent modifications and associated risks ii) ability to fine-tune an effective and safe dose for each patient, iii) can easily stop treatment if adverse effects en-countered and iv) is relatively less expensive compared to gene- or cell-therapy. Related Articles | Metrics

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Modulation of mitochondrial respiration underpins neuronal differentiation enhanced by lutein Kui Xie,Sherry Ngo, Jing Rong, Allan Sheppard 2019, 14 (1):  87-99.  doi: 10.4103/1673-5374.243713 Abstract ( 185 )   PDF (1879KB) ( 291 )   Save Lutein is a dietary carotenoid of particular nutritional interest as it is preferentially taken up by neural tissues. Often linked with beneficial effects on vision, a broader role for lutein in neuronal differentiation has emerged recently, although the underlying mechanisms for these effects are not yet clear. The purpose of this study was to investigate the effect of lutein on neuronal differentiation and explore the associated underpinning mechanisms. We found that lutein treatment enhanced the differentiation of SH-SY5Y cells, specifically increasing neuronal arborization and expression of the neuronal process filament protein microtubule-associated protein 2. This effect was mediated by the intracellular phosphoinositide-3-kinase (PI3K) signaling pathway. While PI3K activity is a known trigger of neuronal differentiation, more recently it has also been shown to modulate the metabolic state of cells. Our analysis of bioenergetics found that lutein treatment increased glucose consumption, rates of glycolysis and enhanced respiratory activity of mitochondrial complexes. Concomitantly, the generation of reactive oxygen species was increased (consistent with previous reports that reactive oxygen species promote neuronal differentiation), as well as the production of the key metabolic intermediate acetyl-CoA, an essential determinant of epigenetic status in the cell. We suggest that lutein-stimulated neuronal differentiation is mediated by PI3K-dependent modulation of mitochondrial respiration and signaling, and that the consequential metabolic shifts initiate epigenetically dependent transcriptomic reprogramming in support of this morphogenesis. These observations support the potential importance of micronutrients supplementation to neurogenesis, both during normal development and in regenerative repair. Related Articles | Metrics

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A novel large animal model of recurrent migraine established by repeated administration of inflammatory soup into the dura mater of the rhesus monkey Ning Chen, Wei Su, Shu-Hui Cui, Jian Guo, Jia-Chuan Duan, Hong-Xia Li, Li He 2019, 14 (1):  100-106.  doi: 10.4103/1673-5374.243715 Abstract ( 255 )   PDF (1214KB) ( 290 )   Save Several animal models of migraine have been established, and those based on trigeminovascular system activation are widely accepted. How¬ever, most of these models have been established on lower animals, such as rodents, and involve only a single administration of a noxious stimulus. In this study, an inflammatory soup (10 μL), consisting of prostaglandin E2 (0.2 mM), serotonin (2 mM), bradykinin (2 mM) and histamine (2 mM), was injected into the dura mater of conscious rhesus monkeys through an indwelling catheter. The infusion started on day 8 and was repeated every 3 days, for a total of six administrations, to induce neurogenic inflammation. We performed behavioral assessments and measured the expression of the oncogene c-fos, neuronal nitric oxide synthase (nNOS) and calcitonin gene related peptide (CGRP) in the trigeminal system and in multiple brain regions involved in pain processing by immunohistochemical staining. Compared with monkeys in the control group, three of the four animals in the inflammatory soup group displayed decreased motor behaviors, and two showed increased ipsilateral nose and mouth secretions during the stimulus period. Higher expression levels of c-fos, nNOS and CGRP were found in various brain areas of experimental animals compared with controls, including the trigeminal nucleus caudalis, thalamus, hypothalamus, midbrain, pons and other areas involved in pain perception. These results suggest that repeated inflammatory soup stimulation of the dura activates the trigeminovascular system and produces migraine-like pathological changes and abnormal behaviors in conscious rhesus monkeys. Related Articles | Metrics

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Time-effect relationship of acupuncture on histopathology, ultrastructure, and neuroethology in the acute phase of cerebral hemorrhage Zuo-Wei Li,Xiao-Nan Zheng,Ping Li 2019, 14 (1):  107-113.  doi: 10.4103/1673-5374.243714 Abstract ( 176 )   PDF (1015KB) ( 298 )   Save Many clinical studies have addressed the treatment of acute cerebral hemorrhage using acupuncture. However, few studies have exam¬ined the relationship between time of acupuncture and curative effect on cerebral hemorrhage. By observing the effect of acupuncture on changes in histopathology, ultrastructure, and neuroethology in a cerebral hemorrhage model of rats, we have directly examined the time-effect relationship of acupuncture. The rat model of cerebral hemorrhage was produced by slowly injecting autologous blood to the right caudate nucleus. The experimental groups were: 3-, 9-, 24-, and 48-hour model groups; and 3-, 9-, 24-, and 48-hour acupuncture groups. The sham-operation group was used for comparison. Acupuncture was performed at the Neiguan (PC6) and Renzhong (DU26) acupoints, twice a day, 6 hours apart, for 5 consecutive days. Brain tissue changes were observed by light microscopy and transmission electron microscopy. Neuroethology was assessed using Bederson and Longa scores. Our results show that compared with the sham-op¬eration and model groups, Bederson and Longa scores were lower in each acupuncture group, with visibly improved histopathology and brain tissue ultrastructure. Further, the results were better in the 3- and 9-hour acupuncture groups than the 24- and 48-hour acupuncture groups. Our findings show that acupuncture treatment can relieve pathological and ultrastructural deterioration and neurological impair¬ment caused by the acute phase of cerebral hemorrhage, and may protect brain tissue during this period. In addition, earlier acupuncture intervention following cerebral hemorrhage (by 3 or 9 hours) is associated with a better treatment outcome. Related Articles | Metrics

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Detecting white matter alterations in multiple sclerosis using advanced diffusion magnetic resonance imaging Sourajit M. Mustafi, Jaroslaw Harezlak, Chandana Kodiweera, Jennifer S. Randolph, James C. Ford, Heather A. Wishart, Yu-Chien Wu 2019, 14 (1):  114-123.  doi: 10.4103/1673-5374.243716 Abstract ( 148 )   PDF (964KB) ( 427 )   Save Multiple sclerosis is a neurodegenerative and inflammatory disease, a hallmark of which is demyelinating lesions in the white matter. We hypothesized that alterations in white matter microstructures can be non-invasively characterized by advanced diffusion magnetic resonance imaging. Seven diffusion metrics were extracted from hybrid diffusion imaging acquisitions via classic diffusion tensor imaging, neurite orientation dispersion and density imaging, and q-space imaging. We investigated the sensitivity of the diffusion metrics in 36 sets of regions of interest in the brain white matter of six female patients (age 52.8 ± 4.3 years) with multiple sclerosis. Each region of interest set included a conventional T2-defined lesion, a matched perilesion area, and normal-appearing white matter (NAWM). Six patients with multiple sclerosis (n = 5) or clinically isolated syndrome (n = 1) at a mild to moderate disability level were recruited. The patients exhibited microstructural alterations from NAWM transitioning to perilesion areas and lesions, consistent with decreased tissue restriction, decreased axonal density, and increased classic diffusion tensor imaging diffusivity. The findings suggest that diffusion compartment modeling and q-space analysis appeared to be sensitive for detecting subtle microstructural alterations between perilesion areas and NAWM. Related Articles | Metrics

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Olfactory ensheathing cells promote nerve regeneration and functional recovery after facial nerve defects Jian Gu, He Xu, Ya-Ping Xu, Huan-Hai Liu, Jun-Tian Lang, Xiao-Ping Chen, Wei-Hua Xu, Yue Deng, Jing-Ping Fan 2019, 14 (1):  124-131.  doi: 10.4103/1673-5374.243717 Abstract ( 127 )   PDF (1023KB) ( 546 )   Save Olfactory ensheathing cells from the olfactory bulb and olfactory mucosa have been found to increase axonal sprouting and pathfinding and promote the recovery of vibrissae motor performance in facial nerve transection injured rats. However, it is not yet clear whether olfactory ensheathing cells promote the reparation of facial nerve defects in rats. In this study, a collagen sponge and silicone tube neural conduit was implanted into the 6-mm defect of the buccal branch of the facial nerve in adult rats. Olfactory ensheathing cells isolated from the olfactory bulb of newborn Sprague-Dawley rats were injected into the neural conduits connecting the ends of the broken nerves, the morphology and function of the regenerated nerves were compared between the rats implanted with olfactory ensheathing cells with the rats injected with saline. Facial paralysis was assessed. Nerve electrography was used to measure facial nerve-induced action potentials. Visual inspection, anatomical microscopy and hematoxylin-eosin staining were used to assess the histomorphology around the trans¬planted neural conduit and the morphology of the regenerated nerve. Using fluorogold retrograde tracing, toluidine blue staining and lead uranyl acetate staining, we also measured the number of neurons in the anterior exterior lateral facial nerve motor nucleus, the number of myelinated nerve fibers, and nerve fiber diameter and myelin sheath thickness, respectively. After surgery, olfactory ensheathing cells de¬creased facial paralysis and the latency of the facial nerve-induced action potentials. There were no differences in the general morphology of the regenerating nerves between the rats implanted with olfactory ensheathing cells and the rats injected with saline. Between-group results showed that olfactory ensheathing cell treatment increased the number of regenerated neurons, improved nerve fiber morphology, and increased the number of myelinated nerve fibers, nerve fiber diameter, and myelin sheath thickness. In conclusion, implantation of olfactory ensheathing cells can promote regeneration and functional recovery after facial nerve damage in rats. Related Articles | Metrics

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Folic acid contributes to peripheral nerve injury repair by promoting Schwann cell proliferation, migration, and secretion of nerve growth factor Wei-Bo Kang, Yong-Jie Chen, Du-Yi Lu, Jia-Zhi Yan 2019, 14 (1):  132-139.  doi: 10.4103/1673-5374.243718 Abstract ( 258 )   PDF (2287KB) ( 355 )   Save After peripheral nerve injury, intraperitoneal injection of folic acid improves axon quantity, increases axon density and improves electromy¬ography results. However, the mechanisms for this remain unclear. This study explored whether folic acid promotes peripheral nerve injury repair by affecting Schwann cell function. Primary Schwann cells were obtained from rats by in vitro separation and culture. Cell prolif¬eration, assayed using the Cell Counting Kit-8 assay, was higher in cells cultured for 72 hours with 100 mg/L folic acid compared with the control group. Cell proliferation was also higher in the 50, 100, 150, and 200 mg/L folic acid groups compared with the control group after culture for 96 hours. Proliferation was markedly higher in the 100 mg/L folic acid group compared with the 50 mg/L folic acid group and the 40 ng/L nerve growth factor group. In Transwell assays, the number of migrated Schwann cells dramatically increased after culture with 100 and 150 mg/L folic acid compared with the control group. In nerve growth factor enzyme-linked immunosorbent assays, treatment of Schwa nn cell cultures with 50, 100, and 150 mg/L folic acid increased levels of nerve growth factor in the culture medium compared with the con¬trol group at 3 days. The nerve growth factor concentration of Schwann cell cultures treated with 100 mg/L folic acid group was remarkably higher than that in the 50 and 150 mg/L folic acid groups at 3 days. Nerve growth factor concentration in the 10, 50, and 100 mg/L folic acid groups was higher than that in the control group at 7 days. The nerve growth factor concentration in the 50 mg/L folic acid group was re¬markably higher than that in the 10 and 100 mg/L folic acid groups at 7 days. In vivo, 80 μg/kg folic acid was intraperitoneally administrated for 7 consecutive days after sciatic nerve injury. Immunohistochemical staining showed that the number of Schwann cells in the folic acid group was greater than that in the control group. We suggest that folic acid may play a role in improving the repair of peripheral nerve injury by promoting the proliferation and migration of Schwann cells and the secretion of nerve growth factors. Related Articles | Metrics

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Effects of TRPA1 activation and inhibition on TRPA1and CGRP expression in dorsal root ganglion neurons Xiao-Lei Wang, Li-Wei Cui, Zhen Liu, Yue-Ming Gao, Sheng Wang, Hao Li, Hu-Xiang Liu, Ling-Jia Yu 2019, 14 (1):  140-148.  doi: 10.4103/1673-5374.243719 Abstract ( 192 )   PDF (2695KB) ( 318 )   Save Transient receptor potential ankyrin 1 (TRPA1) is a key player in pain and neurogenic inflammation, and is localized in nociceptive primary sensory dorsal root ganglion (DRG) neurons. TRPA1 plays a major role in the transmission of nociceptive sensory signals. The generation of neurogenic inflammation appears to involve TRPA1-evoked release of calcitonin gene-related peptide (CGRP). However, it remains unknown whether TRPA1 or CGRP expression is affected by TRPA1 activation. Thus, in this study, we examined TRPA1 and CGRP expression in DRG neurons in vitro after treatment with the TRPA1 activator formaldehyde or the TRPA1 blocker menthol. In addition, we examined the role of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in this process. DRG neurons in culture were exposed to formaldehyde, menthol, the ERK1/2 inhibitor PD98059 + formaldehyde, or PD98059 + menthol. After treatment, real-time polymerase chain reaction, western blot assay and double immunofluorescence labeling were performed to evaluate TRPA1 and CGRP expression in DRG neurons. Formaldehyde elevated mRNA and protein levels of TRPA1 and CGRP, as well as the proportion of TRPA1- and CGRP-positive neurons. In contrast, menthol reduced TRPA1 and CGRP expression. Furthermore, the effects of formaldehyde, but not menthol, on CGRP expression were blocked by pretreatment with PD98059. PD98059 pretreatment did not affect TRPA1 expression in the presence of formaldehyde or menthol. Related Articles | Metrics

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Microsurgical efficacy in 326 children with tethered cord syndrome: a retrospective analysis Ai-Jia Shang, Chang-Hao Yang, Cheng Cheng, Ben-Zhang Tao, Yuan-Zheng Zhang, Hai-Hao Gao, Shao-Cong Bai 2019, 14 (1):  149-155.  doi: 10.4103/1673-5374.243720 Abstract ( 222 )   PDF (703KB) ( 213 )   Save Tethered cord syndrome is a progressive disease with a typically insidious onset in infants and children, and which can lead to persistent progress of neurological deficits and a high rate of disability without timely intervention. The purpose of this study was to investigate the curative effect of microsurgery in children with different types of tethered cord syndrome. In this study, we analyzed 326 patients with tethered cord syndrome, aged from 2 months to 14 years old, who were followed for 3–36 months after microscopic surgery. Based on clinical manifestations and imaging findings, these patients were classified into five types: tight filum terminale (53 cases), lipomyelome¬ningocele (55 cases), lipomatous malformation (124 cases), postoperative adhesions (56 cases), and split cord malformation (38 cases). All patients underwent microsurgery. Curative effects were measured before and 3 months after surgery by Spina Bifida Neurological Scale based on sensory and motor functions, reflexes, and bladder and bowel function. The results showed that Spina Bifida Neurological Scale scores improved in all five types after surgery. Overall effective rates in these patients were 75%. Effective rates were 91% in tight filum terminale, 84% in lipomyelomeningocele, 65% in lipomatous malformation, 75% in postoperative adhesion, and 79% in split cord mal¬formation. Binary logistic regression analysis revealed that types of tethered cord syndrome (lipoma-type or not) and symptom duration before surgery were independent influencing factors of surgical outcome. These results show that therapeutic effect is markedly different in patients with different types of tethered cord syndrome. Suitable clinical classification for tethered cord syndrome will be helpful in predicting prognosis and guiding treatment. This trial has been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800016464). Related Articles | Metrics

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Neurolin expression in the optic nerve and immunoreactivity of Pax6-positive niches in the brain of rainbow trout (Oncorhynchus mykiss) after unilateral eye injury Evgeniya V. Pushchina, Anatoly A. Varaksin 2019, 14 (1):  156-171.  doi: 10.4103/1673-5374.243721 Abstract ( 160 )   PDF (4599KB) ( 184 )   Save In contrast to astrocytes in mammals, fish astrocytes promote axon regeneration after brain injury and actively participate in the regeneration process. Neurolin, a regeneration-associated, Zn8-labeled protein, is involved in the repair of damaged optic nerve in goldfish. At 1 week after unilateral eye injury, the expression of neurolin in the optic nerve and chiasm, and the expression of Pax6 that influences nervous system development in various brain regions in the rainbow trout (Oncorhynchus mykiss) were detected. Immunohistochemical staining revealed that the number of Zn8+ cells in the optic nerve head and intraorbital segment was obviously increased, and the increase in Zn8+ cells was also observed in the proximal and distal parts of injured optic nerve. This suggests that Zn8+ astrocytes participate in optic nerve regeneration. ELISA results revealed that Pax6 protein increased obviously at 1 week post-injury. Immunohistochemical staining revealed the appearance of Pax6+ neurogenic niches and a larger number of neural precursor cells, which are mainly from Pax6+ radial glia cells, in the nuclei of the diencephalon and optic tectum of rainbow trout (Oncorhynchus mykiss). Taken together, unilateral eye injury can cause optic nerve reaction, and the formation of neurogenic niches is likely a compensation phenomenon during the repair process of optic nerve injury in rainbow trout (Oncorhynchus mykiss). Related Articles | Metrics

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Brain pathways of pain empathy activated by pained facial expressions: a meta-analysis of fMRI using the activation likelihood estimation method Ruo-Chu Xiong, Xin Fu, Li-Zhen Wu, Cheng-Han Zhang, Hong-Xiang Wu, Yu Shi, Wen Wu 2019, 14 (1):  172-178.  doi: 10.4103/1673-5374.243722 Abstract ( 200 )   PDF (357KB) ( 391 )   Save OBJECTIVE: The objective of this study is to summarize and analyze the brain signal patterns of empa¬thy for pain caused by facial expressions of pain utilizing activation likelihood estimation, a meta-analysis method. DATA SOURCES: Studies concerning the brain mechanism were searched from the Science Citation Index, Science Direct, PubMed, DeepDyve, Cochrane Library, SinoMed, Wanfang, VIP, China National Knowledge Infrastructure, and other databases, such as SpringerLink, AMA, Science Online, Wiley Online, were collected. A time limitation of up to 13 December 2016 was applied to this study. DATA SELECTION: Studies presenting with all of the following criteria were considered for study in¬clusion: Use of functional magnetic resonance imaging, neutral and pained facial expression stimuli, involvement of adult healthy human participants over 18 years of age, whose empathy ability showed no difference from the healthy adult, a painless basic state, results presented in Talairach or Montreal Neuro¬logical Institute coordinates, multiple studies by the same team as long as they used different raw data. OUTCOME MEASURES: Activation likelihood estimation was used to calculate the combined main acti¬vated brain regions under the stimulation of pained facial expression. RESULTS: Eight studies were included, containing 178 subjects. Meta-analysis results suggested that the anterior cingulate cortex (BA32), anterior central gyrus (BA44), fusiform gyrus, and insula (BA13) were activated positively as major brain areas under the stimulation of pained facial expression. CONCLUSION: Our study shows that pained facial expression alone, without viewing of painful stimuli, activated brain regions related to pain empathy, further contributing to revealing the brain’s mechanisms of pain empathy. Related Articles | Metrics