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15 April 2018, Volume 13 Issue 4 Previous Issue    Next Issue

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Acupuncture and neuroregeneration in ischemic stroke Qwang-Yuen Chang, Yi-Wen Lin, Ching-Liang Hsieh 2018, 13 (4):  573-583.  doi: 10.4103/1673-5374.230272 Abstract ( 148 )   PDF (566KB) ( 343 )   Save Acupuncture is potentially beneficial for post-stroke rehabilitation and is considered a promising preventive strategy for stroke. Electroacupuncture pretreatment or treatment after ischemic stroke by using appropriate electroacupuncture parameters generates neuroprotective and neuroregenerative effects that increase cerebral blood flow, regulate oxidative stress, attenuate glutamate excitotoxicity, maintain bloodbrain barrier integrity, inhibit apoptosis, increase growth factor production, and induce cerebral ischemic tolerance. Related Articles | Metrics

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The adjustment of γ-aminobutyric acidA tonic subunits in Huntington’s disease: from transcription to translation to synaptic levels into the neostriatum Abraham Rosas-Arellano, Argel Estrada-Mondragón, Carola A. Mantellero, Carlos Tejeda-Guzmán, Maite A. Castro 2018, 13 (4):  584-590.  doi: 10.4103/1673-5374.230270 Abstract ( 124 )   PDF (806KB) ( 284 )   Save γ-Aminobutyric acid (GABA), plays a key role in all stages of life, also is considered the main inhibitory neurotransmitter. GABA activates two kind of membrane receptors known as GABAA and GABAB, the first one is responsible to render tonic inhibition by pentameric receptors containing α4−6, β3, δ, or ρ1−3 subunits, they are located at perisynaptic and/or in extrasynaptic regions. The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation. On this basis, GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington’s disease. Huntington’s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein. For experimental studies of Huntington’s disease mouse models have been developed, such as R6/1, R6/2, HdhQ92, HdhQ150, as well as YAC128. In all of them, some key experimental reports are focused on neostriatum. The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures, its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively, they display strong expression of many types of GABAA receptors, including tonic subunits. The studies about of GABAA tonic subunits and Huntington’s disease into the neostriatum are rising in recent years, suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition, a hallmark of Huntignton’s disease. Related Articles | Metrics

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Bridging the gap: axonal fusion drives rapid functional recovery of the nervous system Jean-Sébastien Teoh, Michelle Yu-Ying Wong, Tarika Vijayaraghavan, Brent Neumann 2018, 13 (4):  591-594.  doi: 10.4103/1673-5374.230271 Abstract ( 155 )   PDF (548KB) ( 214 )   Save Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently self-repair. This inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to patients. Compared to humans, a number of species possess far greater regenerative capabilities, and can therefore provide important insights into how our own nervous systems can be repaired. In particular, several invertebrate species have been shown to rapidly initiate regeneration post-injury, allowing separated axon segments to re-join. This process, known as axonal fusion, represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original structure. Our recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged neurons. Moreover, we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion, and discovered that the level of axonal fusion can be enhanced by promoting a neuron’s intrinsic growth potential. A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting. Related Articles | Metrics

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Collagen for brain repair: therapeutic perspectives Buket Ucar, Christian Humpel 2018, 13 (4):  595-598.  doi: 10.4103/1673-5374.230273 Abstract ( 132 )   PDF (301KB) ( 287 )   Save Biomaterials have increasingly become a focus of research on neuroprotection and neuroregeneration. Collagen, in terms of brain repair, presents many advantages such as being remarkably biocompatible, biodegradable, versatile and non-toxic. Collagen can be used to form injectable scaffolds and micro/nano spheres in order to: (i) locally release therapeutic factors with the aim of protecting degenerating neurons in neurodegenerative conditions such as Alzheimer’s or Parkinson’s diseases, (ii) encapsulate stem cells for safe delivery, (iii) encapsulate genetically modified cells to provide a long term source of trophic factors, (iv) fill in the voids from injury to serve as a structural support and provide a permissive microenvironment to promote axonal growth. This mini-review summarizes different applications of collagen biomaterial for central nervous system protection and repair, as well as the future perspectives. Overall, collagen is a promising natural biomaterial with various applications which has the potential to progress the development of therapeutic strategies in central nervous system injuries and degeneration. Related Articles | Metrics

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Stimulating effect of thyroid hormones in peripheral nerve regeneration: research history and future direction toward clinical therapy I. Barakat-Walter, R. Kraftsik 2018, 13 (4):  599-608.  doi: 10.4103/1673-5374.230274 Abstract ( 153 )   PDF (1088KB) ( 236 )   Save   Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions. Despite extensive investigation, testing various surgical repair techniques and neurotrophic molecules, at present, a satisfactory method to ensuring successful recovery does not exist. For successful molecular therapy in nerve regeneration, it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth. Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination. Therefore, any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration. Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system, so they could be candidates for nervous system regeneration. This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration. Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves. We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves, and accelerates functional recovering. This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves. The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells. Related Articles | Metrics

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Harnessing migraines for neural regeneration Jonathan M. Borkum 2018, 13 (4):  609-615.  doi: 10.4103/1673-5374.230275 Abstract ( 103 )   PDF (267KB) ( 339 )   Save The success of naturalistic or therapeutic neuroregeneration likely depends on an internal milieu that facilitates the survival, proliferation, migration, and differentiation of stem cells and their assimilation into neural networks. Migraine attacks are an integrated sequence of physiological processes that may protect the brain from oxidative stress by releasing growth factors, suppressing apoptosis, stimulating neurogenesis, encouraging mitochondrial biogenesis, reducing the production of oxidants, and upregulating antioxidant defenses. Thus, the migraine attack may constitute a physiologic environment conducive to stem cells. In this paper, key components of migraine are reviewed – neurogenic inflammation with release of calcitonin gene-related peptide (CGRP) and substance P, plasma protein extravasation, platelet activation, release of serotonin by platelets and likely by the dorsal raphe nucleus, activation of endothelial nitric oxide synthase (eNOS), production of brain-derived neurotrophic factor (BDNF) and, in migraine aura, cortical spreading depression – along with their potential neurorestorative aspects. The possibility is considered of using these components to facilitate successful stem cell transplantation. Potential methods for doing so are discussed, including chemical stimulation of the TRPA1 ion channel, conjoint activation of a subset of migraine components, invasive and noninvasive deep brain stimulation of the dorsal raphe nucleus, transcranial focused ultrasound, and stimulation of the Zusanli (ST36) acupuncture point. Related Articles | Metrics

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Synaptic dysfunction in Alzheimer’s disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention Jade Marsh, Pavlos Alifragis 2018, 13 (4):  616-623.  doi: 10.4103/1673-5374.230276 Abstract ( 117 )   PDF (789KB) ( 369 )   Save   The most prevalent form of dementia in the elderly is Alzheimer’s disease. A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42 (Aβ42), a small hydrophobic peptide. Unfortunately, attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease. It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach. The accumulation of Aβ42 seems to affect various aspects of physiological cell functions. In this review, we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction, with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release. We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer’s disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease. Although the precise mechanisms that trigger synaptic dysfunction are still under investigation, the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention. Related Articles | Metrics

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Young blood products: emerging treatment for Alzheimer’s disease? 2018, 13 (4):  624-627.  doi: 10.4103/1673-5374.230277 Abstract ( 131 )   PDF (467KB) ( 290 )   Save Alzheimer’s disease is the most common neurodegenerative disorder and no disease-modifying treatment is currently available. Research has shown that while brain neurogenesis continues in adult life, it declines with age. Using parabiosis, plasma transfusions and direct administration of neural growth factors, animal studies have demonstrated the positive impact of exposure to young blood products on neurogenesis and synaptic plasticity in an aging brain. The hippocampus and the sub-ventricular zones were identified as the main regions affected. Promising findings have prompted researchers to experiment their effects in subjects with an established neurocognitive disorder, such as Alzheimer’s disease. They argued that modification of brain vasculature, reactivation of adult neural stem cells, and remodeling of their synaptic activity/plasticity may lead to cognitive enhancement and increased neurogenesis. One pilot human study found that young donor plasma infusion protocols for adults with Alzheimer’s disease were safe and feasible; however, no statistically significant improvements in cognition were detected. There is a need to conduct additional placebo-controlled human studies in larger samples. Future studies should focus on identifying an “optimal age” at which an intervention in humans may yield significant cognitive enhancement, as well as determining the types of transfusions with the best efficacy and tolerability profiles. Related Articles | Metrics

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Dissecting the multifactorial nature of demyelinating disease Karolina Kucharova, William B. Stallcup 2018, 13 (4):  628-632.  doi: 10.4103/1673-5374.230281 Abstract ( 121 )   PDF (680KB) ( 321 )   Save Chondroitin sulfate proteoglycan-4 (CSPG4) is a surface component of two key cell types (oligodendrocyte progenitor cells (OPCs) and myeloid cells) present in lysolecithin-induced lesions in mouse spinal cord. Two types of CSPG4 manipulations have been used to study the roles of these cells in myelin damage and repair: (1) OPC and myeloid-specific ablation of CSPG4, and (2) transplantation of enhanced green fluorescent protein (EGFP)-labeled progenitors to distinguish between bone marrow-derived macrophages and resident microglia. Ablation of CSPG4 in OPCs does not affect myelin damage, but decreases myelin repair, due to reduced proliferation of CSPG4-null OPCs that diminishes generation of mature oligodendrocytes for remyelination. Ablation of CSPG4 in myeloid cells greatly decreases recruitment of macrophages to spinal cord lesions, resulting in smaller initial lesions, but also in significantly diminished myelin repair. In the absence of macrophage recruitment, OPC proliferation is greatly impaired, again leading to decreased generation of myelinating oligodendrocytes. Macrophages may promote OPC proliferation via phagocytosis of myelin debris and/or secretion of factors that stimulate OPC mitosis. Microglia are not able to substitute for macrophages in promoting OPC proliferation. An additional feature of lesions in myeloid-specific CSPG4 null mice is the persistence of poorly-differentiated platelet-derived growth factor receptor α (PDGFRα) + macrophages that may prolong damage. Related Articles | Metrics

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Do large brains of long-living mammals prefer non-newly generated, immature neurons? Ottavia Palazzo, Chiara La Rosa, Matteo Piumatti, Luca Bonfanti 2018, 13 (4):  633-634.  doi: 10.4103/1673-5374.230282 Abstract ( 103 )   PDF (583KB) ( 260 )   Save Brain plasticity is heterogeneous in mammals: Brain regeneration and repair are the dream of every neurobiologist as well as every common citizen in the world who knows that most neurological diseases, dementia and other age-related problems affecting the central nervous system (CNS) do represent a heavy health and social burden. Efficacious regenerative processes are not a natural property of the mammalian CNS,rather, due to evolutionary constraints they seem substantially reduced (if compared to those occurring in non-mammalian vertebrates) and hardly inducible by therapeutic approaches (reviewed in Martino et al., 2011).Paradoxically, different types of remarkable structural plastic processes have been shown to occur in the young and adult mammalian brain,spanning from widespread synaptic plasticity and gliogenesis to a more spatially-restricted, yet clearly demonstrable, genesis of new neurons (references in Martino et al., 2011). The failure in mammalian brain regeneration can be explained by a combination of several factors acquired through evolution (e.g., brain complexity, scarcity of stem cells, incapability of cell de-differentiation, role of immune system; see Bonfanti,2011 for review). Ultimately, all aspects involved converge into two main reasons: i) unlike non-mammalian vertebrates (e.g., fish or amphibians) in which neurogenic processes are far more extended and also provide repair, mammals have retained mostly the physiological role of plasticity,useful to cope with environmental changes but hardly helpful in regeneration;ii) adult mammalian neurogenesis appears to be highly reduced in humans with respect to rodents (Sanai et al., 2011; Paredes et al.,2015), recent work carried out in dolphins further confirming that it can be vestigial in large-brained, long-living mammals (Parolisi et al., 2017).Especially humans face further neurological risks in the future since they possess less potential for brain regeneration than other animal species in contrast with their extended (and progressively increasing) lifespan. Related Articles | Metrics

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Epigenetic interventions for brain rejuvenation: anchoring age-related transposons Adonis Sfera, Lisa Fayard, Carolina Osorio, Amy Price 2018, 13 (4):  635-636.  doi: 10.4103/1673-5374.230283 Abstract ( 112 )   PDF (253KB) ( 240 )   Save Highlights: 1. Iron and homocysteine accumulation in aging neurons alter genomic methylation. 2. The altered methylome reactivates neuronal cell cycle, enabling transposable element mobilization. 3. miR29/p53 axis restores age-related methylation shifts, reactivating neuronal plasticity. 4. Augmentation of miR-29/p53 axis may preempt neurodegenerative disorders. Related Articles | Metrics

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Fluorescence detection of Europium-doped very small superparamagnetic iron oxide nanoparticles in murine hippocampal slice cultures Martin Pohland, Yuske Kobayashi, Jana Glumm 2018, 13 (4):  637-638.  doi: 10.4103/1673-5374.230284 Abstract ( 106 )   PDF (344KB) ( 261 )   Save In the late 1980s, superparamagnetic iron oxide nanoparticles (SPIO) moved into focus as contrast agents in magnetic resonance imaging (MRI), due to their strong relaxivity and resulting higher resolution of images. At the time, no one anticipated their high potential in basic research or for medical diagnostic and treatment. Since then, SPIO have been evaluated not only as specific markers for MRI, but also for cell labeling and tracking . In addition, SPIO are being investigated as carriers for targeted administration of therapeutics, e.g., drugs or gene sequences , in cancer treatment via magnetic hyperthermia and in neuronal regeneration. Related Articles | Metrics

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Axotomy induces damage to glial cells remote from the transection site in the peripheral nervous system Anatoly B. Uzdensky 2018, 13 (4):  639-640.  doi: 10.4103/1673-5374.230285 Abstract ( 111 )   PDF (563KB) ( 254 )   Save Traumatic cerebral or spinal cord injury induced by military, traffic,and sports accidents, falls or environmental and anthropogenic catastrophes are among main causes of people mortality and disability,especially in young and middle age men (Kobeissy, 2015). Axon transection, or axotomy, occurs in wounds and during surgery. Central neurons do not regenerate and die, but in the peripheral nervous system 25–30% of axotomized motor or sensory neurons survive and can regenerate and restore lost connections to their target cells. In order to treat the consequences of nerve injury, the balance between neurodegeneration and neuroprotection processes should be rapidly shifted to neuron survival. Unfortunately, reliable neuroprotective medications with proven efficiency are not found yet. So, comprehensive and deep study of molecular processes that occur after axon transection is required. Related Articles | Metrics

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Targeted tissue engineering: hydrogels with linear capillary channels for axonal regeneration after spinal cord injury Shengwen Liu, Armin Blesch 2018, 13 (4):  641-642.  doi: 10.4103/1673-5374.230286 Abstract ( 104 )   PDF (291KB) ( 244 )   Save Spinal cord injury (SCI) frequently results in the permanent loss of function below the level of injury due to the failure of axonal reg eneration in the adult mammalian central nervous system (CNS).The limited intrinsic growth capacity of adult neurons, a lack of growth-promoting factors and the multifactorial inhibitory microenvironment around the lesion site contribute to the lack of axonal regeneration. Strategies such as transplantation of cells, delivery of bioactive compounds and gene transfer have been investigated as a means to promote axonal regrowth through the lesion, to form new synaptic connections and to improve functional outcomes. Although growth of some axonal populations can be robustly enhanced by cellular implants alone or in combination with neurotrophic factors,axons usually extend in random orientation and even reverse growth direction in the lesion site. Thus, regenerating axons often fail to approach the distal edge of the lesion site, a pre-requisite for proper contact with spared host neurons. The lack of a 3-dimensional organization in the injury site is therefore an additional barrier for successful axonal bridging. Two approaches, physical guidance through structured scaffolds and chemical guidance by growth factor gradients, have emerged as potential means to provide directional cues for axonal growth through the lesion. Related Articles | Metrics

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Neuromodulator interactions and spinal cord injury in lamprey David Parker, Thomas J. McClelland 2018, 13 (4):  643-644.  doi: 10.4103/1673-5374.230287 Abstract ( 104 )   PDF (455KB) ( 225 )   Save Neuromodulation is mediated by neurotransmitters that typically act on G-protein-coupled receptors. It can confer behavioural flexibility by modifying the functional properties of anatomically hard-wired neural circuits.Single neuromodulators generally have divergent cellular and synaptic effects , and different modulators, of which there are many in even simpler systems, can interact by converging onto the same effectors. These interactions can generate synergistic, antagonistic,or novel effects. Further modulator complexity is offered by the potential for concentration, time,and state-dependent influences.All of these effects can make neuromodulation highly flexible, making it difficult to predict or explain the functional effects resulting from the targeting of even a single modulatory system. As many clinically used drugs target G-protein-coupled receptors, being able to explain and predict these effects is important. Related Articles | Metrics

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Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression Ginetta Collo, Emilio Merlo Pich 2018, 13 (4):  645-646.  doi: 10.4103/1673-5374.230288 Abstract ( 123 )   PDF (346KB) ( 314 )   Save Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life, low mood and selected emotional, cognitive, physical and behavioral symptoms. Depression is a common disorder, affecting 5–15% of the general population. When diagnosed as major depressive disorder (MDD), patients are currently treated with pharmacological agents such as serotonin or noradrenaline  uptake inhibitors (SSRI or SNRI) or tricyclics. Patients that fail to respond to two or more antidepressant drugs - at an adequate dose for an adequate duration given sequentially – are considered affected by “treatment-resistant depression (TRD)”. TRD patients account for the 12–28% of the total MDD patients in charge to mental health services and are generally eligible to adjunctive pharmacotherapies with antipsychotics or lithium, behavioral therapies or electroconvulsive treatment (ECT). Unfortunately, several TRD patients display a persistent lack of response to the current adjunctive treatments, resulting in a relevant social burden and incurring in high direct medical costs to the health care system. Related Articles | Metrics

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Impacts of increased α-synuclein on clathrin-mediated endocytosis at synapses: implications for neurodegenerative diseases Audrey T. Medeiros, Luigi Bubacco, Jennifer R. Morgan 2018, 13 (4):  647-648.  doi: 10.4103/1673-5374.230289 Abstract ( 128 )   PDF (467KB) ( 239 )   Save α-Synuclein causes synaptic pathologies in several neurodegenerative diseases: Parkinson’s disease (PD) is a neurodegenerative disease that impacts the lives of millions of people worldwide. A pathological hallmark of PD, as well as dementia with Lewy bodies (DLB) and several Alzheimer’s disease variants, is the appearance of intracellular inclusions called Lewy bodies, which contain high levels of aggregated α-synuclein. α-Synuclein is a presynaptic protein that normally associates with synaptic vesicle membranes and regulates synaptic vesicle trafficking under physiological conditions . However, in familial PD, multiplication and several point mutations in the α-synuclein gene (SNCA) ultimately lead to toxic aggregation of the α-synuclein protein and subsequent degeneration of dopaminergic neurons in the substantia nigra, although other brain areas are also affected . Related Articles | Metrics

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Dopaminergic mediation in the brain aging and neurodegenerative diseases: a role of senescent cells Pavel V. Nekrasov, Vasily V. Vorobyov 2018, 13 (4):  649-650.  doi: 10.4103/1673-5374.230290 Abstract ( 171 )   PDF (250KB) ( 239 )   Save Aging is well known to be the main risk factor for the neurodegenerative pathologies, in particular, Parkinson’s disease (PD) and Alzheimer’s disease (AD). In aging and in the diseases, similar changes in various hallmarks of neurodegeneration (lipofuscin accumulation,autophagia weakening, and disturbances in functions of mitochondria and lysosomes) were shown. Furthermore, dopaminergic system (DAS) involvement in mechanisms of aging, PD, and AD were revealed. Dopamine-producing neurons are predominantly concentrated in the substantia nigra (SN) and the ventral tegmental area (VTA). Dopamine (DA) terminals are  widespread in the brain, dominating in the hippocampus, prefrontal cortex, striatum, and olfactory bulbs.DA oxidization is well known to be accompanied by generation of various highly toxic compounds, in particular, reactive oxygen species (ROS).This is aggravated by auto-oxidization of DA with consequent accumulation of toxic DA-quinones (DA-Q) and other DA .Uncombined DA-Q is quickly neutralized by nucleophilic glutathione resulting in accumulation of 5-S-glutathionyl-DA, which, in turn, is transformed by enzymatic degradation into 5-S-cystenil-DA, one of the components of neuromelanin (NM). NM,predominantly accumulated in the SN, is able to bind free iron and,thus, to block both oxidative transformation of DA into its toxic forms and the ROS generation. These mechanisms allow the protection of neurons from the oxidative stress , thus, supporting normal functioning of DAS, in particular. Related Articles | Metrics

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Astrocytic Kir4.1 potassium channels as a novel therapeutic target for epilepsy and mood disorders Yukihiro Ohno 2018, 13 (4):  651-652.  doi: 10.4103/1673-5374.230355 Abstract ( 136 )   PDF (299KB) ( 255 )   Save Astrocytic Kir4.1 channels and spatial potassium buffering: Astrocytes play a crucial role in maintaining the structural and functional integrity of the brain, which includes formation of the blood-brain barrier, maintenance of water and ion homeostasis, metabolism of neurotransmitters and secretion of various neuroactive molecules. Among these functions, spatial potassium (K+) buffering by astrocytes is an essential system for controlling extracellular K+ concentration ([K+]o) and neuronal . Neurons normally release considerable amounts of K+ during the repolarization phase of an action potential. At tripartite synapses, a single action potential elevates the local [K+]o level by about 1 mM and, if uncorrected, [K+]o reaches 10 mM or more, causing abnormal discharges and finally spreading depression.Spatial K+ buffering by astrocytes is a K+-clearance system which removes an excess of extracellular K+ and transports it to the regions of low [K+]o such as capillary vessels . In addition,the spatial K+ buffering system is coupled to astrocytic glutamate uptake by glutamate transporters (e.g., EAAT1 and EAAT2) and water transport by aquaporin-4 (AQP4) Related Articles | Metrics

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Exendin-4 inhibits high-altitude cerebral edema by protecting against neurobiological dysfunction Zhong-Lei Sun, Xian-Feng Jiang, Yuan-Chi Cheng, Ying-Fu Liu, Kai Yang, Shuang-Long Zhu, Xian-Bin Kong, Yue Tu 2018, 13 (4):  653-663.  doi: 10.4103/1673-5374.230291 Abstract ( 171 )   PDF (2261KB) ( 255 )   Save The anti-inflammatory and antioxidant effects of exendin-4 (Ex-4) have been reported previously. However, whether (Ex-4) has anti-inflammatory and antioxidant effects on high-altitude cerebral edema (HACE) remains poorly understood. In this study, two rat models of HACE were established by placing rats in a hypoxic environment with a simulated altitude of either 6000- or 7000-m above sea level (MASL)for 72 hours. An altitude of 7000 MASL with 72-hours of hypoxia was found to be the optimized experimental paradigm for establishing HACE models. Then, in rats where a model of HACE was established by introducing them to a 7000 MASL environment with 72-hours of hypoxia treatment, 2, 10 and, 100 μg of Ex-4 was intraperitoneally administrated. The open field test and tail suspension test were used to test animal behavior. Routine methods were used to detect change in inflammatory cells. Hematoxylin-eosin staining was performed to determine pathological changes to brain tissue. Wet/dry weight ratios were used to measure brain water content. Evans blue leakage was used to determine blood-brain barrier integrity. Enzyme-linked immunosorbent assay (ELISA) was performed to measure markers of inflammation and oxidative stress including superoxide dismutase, glutathione, and malonaldehyde values, as well as interleukin-6,tumor necrosis factor-alpha, cyclic adenosine monophosphate levels in the brain tissue. Western blot analysis was performed to determine the levels of occludin, ZO-1, SOCS-3, vascular endothelial growth factor, EPAC1, nuclear factor-kappa B, and aquaporin-4. Our results demonstrate that Ex-4 preconditioning decreased brain water content, inhibited inflammation and oxidative stress, alleviated brain tissue injury, maintain blood-brain barrier integrity, and effectively improved motor function in rat models of HACE. These findings suggest that Ex-4 exhibits therapeutic potential in the treatment of HACE. Related Articles | Metrics

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Panax ginseng extract attenuates neuronal injury and cognitive deficits in rats with vascular dementia induced by chronic cerebral hypoperfusion Jun-De Zhu, Jun-Jie Wang, Xian-Hu Zhang, Yan Yu, Zhao-Sheng Kang 2018, 13 (4):  664-672.  doi: 10.4103/1673-5374.230292 Abstract ( 160 )   PDF (970KB) ( 330 )   Save Panax ginseng is a slow-growing perennial plant. Panax ginseng extract has numerous biological activities, including antitumor, anti-inflammatory and antistress activities. Panax ginseng extract also has a cognition-enhancing effect in rats with alcohol-induced memory impairment. In this study, we partially occluded the bilateral carotid arteries in the rat to induce chronic cerebral hypoperfusion, a wellknown model of vascular dementia. The rats were then intragastrically administered 50 or 100 mg/kg Panax ginseng extract. Morris water maze and balance beam tests were used to evaluate memory deficits and motor function, respectively. Protein quantity was used to evaluate cholinergic neurons. Immunofluorescence staining was used to assess the number of glial fibrillary acidic protein-positive cells.Western blot assay was used to evaluate protein levels of vascular endothelial growth factor, basic fibroblast growth factor, Bcl-2 and Bax.Treatment with Panax ginseng extract for 8 weeks significantly improved behavioral function and increased neuronal density and VEGF and bFGF protein expression in the hippocampal CA3 area. Furthermore, Panax ginseng extract reduced the number of glial fibrillary acidic protein-immunoreactive cells, and it decreased apoptosis by upregulating Bcl-2 and downregulating Bax protein expression. The effect of Panax ginseng extract was dose-dependent and similar to that of nimodipine, a commonly used drug for the treatment of vascular dementia. These findings suggest that Panax ginseng extract is neuroprotective against vascular dementia induced by chronic cerebral hypoperfusion,and therefore might have therapeutic potential for preventing and treating the disease. Related Articles | Metrics

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Dry needling at myofascial trigger points mitigates chronic post-stroke shoulder spasticity Li Tang, Yan Li, Qiang-Min Huang, Yang Yang 2018, 13 (4):  673-676.  doi: 10.4103/1673-5374.230293 Abstract ( 183 )   PDF (372KB) ( 289 )   Save Post-stroke spasticity is associated with restriction in the range of motion of the shoulder. Reducing muscular dystrophy may help relieve muscular dysfunction in patients with post-stroke shoulder spasticity. Dry needle therapy is a method of needling the trigger points using a syringe needle without the use of a drug. Dry needle therapy is commonly used for pain at the shoulder, neck, waist, and back. In this case study, a 62-year-old male patient affected with cerebral hemorrhage of the right frontal lobe had received rehabilitative treatment for 12 years. However, he still experienced shoulder spasticity. The patient received daily dry needling at the trigger points of infraspinatus,teres minor, posterior deltoid, and pectoralis major on 9 days. After the first and ninth treatment, the Modified Ashworth Scale and the passive range of motion of the shoulder was used to assess the effect of the treatment. The spasticity and range of motion of the shoulder showed obvious improvement. These results indicate that dry needling at the myofascial trigger points can effectively treat chronic poststroke shoulder spasticity. Related Articles | Metrics

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The Rho-associated kinase inhibitors Y27632 and fasudil promote microglial migration in the spinal cord via the ERK signaling pathway Pei-Cai Fu, Rong-Hua Tang, Zhi-Yuan Yu, Min-Jie Xie, Wei Wang, Xiang Luo 2018, 13 (4):  677-683.  doi: 10.4103/1673-5374.230294 Abstract ( 137 )   PDF (1881KB) ( 333 )   Save Rho-associated kinase (ROCK) is a key regulatory protein involved in inflammatory secretion in microglia in the central nervous system. Our previous studies showed that ROCK inhibition enhances phagocytic activity in microglia through the extracellular signal-regulated kinase (ERK) signaling pathway, but its effect on microglial migration was unknown. Therefore, in this study, we investigated the effects of the ROCK inhibitors Y27632 and fasudil on the migratory activity of primary cultured microglia isolated from the spinal cord, and we examined the underlying mechanisms. The microglia were treated with Y27632, fasudil and/or the ERK inhibitor U0126. Cellular morphology was observed by immunofluorescence. Transwell chambers were used to assess cell migration. ERK levels were measured by incell western blot assay. Y27632 and fasudil increased microglial migration, and the microglia were irregularly shaped and had many small processes. These inhibitors also upregulated the levels of phosphorylated ERK protein. The ERK inhibitor U0126 suppressed these effects of Y27632 and fasudil. These findings suggest that the ROCK inhibitors Y27632 and fasudil promote microglial migration in the spinal cord through the ERK signaling pathway. Related Articles | Metrics

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Macrophage depletion and Schwann cell transplantation reduce cyst size after rat contusive spinal cord injury Yee-Shuan Lee, Lucy H. Funk, Jae K. Lee, Mary Bartlett Bunge 2018, 13 (4):  684-691.  doi: 10.4103/1673-5374.230295 Abstract ( 153 )   PDF (3828KB) ( 293 )   Save Schwann cell transplantation is a promising therapy for the treatment of spinal cord injury (SCI) and is currently in clinical trials. In our continuing efforts to improve Schwann cell transplantation strategies,we sought to determine the combined effects of Schwann cell transplantation with macrophage depletion. Since macrophages are major inflammatory contributors to the acute spinal cord injury, and are the major phagocytic cells, we hypothesized that transplanting Schwann cells after macrophage depletion will improve cell survival and integration with host tissue after SCI. To test this hypothesis, rat models of contusive SCI at thoracic level 8 were randomly subjected to macrophage depletion or not. In rat subjected to macrophage depletion, liposomes filled with clodronate were intraperitoneally injected at 1, 3, 6, 11, and 18 days post injury. Rats not subjected to macrophage depletion were intraperitoneally injected with liposomes filled with phosphate buffered saline. Schwann cells were transplanted 1 week post injury in all rats.Biotinylated dextran amine (BDA) was injected at thoracic level 5 to evalute axon regeneration. The Basso,Beattie, and Bresnahan locomotor test, Gridwalk test, and sensory test using von Frey filaments were performed to assess functional recovery. Immunohistochemistry was used to detect glial fibrillary acidic protein, neurofilament, and green fluorescent protein (GFP), and also to visulize BDA-labelled axons. The GFP labeled Schwann cell and cyst and lesion volumes were quantified using stained slides. The numbers of BDA-positive axons were also quantified. At 8 weeks after Schwann cell transplantation, there was a significant reduction in cyst and lesion volumes in the combined treatment group compared to Schwann cell transplantation alone. These changes were not associated, however, with improved Schwann cell survival,axon growth, or locomotor recovery. Although combining Schwann cell transplantation with macrophage depletion does improve histopathology of the injury site, the effect on axon growth and behavioral recovery appears no better than what can be achieved with Schwann cell transplants alone Related Articles | Metrics

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Treatment with acetyl-L-carnitine exerts a neuroprotective effect in the sciatic nerve following loose ligation: a functional and microanatomical study Daniele Tomassoni, Lorenzo Di Cesare Mannelli, Vincenzo Bramanti, Carla Ghelardini, Francesco Amenta, Alessandra Pacini 2018, 13 (4):  692-698.  doi: 10.4103/1673-5374.230297 Abstract ( 371 )   PDF (916KB) ( 211 )   Save Peripheral neuropathies are chronic painful syndromes characterized by allodynia, hyperalgesia and altered nerve functionality. Nerve tissue degeneration represents the microanatomical correlate of peripheral neuropathies. Aimed to improve the therapeutic possibilities, this study investigated the hypersensitivity and the neuromorphological alterations related to the loose ligation of the sciatic nerve in rats. Effects elicited by treatment with acetyl-L-carnitine (ALCAR) in comparison to gabapentin were assessed. Axonal injury, reduction of myelin deposition and accumulation of inflammatory cells were detected in damaged nerve. A decrease of phosphorylated 200-kDa neurofilament (NFP) immunoreactivity and a redistribution in small clusters of myelin basic like-protein (MBP) were observed in ipsilateral nerves. Treatment with ALCAR (100 mg/kg intraperitoneally - i.p.) and gabapentin (70 mg/kg i.p.) administered bis in die for 14 days induced a significant pain relieving effect. ALCAR, but not gabapentin, significantly countered neuromorphological changes and increased axonal NFP immunoreactivity. These findings indicate that both ALCAR and gabapentin significantly decreased the hypersensitivity related to neuropathic lesions. The observation of the positive ALCAR effect on axonal and myelin sheath alterations in damaged nerve supports its use as neurorestorative agent against neuropathies through mechanism(s) consistent to those focused in this study. Related Articles | Metrics

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End-to-end and end-to-side neurorrhaphy between thick donor nerves and thin recipient nerves: an axon regeneration study in a rat model Tohru Tateshita, Kazuki Ueda, Akiyoshi Kajikawa 2018, 13 (4):  699-703.  doi: 10.4103/1673-5374.230296 Abstract ( 128 )   PDF (1730KB) ( 388 )   Save During nerve reconstruction, nerves of different thicknesses are often sutured together using end-to-side neurorrhaphy and end-to-end neurorrhaphy techniques. In this study, the effect of the type of neurorrhaphy on the number and diameter of regenerated axon fibers was studied in a rat facial nerve repair model. An inflow-type end-to-side and end-to-end neurorrhaphy model with nerve stumps of different thicknesses (2:1 diameter ratio) was created in the facial nerve of 14 adult male Sprague-Dawley rats. After 6 and 12 weeks, nerve regeneration was evaluated in the rats using the following outcomes: total number of myelinated axons, average minor axis diameter of the myelinated axons in the central and peripheral sections, and axon regeneration rate. End-to-end neurorrhaphy resulted in a significantly greater number of regenerated myelinated axons and rate of regeneration after 6 weeks than end-to-side neurorrhaphy; however, no such differences were observed at 12 weeks. While the regenerated axons were thicker at 12 weeks than at 6 weeks, no significant differences in axon fiber thickness were detected between end-to-end and end-toside neurorrhaphy. Thus, end-to-end neurorrhaphy resulted in greater numbers of regenerated axons and increased axon regeneration rate during the early postoperative period. As rapid reinnervation is one of the most important factors influencing the restoration of target muscle function, we conclude that end-to-end neurorrhaphy is desirable when suturing thick nerves to thin nerves. Related Articles | Metrics

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Brain remodeling after chronic median nerve compression in a rat model Bing-Bo Bao, Dan-Qian Qu, Hong-Yi Zhu, Tao Gao, Xian-You Zheng 2018, 13 (4):  704-708.  doi: 10.4103/1673-5374.230298 Abstract ( 153 )   PDF (673KB) ( 191 )   Save Carpal tunnel syndrome is the most common compressive neuropathy, presenting with sensorimotor dysfunction. In carpal tunnel syndrome patients, irregular afferent signals on functional magnetic resonance imaging are associated with changes in neural plasticity during peripheral nerve injury. However, it is difficult to obtain multi-point neuroimaging data of the brain in the clinic. In the present study, a rat model of median nerve compression was established by median nerve ligation, i.e., carpal tunnel syndrome model. Sensory cortex remodeling was determined by functional magnetic resonance imaging between normal rats and carpal tunnel syndrome models at 2 weeks and 2 months after operation. Stimulation of bilateral paws by electricity for 30 seconds, alternating with 30 seconds of rest period (repeatedly 3 times), resulted in activation of the contralateral sensorimotor cortex in normal rats. When carpal tunnel syndrome rats received this stimulation, the contralateral cerebral hemisphere was markedly activated at 2 weeks after operation, including the primary motor cortex, cerebellum, and thalamus. Moreover, this activation was not visible at 2 months after operation. These findings suggest that significant remodeling of the cerebral cortex appears at 2 weeks and 2 months after median nerve compression. Related Articles | Metrics

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Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer’s disease Ya-Ru Wen, Jun-Hua Yang, Xiao Wang, Zhi-Bin Yao 2018, 13 (4):  709-716.  doi: 10.4103/1673-5374.230299 Abstract ( 145 )   PDF (2798KB) ( 285 )   Save Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer’s disease. The therapeutic effect of current pharmacotherapies is unsatisfactory, and some treatments cause severe side effects. The meningeal lymphatic vessels might be a new route for amyloid-β clearance. This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain. First, human lymphatic endothelial cells were treated with 100 ng/mL recombinant human vascular endothelial growth factor-C (rhVEGF-C) protein. Light microscopy verified that rhVEGF-C, a specific ligand for vascular endothelial growth factor receptor-3 (VEGFR-3), significantly promoted tube formation of human lymphatic endothelial cells in vitro. In an in vivo study, 200 μg/mL rhVEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice, once every 2 days, four times in total. Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer’s disease mice. One week after rhVEGF-C administration, enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain. The Morris water maze test demonstrated that spatial cognition was restored. These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice, suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer’s disease. Related Articles | Metrics

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Intracerebroventricularly-administered 1-methyl-4-phenylpyridinium ion and brain-derived neurotrophic factor affect catecholaminergic nerve terminals and neurogenesis in the hippocampus, striatum and substantia nigra Jun-Fang Chen, Man Wang, Ying-Han Zhuang, Thomas Behnisch 2018, 13 (4):  717-726.  doi: 10.4103/1673-5374.230300 Abstract ( 126 )   PDF (3459KB) ( 274 )   Save Parkinson’s disease is a progressive neurological disease characterized by the degeneration of dopaminergic neurons in the substantia nigra. A highly similar pattern of neurodegeneration can be induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium ion (MPP+), which cause the death of dopaminergic neurons. Administration of MPTP or MPP+ results in Parkinson’s disease-like symptoms in rodents. However, it remains unclear whether intracerebroventricular MPP+ administration affects neurogenesis in the substantia nigra and subgranular zone or whether brain-derived neurotrophic factor alters the effects of MPP+. In this study, MPP+ (100 nmol) was intracerebroventricularly injected into mice to model Parkinson’s disease. At 7 days after administration, the number of bromodeoxyuridine (BrdU)-positive cells in the subgranular zone of the hippocampal dentate gyrus increased, indicating enhanced neurogenesis. In contrast, a reduction in BrdU-positive cells was detected in the substantia nigra. Administration of brain-derived neurotrophic factor (100 ng) 1 day after MPP+ administration attenuated the effect of MPP+ in the subgranular zone and the substantia nigra. These findings reveal the complex interaction between neurotrophic factors and neurotoxins in the Parkinsonian model that result in distinct effects on the catecholaminergic system and on neurogenesis in different brain regions. Related Articles | Metrics

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"Structural neural connectivity of the vestibular nuclei in the human brain: a diffusion tensor imaging study Sung Ho Jang, Mi Young Lee, Sang Seok Yeo, Hyeok Gyu Kwon 2018, 13 (4):  727-730.  doi: 10.4103/1673-5374.230304 Abstract ( 147 )   PDF (454KB) ( 273 )   Save Many animal studies have reported on the neural connectivity of the vestibular nuclei (VN). However, little is reported on the structural neural connectivity of the VN in the human brain. In this study, we attempted to investigate the structural neural connectivity of the VN in 37 healthy subjects using diffusion tensor tractography. A seed region of interest was placed on the isolated VN using probabilistic diffusion tensor tractography. Connectivity was defined as the incidence of connection between the VN and each brain region. The VN showed 100% connectivity with the cerebellum, thalamus, oculomotor nucleus, trochlear nucleus, abducens nucleus, and reticular formation, irrespective of thresholds. At the threshold of 5 streamlines, the VN showed connectivity with the primary motor cortex (95.9%), primary somatosensory cortex (90.5%), premotor cortex (87.8%), hypothalamus (86.5%), posterior parietal cortex (75.7%), lateral prefrontal cortex (70.3%), ventromedial prefrontal cortex (51.4%), and orbitofrontal cortex (40.5%), respectively. These results suggest that the VN showed high connectivity with the cerebellum, thalamus, oculomotor nucleus, trochlear nucleus, abducens nucleus, and reticular formation, which are the brain regions related to the functions of the VN, including equilibrium, control of eye movements, conscious perception of movement, and spatial orientation. Related Articles | Metrics

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Compound of icariin, astragalus, and puerarin mitigates iron overload in the cerebral cortex of Alzheimer’s disease mice Yu Zhang, Wei-Na Kong, Xi-Qing Chai 2018, 13 (4):  731-736.  doi: 10.4103/1673-5374.230302 Abstract ( 128 )   PDF (402KB) ( 237 )   Save Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer’s disease. Icariin, astragalus, and puerarin have been shown to suppress iron overload in the cerebral cortex and improve spatial learning and memory disorders in Alzheimer’s disease mice, although the underlying mechanism remains unclear. In the present study, APPswe/PS1ΔE9 transgenic mice were administered icariin, astragalus, and puerarin (120, 80, and 80 mg/kg, respectively, once a day, for 3 months). Iron levels were detected by flame atomic absorption spectroscopy. Interleukin-1β, interleukin-6, and tumor necrosis factor-α levels were measured in the cerebral cortex by enzyme linked immunosorbent assay. Glutathione peroxidase and superoxide dismutase activity and malondialdehyde content were determined by colorimetry. Our results demonstrate that after treatment, iron levels and malondialdehyde content are decreased, while glutathione peroxidase and superoxide dismutase activities are increased. Further, interleukin-1β, interleukin-6, and tumor necrosis factor-α levels were reduced. These results confirm that compounds of icariin, astragalus, and puerarin may alleviate iron overload by reducing oxidative stress and the inflammatory response Related Articles | Metrics

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Alpha-7 nicotinic acetylcholine receptor agonist treatment in a rat model of Huntington’s disease and involvement of heme oxygenase-1 Laura Foucault-Fruchard, Claire Tronel, Sylvie Bodard, Zuhal Gulhan, Julie Busson, Sylvie Chalon, Daniel Antier 2018, 13 (4):  737-741.  doi: 10.4103/1673-5374.230301 Abstract ( 117 )   PDF (390KB) ( 291 )   Save Neuroinflammation is a common element involved in the pathophysiology of neurodegenerative diseases. We recently reported that repeated alpha-7 nicotinic acetylcholine receptor (α7nAChR) activations by a potent agonist such as PHA 543613 in quinolinic acid-injured rats exhibited protective effects on neurons. To further investigate the underlying mechanism, we established rat models of early-stage Huntington’s disease by injection of quinolinic acid into the right striatum and then intraperitoneally injected 12 mg/kg PHA 543613 or sterile water, twice a day during 4 days. Western blot assay results showed that the expression of heme oxygenase-1 (HO-1), the key component of the cholinergic anti-inflammatory pathway, in the right striatum of rat models of Huntington’s disease subjected to intraperitoneal injection of PHA 543613 for 4 days was significantly increased compared to the control rats receiving intraperitoneal injection of sterile water, and that the increase in HO-1 expression was independent of change in α7nAChR expression. These findings suggest that HO-1 expression is unrelated to α7nAChR density and the increase in HO-1 expression likely contributes to α7nAChR activation-related neuroprotective effect in early-stage Huntington’s disease. Related Articles | Metrics

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Use of curcumin in diagnosis, prevention, and treatment of Alzheimer’s disease Min Chen, Zhi-Yun Du, Xi Zheng, Dong-Li Li, Ren-Ping Zhou, Kun Zhang 2018, 13 (4):  742-752.  doi: 10.4103/1673-5374.230303 Abstract ( 227 )   PDF (617KB) ( 947 )   Save This review summarizes and describes the use of curcumin in diagnosis, prevention, and treatment of Alzheimer’s disease. For diagnosis of Alzheimer’s disease, amyloid-β and highly phosphorylated tau protein are the major biomarkers. Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β. Because of its multi-target effects, curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease, hypertension, and hyperlipidemia. For prevention and treatment of Alzheimer’s disease, curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels, mitochondria, and synapses, reduce risk factors for a variety of chronic diseases, and decrease the risk of Alzheimer’s disease. The effect of curcumin on Alzheimer’s disease involves multiple signaling pathways: anti-amyloid and metal iron chelating properties, antioxidation and anti-inflammatory activities. Indeed, there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer’s disease. Related Articles | Metrics