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15 September 2018, Volume 13 Issue 9 Previous Issue    Next Issue

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Neuroprotection by immunomodulatory agents in animal models of Parkinson’s disease Bridget Martinez, Philip V. Peplow 2018, 13 (9):  1493-1506.  doi: 10.4103/1673-5374.237108 Abstract ( 99 )   PDF (616KB) ( 171 )   Save Parkinson’s disease (PD) is an age-related neurodegenerative disease for which the characteristic motor symptoms emerge after an extensive loss of dopamine containing neurons. The cell bodies of these neurons are present in the substantia nigra, with the nerve terminals being in the striatum. Both innate and adaptive immune responses may contribute to dopaminergic neurodegeneration and disease progression is potentially linked to these. Studies in the last twenty years have indicated an important role for neuroinflammation in PD through degeneration of the nigrostriatal dopaminergic pathway. Characteristic of neuroinflammation is the activation of brain glial cells, principally microglia and astrocytes that release various soluble factors. Many of these factors are proinflammatory and neurotoxic and harmful to nigral dopaminergic neurons. Recent studies have identified several different agents with immunomodulatory properties that protected dopaminergic neurons from degeneration and death in animal models of PD.All of the agents were effective in reducing the motor deficit and alleviating dopaminergic neurotoxicity and, when measured, preventing the decrease of dopamine upon being administered therapeutically after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine, rotenone-lesioning or delivery of adeno-associated virus-α-synuclein to the ventral midbrain of animals. Some of these agents were shown to exert an anti-inflammatory action, decrease oxidative stress, and reduce lipid peroxidation products.Activation of microglia and astrocytes was also decreased, as well as infiltration of T cells into the substantia nigra. Pretreatment with fingolimod, tanshinoine I, dimethyl fumarate, thalidomide, or cocaine- and amphetamine-regulated transcript peptide as a preventive strategy ameliorated motor deficits and nigral dopaminergic neurotoxicity in brain-lesioned animals. Immunomodulatory agents could be used to treat patients with early clinical signs of the disease or potentially even prior to disease onset in those identified as having pre-disposing risk, including genetic factors. Related Articles | Metrics

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Role of nuclear factor κB in multiple sclerosis and experimental autoimmune encephalomyelitis Yuan Yue, Sarrabeth Stone, Wensheng Lin 2018, 13 (9):  1507-1515.  doi: 10.4103/1673-5374.237109 Abstract ( 102 )   PDF (462KB) ( 223 )   Save The transcription factor nuclear factor κB (NF-κB) plays major roles in inflammatory diseases through regulation of inflammation and cell viability. Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients, including T cells, microglia/macrophages, astrocytes, oligodendrocytes, and neurons. Interestingly, data from animal model studies, particularly studies of experimental autoimmune encephalomyelitis (EAE), have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS. In this review, we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model EAE. Related Articles | Metrics

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Nanometer ultrastructural brain damage following low intensity primary blast wave exposure Hailong Song, Landry M. Konan, Jiankun Cui, Catherine E. Johnson, Graham K. Hubler, Ralph G. DePalma, Zezong Gu 2018, 13 (9):  1516-1519.  doi: 10.4103/1673-5374.237110 Abstract ( 144 )   PDF (361KB) ( 167 )   Save Blast-induced mild traumatic brain injury (mTBI) is of particular concern among military personnel due to exposure to blast energy during military training and combat. The impact of primary low-intensity blast mediated pathophysiology upon later neurobehavioral disorders has been controversial. Developing a military preclinical blast model to simulate the pathophysiology of human blast injury is an important first step. This article provides an overview of primary blast effects and perspectives of our recent studies demonstrating ultrastructural changes in the brain and behavioral disorders resulting from open-field blast exposures up to 46.6 kPa using a murine model. The model is scalable and permits exposure to varying magnitudes of primary blast injuries by placing animals at different distances from the blast center or by changing the amount of C4 charge. We here review the implications and future applications and directions of using this animal model to uncover the underlying mechanisms related to primary blast injury. Overall, these studies offer the prospect of enhanced understanding of the pathogenesis of primary low-intensity blast-induced TBI and insights for prevention, diagnosis and treatment of blast induced TBI, particularly mTBI/concussion related to current combat exposures. Related Articles | Metrics

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Seeing the wood for the trees: towards improved quantification of glial cells in central nervous system tissue Sinéad Healy, Jill McMahon, Una FitzGerald 2018, 13 (9):  1520-1523.  doi: 10.4103/1673-5374.235222 Abstract ( 117 )   PDF (797KB) ( 134 )   Save The following mini-review attempts to guide researchers in the quantification of fluorescently-labelled proteins within cultured thick or chromogenically-stained proteins within thin sections of brain tissue. It follows from our examination of the utility of Fiji ImageJ thresholding and binarization algorithms. Describing how we identified the maximum intensity projection as the best of six tested for two dimensional (2D)-rendering of three-dimensional (3D) images derived from a series of z-stacked micrographs, the review summarises our comparison of 16 global and 9 local algorithms for their ability to accurately quantify the expression of astrocytic glial fibrillary acidic protein (GFAP), microglial ionized calcium binding adapter molecule 1 (IBA1) and oligodendrocyte lineage Olig2 within fixed cultured rat hippocampal brain slices. The application of these algorithms to chromogenically-stained GFAP and IBA1 within thin tissue sections, is also described. Fiji’s BioVoxxel plugin allowed categorisation of algorithms according to their sensitivity, specificity accuracy and relative quality. The Percentile algorithm was deemed best for quantifying levels of GFAP, the Li algorithm was best when quantifying IBA expression, while the Otsu algorithm was optimum for Olig2 staining, albeit with over-quantification of oligodendrocyte number when compared to a stereological approach. Also, GFAP and IBA expression in 3,3’-diaminobenzidine (DAB)/haematoxylin-stained cerebellar tissue was best quantified with Default, Isodata and Moments algorithms. The workflow presented in Figure 1 could help to improve the quality of research outcomes that are based on the quantification of protein with brain tissue. Related Articles | Metrics

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Altered leukocyte gene expression after traumatic spinal cord injury: clinical implications Paige E. Herman, Ona Bloom 2018, 13 (9):  1524-1529.  doi: 10.4103/1673-5374.237112 Abstract ( 122 )   PDF (976KB) ( 146 )   Save In addition to changes in motor and sensory function, individuals with spinal cord injury (SCI) experience immunological changes. These changes are clinically significant, as infections are the leading cause of death for this population. Along with increased infections, inflammation is commonly observed in persons with SCI, where it may promote many common medical consequences. These include elevated risk of cardiovascular disease, impaired wound healing, diabetes and neuropathic pain. It has also been proposed that chronic inflammation dampens neurological recovery. In order to identify therapeutic strategies to improve immune function, we need a greater understanding of the molecular changes that occur in immune cells after SCI. The purpose of this mini-review is to discuss two recent studies that used functional genomics to investigate gene expression in circulating leukocytes isolated from persons with SCI. In the future, the molecular pathways that are altered after SCI may be targeted to improve immunological function, as well as overall health and functional recovery, after SCI. Related Articles | Metrics

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Promoting axonal regeneration following nerve surgery: a perspective on ultrasound treatment for nerve injuries Konstantin D. Bergmeister, Simeon C. Daeschler, Patrick Rhodius, Philipp Schoenle, Arne Böcker, Ulrich Kneser, Leila Harhaus 2018, 13 (9):  1530-1533.  doi: 10.4103/1673-5374.237113 Abstract ( 123 )   PDF (263KB) ( 137 )   Save Nerve injury is often associated with limited axonal regeneration and thus leads to delayed or incomplete axonal reinnervation. As a consequence of slow nerve regeneration, target muscle function is often insufficient and leads to a lifelong burden. Recently, the diagnosis of nerve injuries has been improved and likewise surgical reconstruction has undergone significant developments. However, the problem of slow nerve regeneration has not been solved. In a recent meta-analysis, we have shown that the application of low-intensity ultrasound promotes nerve regeneration experimentally and thereby can improve functional outcomes. Here we want to demonstrate the experimental effect of low intensity ultrasound on nerve regeneration,the current state of investigations and its possible future clinical applications. Related Articles | Metrics

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Schwann cell Myc-interacting zinc-finger protein 1 without pox virus and zinc finger: epigenetic implications in a peripheral neuropathy David Fuhrmann, Hans-Peter Elsässer 2018, 13 (9):  1534-1537.  doi: 10.4103/1673-5374.235221 Abstract ( 126 )   PDF (762KB) ( 204 )   Save Functionality of adult peripheral nerves essentially relies on differentiation of Schwann cells during postnatal development, as well as fine-tuned re- and transdifferentiation in response to peripheral nerve injury. Epigenetic histone modifications play a major role during the differentiation of embryonic stem cells and diverse organ specific progenitor cells, yet only little is known about the epigenetic regulation of Schwann cells. Just recently, Fuhrmann et al. reported how the transcription factor Myc-interacting zinc-finger protein 1 (Miz1) might contribute to Schwann cell differentiation through repression of the histone demethylase Kdm8. Here, we discuss the potential novel role of Miz1 in Schwann cell differentiation and give a short overview about previously reported histone modifications underlying peripheral nerve development and response to injury. Related Articles | Metrics

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Utilizing zebrafish and okadaic acid to study Alzheimer’s disease Daniel Koehler, Frederick E. Williams 2018, 13 (9):  1538-1541.  doi: 10.4103/1673-5374.237111 Abstract ( 118 )   PDF (152KB) ( 180 )   Save Despite the many years of extensive research using rodent models to study Alzheimer’s disease (AD) no cure or disease halting drug exists. An increasing number of people are suffering from the disease and a therapeutic intervention is needed. Therefore, it is necessary to have complementary models to aid in the drug discovery. The zebrafish animal model is emerging as a valuable model for the investigation of AD and neurodegenerative drug discovery. The main genes involved in human AD have homologous counterparts in zebrafish and have conserved function. The basic brain structure of the zebrafish is also conserved when compared to the mammalian brain. Recently an AD model was established by administering okadaic acid (OKA) to zebrafish. It was used to test the efficacy of a novel drug, lanthionine ketimine-5-ethyl ester, and to elucidate its mechanism of action. This demonstrated the ability of the OKA-induced AD zebrafish model to be implemented in the drug discovery process for therapeutics against AD. Related Articles | Metrics

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The emerging epigenetics of PARK7 and its implication in neurodegenerative disease George D. Vavougios, Sotirios G. Zarogiannis 2018, 13 (9):  1542-1543.  doi: 10.4103/1673-5374.237117 Abstract ( 158 )   PDF (144KB) ( 178 )   Save PARK7/DJ-1 is a multifunctional protein that acts as a regulator in stress responsive cascades. Since its original discovery as a novel oncogene, DJ-1 was further implicated in the correspondingly dubbed PARK7 autosomal recessive early onset Parkinson’s Disease variant, expanding the spectrum of its pathophysiology to neurodegenerative disease. DJ-1’s physiological roles have correspondingly expanded in the literature, effectively revealing an almost ubiquitous presence in cellular compartments and tissues.DJ-1’s functions mediate a diverse armamentarium of cytoprotective effects such as RNA binding, SUMOylation, androgen receptor binding, and regulation of mitochondrial dynamics as well as a recently discovered deglycase activity. Related Articles | Metrics

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Real world studies are essential for drug therapy in Parkinson’s disease Thomas Müller 2018, 13 (9):  1544-1545.  doi: 10.4103/1673-5374.237118 Abstract ( 108 )   PDF (145KB) ( 149 )   Save Prospective real-world data from large patient samples, which report on the long-term effectiveness of the employed different drug therapies, are rare in Parkinson’s disease (PD). The non interventional “Transdermal Rotigotine User Surveillance Study” (TRUST) trial represents such a real-world study. It investigated long-term treatment with different dopamine substituting treatment regimens in 2195 PD patients. Participation in TRUST meant that the treating neurologists were only asked to document and modify the dopaminergic drug regimen without any prior PD patient selection criteria. Thus this unique trial design reflects the real world of patient maintenance. The only intention was to follow patients in a 5:2:2:5:2 ratio for 1) rotigotine without levodopa,2) other dopamine agonists without levodopa (i.e., ropinirole,pramipexole, or other oral dopamine agonist, 3) levodopa without dopamine agonists, 4) levodopa in combination with rotigotine, or 5) levodopa in combination with other dopamine agonists. Patients were observed for ≤ 33 months.~44% of patients received the same treatment over the full duration of their participation in the study. Beneficial effects were observed with all the different therapeutic strategies employed. No clear cut differences were found. Related Articles | Metrics

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Cerebrospinal fluid and neural stem cell niche control Mª Isabel Alonso, Angel Gato 2018, 13 (9):  1546-1547.  doi: 10.4103/1673-5374.237114 Abstract ( 109 )   PDF (268KB) ( 280 )   Save Neurogenesis from inner brain neural stem cells (NSCs) is a process which takes place continuously in mammals throughout their life. However, the main ontogenic difference is the intensity of neurogenesis, which commences as a very intensive and global activity in the early embryonic brain (neural tube), persists in fetal and newborn stages, and declines significantly in adulthood, becoming restricted to specific places with low neurogenic activity such as the subventricular zone (SVZ) and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus. Related Articles | Metrics

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Regulation of neural stem cell fate decisions by mitochondrial dynamics Matthew Laaper, Arezu Jahani-Asl 2018, 13 (9):  1548-1549.  doi: 10.4103/1673-5374.237115 Abstract ( 166 )   PDF (264KB) ( 164 )   Save Stem cells possess the ability to divide symmetrically or asymmetrically to allow for maintenance of the stem cell pool or become committed progenitors and differentiate into various cell lineages.The unique self-renewal capabilities and pluripotency of stem cells are integral to tissue regeneration and repair . Multiple mechanisms including intracellular programs and extrinsic cues are reported to regulate neural stem cell (NSC) fate. A recent study, published in Cell Stem Cell, identified a novel mechanism whereby mitochondrial dynamics drive NSC fate. Related Articles | Metrics

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A radical scavenger edaravone and oligodendrocyte protection/regenerati Hajime Takase, Josephine Lok, Ken Arai 2018, 13 (9):  1550-1551.  doi: 10.4103/1673-5374.237116 Abstract ( 122 )   PDF (377KB) ( 187 )   Save Cerebral white matter is vulnerable to oxidative stress: Oxidative stress is one of the major harmful conditions for the central nervous system (CNS). Oxidative stress is a state from an imbalance between free radical production and their removal by antioxidants,resulting in an excessive amount of reactive oxygen species (ROS) in cells and tissues. ROS causes cell damage due to oxidation of cellular components, including DNAs, proteins, and lipids. During physiological conditions, small amounts of ROS are generated in the process of normal biological activity, and ROS at physiological levels play important roles in maintaining cellular homeostasis. However, during pathological conditions, ROS levels are increased and excessive ROS can lead to deleterious effects on many kinds of cells. Related Articles | Metrics

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Mitochondrial division inhibitor 1 protects cortical neurons from excitotoxicity: a mechanistic pathway Kuai Zhou, Hai-Yuan Yang, Peng-Yu Tang, Wei Liu, Yong-Jun Luo, Bin Lv, Jian Yin, Tao Jiang, Jian Chen, Wei-Hua Cai, Jin Fan 2018, 13 (9):  1552-1560.  doi: 10.4103/1673-5374.235299 Abstract ( 159 )   PDF (1704KB) ( 248 )   Save Mitochondrial division inhibitor 1 (Mdivi-1) is a selective cell-permeable inhibitor of dynamin-related protein-1 (Drp1) and mitochondrial division. To investigate the effect of Mdivi-1 on cells treated with glutamate, cerebral cortex neurons isolated from neonatal rats were treated with 10 mM glutamate for 24 hours. Normal cultured cells and dimethyl sulfoxide-cultured cells were considered as controls. Apoptotic cells were detected by flow cytometry. Changes in mitochondrial morphology were examined by electron microscopy. Drp1, Bax, and casp ase-3 expression was evaluated by western blot assays and immunocytochemistry. Mitochondrial membrane potential was detected using the JC-1 probe. Twenty-four hours after 10 mM glutamate treatment, Drp1, Bax and caspase-3 expression was upregulated, Drp1 and Bax were translocated to mitochondria, mitochondrial membrane potential was decreased and the rate of apoptosis was increased. These effects were inhibited by treatment with 50 μM Mdivi-1 for 2 hours. This finding indicates that Mdivi-1 is a candidate neuroprotective drug that can potentially mitigate against neuronal injury caused by glutamate-induced excitotoxicity. Related Articles | Metrics

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3′-Daidzein sulfonate sodium protects against memory impairment and hippocampal damage caused by chronic cerebral hypoperfusion Xiao Li, Rui-Zhen Liu, Qi Zeng, Zhi-Hua Huang, Jian-Dong Zhang, Zong-Liang Liu, Jing Zeng, Hai Xiao 2018, 13 (9):  1561-1567.  doi: 10.4103/1673-5374.237119 Abstract ( 171 )   PDF (4463KB) ( 362 )   Save 3′-Daidzein sulfonate sodium (DSS) is a new synthetic water-soluble compound derived from daidzein, a soya isoflavone that plays regulatory roles in neurobiology. In this study, we hypothesized that the regulatory role of DSS in neurobiology exhibits therapeutic effects on hippocampal damage and memory impairment. To validate this hypothesis, we established rat models of chronic cerebral hypoperfusion (CCH) by the permanent occlusion of the common carotid arteries using the two-vessel occlusion method. Three weeks after modeling,rat models were intragastrically administered 0.1, 0.2, and 0.4 mg/kg DSS, once a day, for 5 successive weeks. The Morris water maze test was performed to investigate CCH-induced learning and memory deficits. TUNEL assay was used to analyze apoptosis in the hippocampal CA1, CA3 regions and dentate gyrus. Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal CA1, CA3 regions and dentate gyrus. Western blot analysis was performed to investigate the phosphorylation of PKA, ERK1/2 and CREB in the hippocampal PKA/ERK1/2/CREB signaling pathway. Results showed that DSS treatment greatly improved the learning and memory deficits of rats with CCH, reduced apoptosis of neurons in the hippocampal CA1, CA3 regions and dentate gyrus, and increased the phosphorylation of PKA, ERK1/2, and CREB in the hippocampus. These findings suggest that DSS protects against CCH-induced memory impairment and hippocampal damage possibly through activating the PKA/ERK1/2/CREB signaling pathway. Related Articles | Metrics

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Aminooxyacetic acid improves learning and memory in a rat model of chronic alcoholism Ai-Lin Du, Hao-Zhi Qin, Hong-Bo Jiang, Peng-Yan Fu, Ke Lou, Yu-Ming Xu 2018, 13 (9):  1568-1574.  doi: 10.4103/1673-5374.237120 Abstract ( 172 )   PDF (1240KB) ( 283 )   Save Chronic alcoholism seriously damages the central nervous system and leads to impaired learning and memory. Cell damage in chronic alcoholism is strongly associated with elevated levels of hydrogen sulfide (H2S) and calcium ion overload. Aminooxyacetic acid is a cystathionine-β-synthase activity inhibitor that can reduce H2S formation in the brain. This study sought to observe the effect of aminooxyacetic acid on learning and memory in a chronic alcoholism rat model. Rats were randomly divided into three groups. Rats in the control group were given pure water for 28 days. Rats in the model group were given 6% alcohol for 28 days to establish an alcoholism rat model. Rats in the aminooxyacetic acid remedy group were also given 6% alcohol for 28 days and were also intraperitoneally injected daily with aminooxyacetic acid (5 mg/kg) from day 15 to day 28. Learning and memory was tested using the Morris water maze test. The ultrastructure of mitochondria in the hippocampus was observed by electron microscopy. H2S levels in the hippocampus were measured indirectly by spectrophotometry, and ATPase activity was measured using a commercial kit. The expression of myelin basic protein was determined by immunohistochemistry and western blotting. Compared with the control group, latency and swimming distance were prolonged in the navigation test on days 2, 3, and 4 in the model group. In the spatial probe test on day 5, the number of platform crosses was reduced in the model group. Cristae cracks, swelling or deformation of mitochondria appeared in the hippocampus, the hippocampal H2S level was increased, the mitochondrial ATPase activity was decreased, and the expression of myelin basic protein in the hippocampus was down-regulated in the model group compared with the control group. All the above indexes were ameliorated in the aminooxyacetic acid remedy group compared with the model group. These findings indicate that aminooxyacetic acid can improve learning and memory in a chronic alcoholism rat model, which may be associated with reduction of hippocampal H2S level and mitochondrial ATPase activity, and up-regulation of myelin basic protein levels in the hippocampus. Related Articles | Metrics

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High-concentration sevoflurane exposure in mid-gestation induces apoptosis of neural stem cells in rat offspring Yuan Wang, Shao-Wei Yin, Nan Zhang, Ping Zhao 2018, 13 (9):  1575-1584.  doi: 10.4103/1673-5374.237121 Abstract ( 144 )   PDF (1697KB) ( 174 )   Save Sevoflurane is the most commonly used volatile anesthetic during pregnancy. The viability of neural stem cells directly affects the development of the brain. However, it is unknown whether the use of sevoflurane during the second trimester affects the survival of fetal neural stem cells. Therefore, in this study, we investigated whether exposure to sevoflurane in mid-gestation induces apoptosis of neural stem cells and behavioral abnormalities. On gestational day 14, pregnant rats were anesthetized with 2% or 3.5% sevoflurane for 2 hours.The offspring were weaned at 28 days and subjected to the Morris water maze test. The brains were harvested to examine neural stem cell apoptosis by immunofluorescence and to measure Nestin and SOX-2 levels by western blot assay at 6, 24 and 48 hours after anesthesia as well as on postnatal day (P) 0, 14 and 28. Vascular endothelial growth factor (VEGF) and phosphoinositide 3-kinase (PI3K)/AKT pathway protein levels in fetal brain at 6 hours after anesthesia were assessed by western blot assay. Exposure to high-concentration (3.5%) sevoflurane during mid-gestation increased escape latency and path length to the platform, and it reduced the average duration spent in the target quadrant and platform crossing times. At 6, 24 and 48 hours after anesthesia and at P0, P14 and P28, the percentage of Nestin/terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells was increased, but Nestin and SOX-2 protein levels were decreased in the hippocampus of the offspring. At 6 hours after anesthesia, VEGF, PI3K and phospho-AKT (p-AKT) levels were decreased in the fetal brain. These changes were not observed in animals given low-concentration (2%) sevoflurane exposure. Together, our findings indicate that exposure to a high concentration of sevoflurane (3.5%) in mid-gestation decreases VEGF, PI3K and p-AKT protein levels and induces neural stem cell apoptosis, thereby causing learning and memory dysfunction in the offspring. Related Articles | Metrics

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Limb remote ischemic postconditioning protects integrity of the blood-brain barrier after stroke Juan Li, Xiao-Song Hu, Fang-Fang Zhou, Shuai Li, You-Sheng Lin, Wen-Qian Qi, Cun-Fang Qi, Xiao Zhang 2018, 13 (9):  1585-1593.  doi: 10.4103/1673-5374.237122 Abstract ( 134 )   PDF (1735KB) ( 259 )   Save Integrity of the blood-brain barrier structure is essential for maintaining the internal environment of the brain. Development of cerebral infarction and brain edema is strongly associated with blood-brain barrier leakage. Therefore, studies have suggested that protecting the blood-brain barrier may be an effective method for treating acute stroke. To examine this possibility, stroke model rats were established by middle cerebral artery occlusion and reperfusion. Remote ischemic postconditioning was immediately induced by three cycles of 10-minute ischemia/10-minute reperfusion of bilateral hind limbs at the beginning of middle cerebral artery occlusion reperfusion. Neurological function of rat models was evaluated using Zea Longa’s method. Permeability of the blood-brain barrier was assessed by Evans blue leakage. Infarct volume and brain edema were evaluated using 2,3,5-triphenyltetrazolium chloride staining. Expression of matrix metalloproteinase-9 and claudin-5 mRNA was determined by real-time quantitative reverse transcription-polymerase chain reaction. Expression of matrix metalloproteinase-9 and claudin-5 protein was measured by western blot assay. The number of matrix metalloproteinase-9- and claudin-5-positive cells was analyzed using immunohistochemistry. Our results showed that remote ischemic postconditioning alleviated disruption of the blood-brain barrier, reduced infarct volume and edema, decreased expression of matrix metalloproteinase-9 mRNA and protein and the number of positive cells, increased expression of claudin-5 mRNA and protein and the number of positive cells, and remarkably improved neurological function. These findings confirm that by suppressing expression of matrix metalloproteinase-9 and claudin-5 induced by acute ischemia/reperfusion, remote ischemic postconditioning reduces blood-brain barrier injury, mitigates ischemic injury, and exerts protective effects on the brain. Related Articles | Metrics

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Electroacupuncture exerts neuroprotective effects on ischemia/reperfusion injury in JNK knockout mice: the underlying mechanism Chun-Xiao Wu, Yi-Hui Feng, Lu Yang, Zhu-Lian Zhan, Xiu-Hong Xu, Xiao-Ying Hu, Zhi-Hua Zhu, Guo-Ping Zhou 2018, 13 (9):  1594-1601.  doi: 10.4103/1673-5374.235294 Abstract ( 143 )   PDF (1038KB) ( 243 )   Save Simple regulation of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase (MAPK) pathways is not enough to trigger cell apoptosis. However, activation of the stress activated pathway (JNK/p38 MAPK) together with inhibition of the growth factor activated extracellular signal-regulated kinase (ERK) pathway can promote cell apoptosis. We hypothesized that inhibition of the JNK or p38 pro-apoptotic pathway and activating the ERK pathway could be the mechanism of anti-apoptosis following cerebral ischemia/reperfusion injury. To investigate the mechanism of the protective effect of electroacupuncture on cerebral ischemia/reperfusion injury in JNK knockout mice, mouse models of cerebral ischemia/reperfusion injury were established by Longa’s method. Electroacupuncture was conducted at acupoints Chize (LU5), Hegu (LI4), Sanyinjiao (SP6) and Zusanli (ST36) 1.5 hours after ischemia/reperfusion injury for 20 minutes,once a day. The neurological function was evaluated using neurological deficit scores. The expression of phospho-extracellular signal-regulated kinase (p-ERK) and phospho-p38 (p-p38) in JNK knockout mice was detected using double-labeling immunofluorescence and western blot assay. The mRNA expression of ERK and p38 was measured by quantitative real-time polymerase chain reaction. Electroacupuncture improved neurological function, increased the immunoreactivity and relative expression of p-ERK and reduced that of p-p38 in the cerebral cortex and hippocampus on the injured side. Electroacupuncture increased mRNA expression of ERK, but decreased that of p38 in the cerebral cortex and hippocampus on the injured side. In conclusion, electroacupuncture upregulated the protective ERK pathway and inhibited the pro-apoptotic p38 pathway, thereby exerting a neuroprotective effect and improving the neurological function in JNK knockout mice. Related Articles | Metrics

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Baihui (DU20)-penetrating-Qubin (GB7) acupuncture inhibits apoptosis in the perihemorrhagic penumbra Beng Zhang, Xiao-Hong Dai, Xue-Ping Yu, Wei Zou, Wei Teng, Xiao-Wei Sun, Wei-Wei Yu, Hao Liu, Hui Wang, Meng-Juan Sun, Meng Li 2018, 13 (9):  1602-1608.  doi: 10.4103/1673-5374.237123 Abstract ( 112 )   PDF (2280KB) ( 415 )   Save Baihui (DU20)-penetrating-Qubin (GB7) acupuncture can inhibit inflammatory reactions and activate signaling pathways related to proliferation after intracerebral hemorrhage. However, there is no research showing the relationship between this treatment and cell apoptosis. Rat models of intracerebral hemorrhage were established by injecting 60 μL of autologous blood into the right side of the caudate-putamen. Six hours later, the needle traveled subcutaneously from the Baihui acupoint to Qubin acupoint. The needle was alternately rotated (180 ± 10 turns/min) manually along clockwise and counter-clockwise directions. Stimulation lasted for 7 days, and was performed three times each for 6 minutes with 6-minute intervals between stimulations. Rats intraperitoneally receiving Sonic hedgehog pathway activator, purmorphamine (1 mg/kg per day), served as positive controls. Motor and sensory function were assessed using the Ludmila Belayev test. Extent of pathological changes were measured in the perihemorrhagic penumbra using hematoxylin-eosin staining. Apoptosis was examined by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling assay. Expression of smoothened (Smo) and glioma-associated homolog 1 (Gli1) was determined by western blot assay. Our results showed that Baihui-penetrating-Qubin acupuncture promoted recovery of motor and sensory function, reduced the apoptotic cell percentage in the perihemorrhagic penumbra, and up-regulated Smo and Gli1 expression. We conclude that Baihui-penetrating-Qubin acupuncture can mitigate hemorrhage and promote functional recovery of the brain in a rat model of intracerebral hemorrhage, possibly by activating the Sonic hedgehog pathway. Related Articles | Metrics

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Electroacupuncture modulates the activity of the hippocampus-nucleus tractus solitarius-vagus nerve pathway to reduce myocardial ischemic injury Shuai Cui, Kun Wang, Sheng-Bing Wu, Guo-Qi Zhu, Jian Cao, Yi-Ping Zhou, Mei-Qi Zhou 2018, 13 (9):  1609-1618.  doi: 10.4103/1673-5374.237124 Abstract ( 305 )   PDF (1933KB) ( 264 )   Save The hippocampus is involved in the regulation of the autonomic nervous system, together with the hypothalamus and brainstem nuclei, such as the paraventricular nucleus and nucleus tractus solitarius. The vagus nerve-nucleus tractus solitarius pathway has an important role in cardiovascular reflex regulation. Myocardial ischemia has been shown to cause changes in the autonomic nervous system, affecting the dynamic equilibrium of the sympathetic and vagal nerves. However, it remains poorly understood how the hippocampus communicates with brainstem nuclei to regulate the autonomic nervous system and alleviate myocardial ischemic tissue damage. A rat model of acute myocardial ischemia (AMI) was made by ligating the left anterior descending branch of the coronary artery. Three days before ischemia, the hippocampal CA1 region was damaged. Then, 3 days after ischemia, electroacupuncture (EA) at Shenmen (HT7)-Tongli (HT5) was performed (continuous wave, 1 mA, 2 Hz, duration of 30 minutes). Cluster analysis of firing patterns showed that one type of neuron was found in rats in the sham and AMI groups. Three types of neurons were observed in the AMI + EA group. Six types of neurons were found in the AMI + EA + Lesion group. Correlation analysis showed that the frequency of vagus nerve discharge in each group was negatively correlated with heart rate (HR) (P < 0.05, r = .0.424), and positively correlated with mean arterial pressure (MAP) (P < 0.05, r = 0.40987) and the rate-pressure product (RPP) (P < 0.05, r = 0.4252). The total frequency of the nucleus tractus solitarius discharge in each group was positively correlated with vagus nerve discharge (P < 0.01, r = 0.7021), but not with hemodynamic index (HR: P > 0.05, r = .0.03263; MAP: P > 0.05, r = .0.08993; RPP: P > 0.05, r = .0.03263). Some neurons (Neuron C) were negatively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA group (vagus nerve discharge: P < 0.05, r = .0.87749; HR: P < 0.01, r = .0.91902; MAP: P < 0.05, r = .0.85691; RPP: P < 0.01, r = .0.91902). Some neurons (Neurons C, D and E) were positively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA + Lesion group (vagus nerve discharge: P < 0.01, r = 0.8905, P < 0.01, r = 0.9725, P < 0.01, r = 0.9054; HR: P < 0.01, r = 0.9347, P < 0.01, r = 0.9089, P < 0.05, r = 0.8247; MAP: P < 0.05, r = 0.8474, P < 0.01, r = 0.9691, P < 0.01, r = 0.9027; RPP: P < 0.05, r = 0.8637, P < 0.01, r = 0.9407, P < 0.01, r = 0.9027). These findings show that the hippocampus-nucleus tractus solitarius-vagus nerve pathway is involved in the cardioprotective effect of EA at the heart meridian. Some interneurons in the nucleus tractus solitarius may play a particularly important role in the cardiomodulatory process. Related Articles | Metrics

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Evidence for accuracy of pain assessment and painkillers utilization in neuropsychiatric symptoms of dementia in Calabria region, Italy Damiana Scuteri, Maria Roberta Garreffa, Stefania Esposito, Giacinto Bagetta, Maria Diana Naturale, Maria Tiziana Corasaniti 2018, 13 (9):  1619-1621.  doi: 10.4103/1673-5374.237125 Abstract ( 139 )   PDF (156KB) ( 144 )   Save During the clinical course of dementia, beside cognitive impairment and memory loss, a very complex challenge is posed by the neuropsychiatric symptoms (NPSs). Accurate evaluation and treatment of pain impacts positively the agitation of demented patients aged ≥ 65 years. To gather information on the utilization of pain killers in demented patients a preliminary survey has been conducted in collaboration with the Calabrian Pharmacovigilance Territorial Service of the health district of Catanzaro (Italy). The study has taken into consideration the prescriptions of acetylcholinesterase inhibitors and memantine during the period ranging from July 2015 to June 2016 and the percentage of patients treated against pain with nonsteroidal antinflammatory drugs, opioids, and anticonvulsants have been monitored. The latter have been evaluated statistically for difference between the treatment before (pre) and after (post) the settlement of acetylcholinesterase inhibitors (AChEI) or memantine therapy. The results do support accuracy in painkillers utilization in the course of dementia in the regional population of Calabria (Italy). Related Articles | Metrics

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Transcription factor networks involved in cell death in the dorsal root ganglia following peripheral nerve injury Jing Qin, Jian-Cheng Wu, Qi-Hui Wang, Song-Lin Zhou, Su-Su Mao, Chun Yao 2018, 13 (9):  1622-1627.  doi: 10.4103/1673-5374.237183 Abstract ( 163 )   PDF (1904KB) ( 209 )   Save The peripheral nervous system has the potential to regenerate after nerve injury owing to the intrinsic regrowth ability of neurons and the permissive microenvironment. The regenerative process involves numerous gene expression changes, in which transcription factors play a critical role. Previously, we profiled dysregulated genes in dorsal root ganglion neurons at different time points (0, 3 and 9 hours, and 1, 4 and 7 days) after sciatic nerve injury in rats by RNA sequencing. In the present study, we investigated differentially expressed transcription factors following nerve injury, and we identified enriched molecular and cellular functions of these transcription factors by Ingenuity Pathway Analysis. This analysis revealed the dynamic changes in the expression of transcription factors involved in cell death at different time points following sciatic nerve injury. In addition, we constructed regulatory networks of the differentially expressed transcription factors in cell death and identified some key transcription factors (such as STAT1, JUN, MYC and IRF7). We confirmed the changes in expression of some key transcription factors (STAT1 and IRF7) by quantitative reverse transcription-polymerase chain reaction. Collectively, our analyses provide a global overview of transcription factor changes in dorsal root ganglia after sciatic nerve injury and offer insight into the regulatory transcription factor networks involved in cell death. Related Articles | Metrics

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Proanthocyanidin B2 attenuates high-glucose-induced neurotoxicity of dorsal root ganglion neurons through the PI3K/Akt signaling pathway Yuan-Pin Zhang,Si-Yan Liu, Qian-Yu Sun, Jing Ren, Hua-Xiang Liu, Hao Li 2018, 13 (9):  1628-1636.  doi: 10.4103/1673-5374.237174 Abstract ( 177 )   PDF (1964KB) ( 184 )   Save High glucose affects primary afferent neurons in dorsal root ganglia by inhibiting neurite elongation, causing oxidative stress, and inducing neuronal apoptosis and mitochondrial dysfunction, which finally result in neuronal damage. Proanthocyanidin, a potent antioxidant, has been shown to have neuroprotective effects. Proanthocyanidin B2 is a common dimer of oligomeric proanthocyanidins. To date, no studies have reported the neuroprotective effects of proanthocyanidin B2 against high-glucose-related neurotoxicity in dorsal root ganglion neurons. In this study, 10 μg/mL proanthocyanidin B2 was used to investigate its effect on 45 mM high-glucose-cultured dorsal root ganglion neurons. We observed that challenge with high levels of glucose increased neuronal reactive oxygen species and promoted apoptosis, decreased cell viability, inhibited outgrowth of neurites, and decreased growth-associated protein 43 protein and mRNA levels. Proanthocyanidin B2 administration reversed the neurotoxic effects caused by glucose challenge. Blockage of the phosphatidylinositol 3 kinase/Akt signaling pathway with 10 μM LY294002 eliminated the protective effects of proanthocyanidin B2. Therefore, proanthocyanidin B2 might be a potential novel agent for the treatment of peripheral diabetic neuropathy. Related Articles | Metrics

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Patterns of cortical reorganization in facial synkinesis: a task functional magnetic resonance imaging study Yin Wang, Wei-Wei Wang, Xu-Yun Hua, Han-Qiu Liu, Wei Ding 2018, 13 (9):  1637-1642.  doi: 10.4103/1673-5374.235304 Abstract ( 176 )   PDF (610KB) ( 200 )   Save Facial synkinesis, a sequela of peripheral facial nerve palsy, is characterized by simultaneous involuntary facial movement during a voluntary desired one. Maladaptive cortical plasticity might be involved in the dysfunction of facial muscles. This cohort study investigated the cortical functional alterations in patients with unilateral facial synkinesis, using the task functional magnetic resonance imaging. Facial motor tasks, including blinking and smiling, were performed by 16 patients (aged 30.6 ± 4.5 years, 14 females/2 males) and 24 age- and sex-matched healthy controls (aged 29.1 ± 4.2 years, 19 females/5 males). Results demonstrated that activation in the cortico-facial motor representation area was lower during tasks in patients with facial synkinesis compared with healthy controls. Facial movements on either side performed by patients caused more intensive activation of the supplementary motor area on the contralateral side of the affected face, than those on the unaffected side. Our results revealed that there was cortical reorganization in the primary sensorimotor area and the supplementary motor area. This study was registered in Chinese Clinical Trial Registry (registration number: ChiCTR1800014630). Related Articles | Metrics

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Various changes in cryopreserved acellular nerve allografts at −80°C Yan-Yan Huang, Xiao-Lu Xu, Xi-Jun Huang, Jiang-Hui Liu, Jian Qi, Shuang Zhu, Zhao-Wei Zhu, Bo He, Qing-Tang Zhu, Yang-Bin Xu, Li-Qiang Gu, Xiao-Lin Liu 2018, 13 (9):  1643-1649.  doi: 10.4103/1673-5374.237138 Abstract ( 122 )   PDF (1532KB) ( 174 )   Save The experimental design evaluated histological, mechanical, and biological properties of allogeneic decellularized nerves after cryopreservation in a multi-angle, multi-directional manner to provide evidence for long-term preservation. Acellular nerve allografts from human and rats were cryopreserved in a cryoprotectant (10% fetal bovine serum, 10% dimethyl sulfoxide, and 5% sucrose in RPMI1640 medium) at −80°C for 1 year, followed by thawing at 40°C or 37°C for 8 minutes. The breaking force of acellular nerve allografts was measured using a tensile test. Cell survival was determined using L-929 cell suspensions. Acellular nerve allografts were transplanted into a rat model with loss of a 15-mm segment of the left sciatic nerve. Immunohistochemistry staining was used to measure neurofilament 200 expression. Hematoxylin-eosin staining was utilized to detect relative muscle area in gastrocnemius muscle. Electron microscopy was applied to observe changes in allograft ultrastructure. There was no obvious change in morphological appearance or ultrastructure, breaking force, or cytotoxicity of human acellular nerve allografts after cryopreservation at −80°C. Moreover, there was no remarkable change in neurofilament 200 expression, myelin sheath thickness, or muscle atrophy when fresh or cryopreserved rat acellular nerve allografts were applied to repair nerve injury in rats. These results suggest that cryopreservation can greatly extend the storage duration of acellular nerve tissue allografts without concomitant alteration of the physiochemical and biological properties of the engineered tissue to be used for transplantation. Related Articles | Metrics

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Saikosaponin a increases interleukin-10 expression and inhibits scar formation after sciatic nerve injury Meng-Qiang Huang, Xiao-Yu Cao, Xu-Yi Chen, Ying-Fu Liu, Shuang-Long Zhu, Zhong-Lei Sun, Xian-Bin Kong, Jing-Rui Huo, Sai Zhang, Yun-Qiang Xu 2018, 13 (9):  1650-1656.  doi: 10.4103/1673-5374.237139 Abstract ( 127 )   PDF (1022KB) ( 182 )   Save Nerve scarring after peripheral nerve injury can severely hamper nerve regeneration and functional recovery. Further, the anti-inflammatory cytokine, interleukin-10, can inhibit nerve scar formation. Saikosaponin a (SSa) is a monomer molecule extracted from the Chinese medicine, Bupleurum. SSa can exert anti-inflammatory effects in spinal cord injury and traumatic brain injury. However, it has not been shown whether SSa can play a role in peripheral nerve injury. In this study, rats were randomly assigned to three groups. In the sham group, the left sciatic nerve was directly sutured after exposure. In the sciatic nerve injury (SNI) + SSa and SNI groups, the left sciatic nerve was sutured and continuously injected daily with SSa (10 mg/kg) or an equivalent volume of saline for 7 days. Enzyme linked immunosorbent assay results demonstrated that at 7 days after injury, interleukin-10 level was considerably higher in the SNI + SSa group than in the SNI group. Masson staining and western blot assay demonstrated that at 8 weeks after injury, type I and III collagen content was lower and nerve scar formation was visibly less in the SNI + SSa group compared with the SNI group. Simultaneously, sciatic functional index and nerve conduction velocity were improved in the SNI + SSa group compared with the SNI group. These results confirm that SSa can increase the expression of the anti-inflammatory factor, interleukin-10, and reduce nerve scar formation to promote functional recovery of injured sciatic nerve. Related Articles | Metrics

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Treatment with NADPH oxidase inhibitor apocynin alleviates diabetic neuropathic pain in rats Murat Olukman, Aytül Önal, Fatma Gül Çelenk, Yiğit Uyanıkgil, Türker Çavuşoğlu, Neslihan Düzenli, Sibel Ülker 2018, 13 (9):  1657-1664.  doi: 10.4103/1673-5374.232530 Abstract ( 163 )   PDF (1761KB) ( 207 )   Save Increased reactive oxygen species by the activation of NADPH oxidase (NOX) contributes to the development of diabetic complications. Apocynin, a NOX inhibitor, increases sciatic nerve conductance and blood flow in diabetic rats. We investigated potential protective effect of apocynin in rat diabetic neuropathy and its precise mechanism of action at molecular level. Rat models of streptozotocin-induced diabetes were treated with apocynin (30 and 100 mg/kg per day, intragastrically) for 4 weeks. Mechanical hyperalgesia and allodynia were determined weekly using analgesimeter and dynamic plantar aesthesiometer. Western blot analysis and histochemistry/immunohistochemistry were performed in the lumbar spinal cord and sciatic nerve respectively. Streptozotocin injection reduced pain threshold in analgesimeter, but not in aesthesiometer. Apocynin treatment increased pain threshold dose-dependently. Western blot analysis showed an increase in catalase and NOX-p47phox protein expression in the spinal cord. However, protein expressions of neuronal and inducible nitric oxide synthase (nNOS, iNOS), superoxide dismutase, glutathion peroxidase, nitrotyrosine, tumor necrosis factor-α, interleukin-6, interleukin-1β, aldose reductase, cyclooxygenase-2 or MAC-1 (marker for increased microgliosis) in the spinal cord remained unchanged. Western blot analysis results also demonstrated that apocynin decreased NOX-p47phox expression at both doses and catalase expression at 100 mg/kg per day. Histochemistry of diabetic sciatic nerve revealed marked degeneration. nNOS and iNOS immunoreactivities were increased, while S-100 immunoreactivity (Schwann cell marker) was decreased in sciatic nerve. Apocynin treatment reversed these changes dose-dependently. In conclusion, decreased pain threshold of diabetic rats was accompanied by increased NOX and catalase expression in the spinal cord and increased degeneration in the sciatic nerve characterized by increased NOS expression and Schwann cell loss. Apocynin treatment attenuates neuropathic pain by decelerating the increased oxidative stress-mediated pathogenesis in diabetic rats. Related Articles | Metrics

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The novel chalcone analog L2H17 protects retinal ganglion cells from oxidative stress-induced apoptosis Lei Wang, Huai-Cheng Chen, Xi Yang, Jian-Jian Tao, Guang Liang, Jian-Zhang Wu, Wen-Can Wu, Yi Wang, Zong-Ming Song, Xin Zhang 2018, 13 (9):  1665-1672.  doi: 10.4103/1673-5374.237140 Abstract ( 129 )   PDF (2298KB) ( 166 )   Save Chalcone is a plant metabolite widely found in fruits, vegetables, spices and tea, and has anti-tumor, anti-inflammation, immunomodulation, antibacterial and anti-oxidation activities, as well as many other pharmacological and biological effects. Our team has shown that its analogs have antioxidant activity, and oxidative stress is a pathological hallmark of retinal ischemia/reperfusion injury that can lead to retinal damage and visual loss. This investigation aims to identify a chalcone that protects retinal ganglion cells in vitro from the effects of oxidative stress and examine its mechanism. Rat retinal ganglion cell-5 cells were pretreated with chalcones and then exposed to tert-butyl hydroperoxide that causes oxidative damage. Controls received dimethyl sulfoxide only or tert-butyl hydroperoxide in dimethyl sulfoxide. Only (E)-3,4-dihydroxy-2′-methylether ketone (L2H17), of the five chalcone analogs, markedly increased the survival rate of oxidatively injured RGC-5 cells. Thus, subsequent experiments only analyzed the results of the L2H17 intervention. Cell viability and apoptosis were measured. Intracellular superoxide dismutase and reactive oxygen species levels were used to assess induced oxidative stress. The mechanism of action by L2H17 was explored by measuring the ER stress/UPR pathway and the expression and localization of Nrf2. All results demonstrated that L2H17 could reduce the apoptosis of oxidatively injured cells, inhibit caspase-3 activity, increase Bcl-2 expression, decrease Bad expression, increase the activity of superoxide dismutase, inhibit the production of reactive oxygen species, increase Nrf2 immunoreactivity, and reduce the activating transcription factor 4, phospho-eukaryotic initiation factor 2 and CHOP expression. L2H17 protects retinal ganglion cells induced by oxidative stress by regulating Nrf2, which indicates that it has the potential to become a drug for retinal ischemia/reperfusion. Related Articles | Metrics