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15 August 2017, Volume 12 Issue 8 Previous Issue    Next Issue

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Optogenetics and its application in neural degeneration and regeneration Josue D. Ordaz, Wei Wu, Xiao-Ming Xu 2017, 12 (8):  1197-1209.  doi: 10.4103/1673-5374.213532 Abstract ( 196 )   PDF (1909KB) ( 464 )   Save Neural degeneration and regeneration are important topics in neurological diseases. There are limited options for therapeutic interventions in neurological diseases that provide simultaneous spatial and temporal control of neurons. This drawback increases side effects due to non-specific targeting. Optogenetics is a technology that allows precise spatial and temporal control of cells. Therefore, this technique has high potential as a therapeutic strategy for neurological diseases. Even though the application of optogenetics in understanding brain functional organization and complex behaviour states have been elaborated, reviews of its therapeutic potential especially in neurodegeneration and regeneration are still limited. This short review presents representative work in optogenetics in disease models such as spinal cord injury, multiple sclerosis, epilepsy, Alzheimer’s disease and Parkinson’s disease. It is aimed to provide a broader perspective on optogenetic therapeutic potential in neurodegeneration and neural regeneration. Related Articles | Metrics

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Live-cell imaging: new avenues to investigate retinal regeneration Manuela Lahne, David R. Hyde 2017, 12 (8):  1210-1219.  doi: 10.4103/1673-5374.213533 Abstract ( 295 )   PDF (905KB) ( 375 )   Save Sensing and responding to our environment requires functional neurons that act in concert. Neuronal cell loss resulting from degenerative diseases cannot be replaced in humans, causing a functional impairment to integrate and/or respond to sensory cues. In contrast, zebrafish (Danio rerio) possess an endogenous capacity to regenerate lost neurons. Here, we will focus on the processes that lead to neuronal regeneration in the zebrafish retina. Dying retinal neurons release a damage signal, tumor necrosis factor α, which induces the resident radial glia, the Müller glia, to reprogram and re-enter the cell cycle. The Müller glia divide asymmetrically to produce a Müller glia that exits the cell cycle and a neuronal progenitor cell. The arising neuronal progenitor cells undergo several rounds of cell divisions before they migrate to the site of damage to differentiate into the neuronal cell types that were lost. Molecular and immunohistochemical studies have predominantly provided insight into the mechanisms that regulate retinal regeneration. However, many processes during retinal regeneration are dynamic and require live-cell imaging to fully discern the underlying mechanisms. Recently, a multiphoton imaging approach of adult zebrafish retinal cultures was developed. We will discuss the use of live-cell imaging, the currently available tools and those that need to be developed to advance our knowledge on major open questions in the field of retinal regeneration. Related Articles | Metrics

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Neurotrophic factors and corneal nerve regeneration Marta Sacchetti, Alessandro Lambiase 2017, 12 (8):  1220-1224.  doi: 10.4103/1673-5374.213534 Abstract ( 370 )   PDF (1156KB) ( 433 )   Save The cornea has unique features that make it a useful model for regenerative medicine studies. It is an avascular, transparent, densely innervated tissue and any pathological changes can be easily detected by slit lamp examination. Corneal sensitivity is provided by the ophthalmic branch of the trigeminal nerve that elicits protective reflexes such as blinking and tearing and exerts trophic support by releasing neuromediators and growth factors. Corneal nerves are easily evaluated for both function and morphology using standard instruments such as corneal esthesiometer and in vivo confocal microscope. All local and systemic conditions that are associated with damage of the trigeminal nerve cause the development of neurotrophic keratitis, a rare degenerative disease. Neurotrophic keratitis is characterized by impairment of corneal sensitivity associated with development of persistent epithelial defects that may progress to corneal ulcer, melting and perforation. Current neurotrophic keratitis treatments aim at supporting corneal healing and preventing progression of corneal damage. Novel compounds able to stimulate corneal nerve recovery are in advanced development stage. Among them, nerve growth factor eye drops showed to be safe and effective in stimulating corneal healing and improving corneal sensitivity in patients with neurotrophic keratitis. Neurotrophic keratitis represents an useful model to evaluate in clinical practice novel neuro-regenerative drugs. Related Articles | Metrics

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Primary cilia as a novel horizon between neuron and environment Gregory W. Kirschen, Qiaojie Xiong 2017, 12 (8):  1225-1230.  doi: 10.4103/1673-5374.213535 Abstract ( 264 )   PDF (772KB) ( 372 )   Save The primary cilium, a hair-like sensory organelle found on most mammalian cells, has gained recent attention within the field of neuroscience. Although neural primary cilia have been known to play a role in embryonic central nervous system patterning, we are just beginning to appreciate their importance in the mature organism. After several decades of investigation and controversy, the neural primary cilium is emerging as an important regulator of neuroplasticity in the healthy adult central nervous system. Further, primary cilia have recently been implicated in disease states such as cancer and epilepsy. Intriguingly, while primary cilia are expressed throughout the central nervous system, their structure, receptors, and signaling pathways vary by anatomical region and neural cell type. These differences likely bear relevance to both their homeostatic and neuropathological functions, although much remains to be uncovered. In this review, we provide a brief historical overview of neural primary cilia and highlight several key advances in the field over the past few decades. We then set forth a proposed research agenda to fill in the gaps in our knowledge regarding how the primary cilium functions and malfunctions in nervous tissue, with the ultimate goal of targeting this sensory structure for neural repair following injury. Related Articles | Metrics

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Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system Julia J. Segura-Uribe, Rodolfo Pinto-Almazán, Angélica Coyoy-Salgado, Claudia E. Fuentes-Venado, Christian Guerra-Araiza 2017, 12 (8):  1231-1240.  doi: 10.4103/1673-5374.213536 Abstract ( 147 )   PDF (558KB) ( 401 )   Save Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1 (MAP1), MAP2, neurofilament 38 (NF38) by different mechanisms of action and at different levels: neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects. Related Articles | Metrics

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Transcriptional inhibition in Schwann cell development and nerve regeneration Susanne Quintes, Bastian G. Brinkmann 2017, 12 (8):  1241-1246.  doi: 10.4103/1673-5374.213537 Abstract ( 233 )   PDF (410KB) ( 305 )   Save Schwann cells, the myelinating glial cells of the peripheral nervous system are remarkably plastic after nerve trauma. Their transdifferentiation into specialized repair cells after injury shares some features with their development from the neural crest. Both processes are governed by a tightly regulated balance between activators and inhibitors to ensure timely lineage progression and allow re-maturation after nerve injury. Functional recovery after injury is very successful in rodents, however, in humans, lack of regeneration after nerve trauma and loss of function as the result of peripheral neuropathies represents a significant  problem. Our understanding of the basic molecular machinery underlying Schwann cell maturation and plasticity has made significant progress in recent years and novel players have been discovered. While the transcriptional activators of Schwann cell development and nerve repair have been well defined, the mechanisms counteracting negative regulation of (re-)myelination are less well understood. Recently, transcriptional inhibition has emerged as a new regulatory mechanism in Schwann cell development and nerve repair. This mini-review summarizes some of the regulatory mechanisms controlling both processes and the novel concept of “inhibiting the inhibitors” in the context of Schwann cell plasticity. Related Articles | Metrics

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LINGO-1 and AMIGO3, potential therapeutic targets for neurological and dysmyelinating disorders? Simon Foale, Martin Berry, Ann Logan, Daniel Fulton, Zubair Ahmed 2017, 12 (8):  1247-1251.  doi: 10.4103/1673-5374.213538 Abstract ( 223 )   PDF (1178KB) ( 297 )   Save Leucine rich repeat proteins have gained considerable interest as therapeutic targets due to their expression and biological activity within the central nervous system. LINGO-1 has received particular attention since it inhibits axonal regeneration after spinal cord injury in a RhoA dependent manner while inhibiting  leucine rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1) disinhibits neuron outgrowth. Furthermore, LINGO-1 suppresses oligodendrocyte precursor cell maturation and myelin production. Inhibiting the action of LINGO-1 encourages remyelination both in vitro and in vivo. Accordingly, LINGO-1 antagonists show promise as therapies for demyelinating diseases. An analogous protein to LINGO-1, amphoterin-induced gene and open reading frame-3 (AMIGO3), exerts the same inhibitory effect on the axonal outgrowth of central nervous system neurons, as well as interacting with the same receptors as LINGO-1. However, AMIGO3 is upregulated more rapidly after spinal cord injury than LINGO-1 . We speculate that AMIGO3 has a similar inhibitory effect on oligodendrocyte precursor cell maturation and myelin production as with axogenesis. Therefore, inhibiting AMIGO3 will likely encourage central nervous system axonal regeneration as well as the production of myelin from local oligodendrocyte precursor cell, thus providing a promising therapeutic target and an area for future investigation. Related Articles | Metrics

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Modulation of valosin-containing protein by Kyoto University Substances (KUS) as a novel therapeutic strategy for ischemic neuronal diseases Masayuki Hata, Hanako Ohashi Ikeda 2017, 12 (8):  1252-1255.  doi: 10.4103/1673-5374.213540 Abstract ( 213 )   PDF (422KB) ( 293 )   Save Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate (ATP) depletion and subsequent induced endoplasmic reticulum (ER) stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity  of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances (KUSs), that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases. Related Articles | Metrics

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Heterocyclic compounds as key structures for the interaction with old and new targets in Alzheimer’s disease therapy Asha Hiremathad, Luca Piemontese 2017, 12 (8):  1256-1261.  doi: 10.4103/1673-5374.213541 Abstract ( 133 )   PDF (242KB) ( 348 )   Save Nowadays, Alzheimer’s disease (AD) is widely recognized as a real social problem. In fact, only five drugs are FDA approved for the therapy of this widespread neurodegenerative disease, but with low results so far. Three of them (rivastigmine, donepezil and galantamine) are acetylcholinesterase inhibitors, memantine is a N-methyl-D-aspartate receptor antagonist, whereas the fifth formulation is a combination of donepezil with memantine. The prevention and treatment of AD is the new challenge for pharmaceutical industry, as well as for public institutions, physicians, patients, and their families. The discovery of a new and safe way to cure this neurodegenerative disease is urgent and should not be delayed further. Because of the multiple origin of this pathology, a multi-target strategy is currently strongly pursued by researchers. In this review, we have discussed new structures designed to better the activity on the classical AD targets. We have also examined old and new potential drugs that could prove useful future for the therapy of the pathology by acting on innovative, not usual, and not yet fully explored targets like peroxisome proliferator-activated receptor (PPARs). Related Articles | Metrics

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Metabolic pathways as possible therapeutic targets for progressive multiple sclerosis Rebecca M. Heidker, Mitchell R. Emerson, Steven M. LeVine 2017, 12 (8):  1262-1267.  doi: 10.4103/1673-5374.213542 Abstract ( 216 )   PDF (216KB) ( 310 )   Save Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth: insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair  processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here  we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis. Related Articles | Metrics

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Erythropoietin enhanced recovery after peripheral nerve injury Max Modrak, Leigh Sundem, John Elfar 2017, 12 (8):  1268-1269.  doi: 10.4103/1673-5374.213544 Abstract ( 237 )   PDF (127KB) ( 677 )   Save Related Articles | Metrics

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Mitochondrial homeostasis in Parkinson’s disease - a triumvirate rule? Chee-Hoe Ng, Liting Hang, Kah-Leong Lim 2017, 12 (8):  1270-1272.  doi: 10.4103/1673-5374.213546 Abstract ( 317 )   PDF (269KB) ( 298 )   Save Related Articles | Metrics

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A role for lipids as agents to alleviate stroke damage: the neuroprotective effect of 2-hydroxy arachidonic acid Irene F. Ugidos, Diego Pérez-Rodríguez, Arsenio Fernández-López 2017, 12 (8):  1273-1275.  doi: 10.4103/1673-5374.213545 Abstract ( 281 )   PDF (270KB) ( 329 )   Save Related Articles | Metrics

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Reassembly of the axon initial segment and nodes of Ranvier in regenerated axons of the central nervous system Miguel A. Marin, Matthew N. Rasband 2017, 12 (8):  1276-1277.  doi: 10.4103/1673-5374.213543 Abstract ( 362 )   PDF (601KB) ( 323 )   Save Related Articles | Metrics

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Spreading depression and focal venous cerebral ischemia enhance cortical neurogenesis Ryo Tamaki, Samuel Ige Orie,, Beat Alessandri, Oliver Kempski, Axel Heimann 2017, 12 (8):  1278-1286.  doi: 10.4103/1673-5374.213547 Abstract ( 201 )   PDF (764KB) ( 325 )   Save Endogenous neurogenesis can arise from a variety of physiological stimuli including exercise, learning, or “enriched environment” as well as pathological conditions such as ischemia, epilepsy or cortical spreading depression. Whether all these conditions use a common trigger to set off endogenous neurogenesis is yet unclear. We hypothesized that cortical spreading depression (CSD) induces neurogenesis in the cerebral cortex and dentate gyrus after cerebral venous ischemia. Forty-two Wistar rats alternatively underwent sham operation (Sham), induction of ten CSDs or venous ischemia provoked via occlusion of two adjacent superficial cortical vein followed by ten induced CSDs (CSD + 2-VO). As an additional control, 15 naïve rats received no intervention except 5-bromo-2′-deoxyuridine (BrdU) treatment for 7 days. Sagittal brain slices (40 μm thick) were co-stained for BrdU and doublecortin (DCX; new immature neuronal cells) on day 9 or NeuN (new mature neuronal cells) on day 28. On day 9 after sham operation, cell proliferation and neurogenesis occurred in the cortex in rats. The sole induction of CSD had no effect. But on days 9 and 28, more proliferating cells and newly formed neurons in the ipsilateral cortex were observed in rats subjected to CSD + 2VO than in rats subjected to sham operation. On days 9 and 28, cell proliferation and neurogenesis in the ipsilateral dentate gyrus was increased in sham-operated rats than in naïve rats. Our data supports the hypothesis that induced cortical neurogenesis after CSD + 2-VO is a direct effect of ischemia, rather than of CSD alone. Related Articles | Metrics

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Extract of Ginkgo biloba promotes neuronal regeneration in the hippocampus after exposure to acrylamide Wei-ling Huang1, Yu-xin Ma1, Yu-bao Fan, Sheng-min Lai, Hong-qing Liu, Jing Liu, Li Luo, Guo-ying Li, Su-min Tian 2017, 12 (8):  1287-1293.  doi: 10.4103/1673-5374.213548 Abstract ( 198 )   PDF (2255KB) ( 358 )   Save Previous studies have demonstrated a neuroprotective effect of extract of Ginkgo biloba against neuronal damage, but have mainly focused on antioxidation of extract of Ginkgo biloba. To date, limited studies have determined whether extrasct of Ginkgo biloba has a protective effect on neuronal damage. In the present study, acrylamide and 30, 60, and 120 mg/kg extract of Ginkgo biloba were administered for 4 weeks by gavage to establish mouse models. Our results showed that 30, 60, and 120 mg/kg extract of Ginkgo biloba effectively alleviated the abnormal gait of poisoned mice, and up-regulated protein expression levels of doublecortin (DCX), brain-derived neurotrophic factor, and growth associated protein-43 (GAP-43) in the hippocampus. Simultaneously, DCX- and GAP-43-immunoreactive cells increased. These findings suggest that extract of Ginkgo biloba can mitigate neurotoxicity induced by acrylamide, and thereby promote neuronal regeneration in the hippocampus of acrylamide-treated mice. Related Articles | Metrics

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Cortical activation pattern during shoulder simple versus vibration exercises: a functional near infrared spectroscopy study Sung Ho Jang, Sang Seok Yeo, Seung Hyun Lee, Sang Hyun Jin, Mi Young Lee 2017, 12 (8):  1294-1298.  doi: 10.4103/1673-5374.213549 Abstract ( 241 )   PDF (562KB) ( 369 )   Save To date, the cortical effect of exercise has not been fully elucidated. Using the functional near infrared spectroscopy, we attempted to compare the cortical effect between shoulder vibration exercise and shoulder simple exercise. Eight healthy subjects were recruited for this study. Two different exercise tasks (shoulder vibration exercise using the flexible pole and shoulder simple exercise) were performed using a block paradigm. We measured the values of oxygenated hemoglobin in the four regions of interest: the primary sensory-motor cortex (SM1 total, arm somatotopy, and leg and trunk somatotopy), the premotor cortex, the supplementary motor area, and the prefrontal cortex. During shoulder vibration exercise and shoulder simple exercise, cortical activation was observed in SM1 (total, arm somatotopy, and leg and trunk somatotopy), premotor cortex, supplementary motor area, and prefrontal cortex. Higher oxygenated hemoglobin values were also observed in the areas of arm somatotopy of SM1 compared with those of other regions of interest. However, no significant difference in the arm somatotopy of SM1 was observed between the two exercises. By contrast, in the leg and trunk somatotopy of SM1, shoulder vibration exercise led to a significantly higher oxy-hemoglobin value than shoulder simple exercise. These two exercises may result in cortical activation effects for the motor areas relevant to the shoulder exercise, especially in the arm somatotopy of SM1. However, shoulder vibration exercise has an additional cortical activation effect for the leg and trunk somatotopy of SM1. Related Articles | Metrics

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Relationship of nocturnal concentrations of melatonin, gamma-aminobutyric acid and total antioxidants in peripheral blood with insomnia after stroke: study protocol for a prospective non-randomized controlled trial Wei Zhang, Fang Li, Tong Zhang 2017, 12 (8):  1299-1307.  doi: 10.4103/1673-5374.213550 Abstract ( 342 )   PDF (370KB) ( 398 )   Save Melatonin and gamma-aminobutyric acid (GABA) have been shown to regulate sleep. The nocturnal concentrations of melatonin, GABA and total antioxidants may relate to insomnia in stroke patients. In this prospective single-center non-randomized controlled clinical trial performed in the China Rehabilitation Research Center, we analyzed the relationship of nocturnal concentrations of melatonin, GABA and total antioxidants with insomnia after stroke. Patients during rehabilitation of stroke were recruited and assigned to the insomnia group or non-insomnia group. Simultaneously, persons without stroke or insomnia served as normal controls. Each group contained 25 cases. The primary outcome was nocturnal concentrations of melatonin, GABA and total antioxidants in peripheral blood. The secondary outcomes were Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale, Fatigue Severity Scale, Morningness-Eveningness Questionnaire (Chinese version), and National Institute of Health Stroke Scale. The relationship of nocturnal concentrations of melatonin, GABA and total antioxidants with insomnia after stroke was analyzed and showed that they were lower in the insomnia group than in the non-insomnia group. The severity of stroke was higher in the insomnia group than in the non-insomnia group. Correlation analysis demonstrated that the nocturnal concentrations of melatonin and GABA were associated with insomnia after stroke. This trial was registered at ClinicalTrials.gov, identifier: NCT03202121. Related Articles | Metrics

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Xingnao Kaiqiao needling method for acute ischemic stroke: a meta-analysis of safety and efficacy Zhi-xin Yang, Jia-hong Xie, Ding-ding Liu 2017, 12 (8):  1308-1314.  doi: 10.4103/1673-5374.213551 Abstract ( 239 )   PDF (710KB) ( 380 )   Save OBJECTIVE: To evaluate the effectiveness and safety of the Xingnao Kaiqiao needling method for treating acute ischemic stroke. DATA SOURCES: We retrieved relevant randomized controlled trials involving Xingnao Kaiqiao acupuncture for treatment of acute ischemic stroke. The China National Knowledge Infrastructure, Weipu Information Resources System, Wanfang Medical Data System, Chinese Biomedical Literature Database, Cochrane Library, and PubMed were searched from June 2006 to March 2016. DATA SELECTION: We analyzed randomized and semi-randomized clinical controlled trials that compared Xingnao Kaiqiao acupuncture with various control treatments, such as conventional drugs or other acupuncture therapies, for treatment of acute ischemic stroke. The quality of articles was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1), and the study was carried out using Cochrane system assessment methods. RevMan 5.2 was used for the meta-analysis of the included studies. OUTCOME MEASURES: The mortality rate, disability rate, activities of daily living (Barthel Index), and clinical efficacy were observed. RESULTS: Twelve studies met the inclusion criteria for this review. The meta-analysis showed that between Xingnao Kaiqiao acupuncture and the control treatment, Xingnao Kaiqiao acupuncture reduced the disability rate [risk ratio (RR) = 0.51, 95% confidence interval (CI) = 0.27–0.98, z = 2.03, P < 0.05], elevated the  activities of daily living (weighted mean difference = 12.23, 95% CI: 3.66–20.08, z = 2.80, P < 0.005), and had greater clinical efficacy (RR = 1.61, 95% CI: 1.23–2.09, z = 3.53, P < 0.0004). However, there was no significant difference in mortality rate (RR = 0.61, 95% CI: 0.15–2.45, z = 0.70, P > 0.05). CONCLUSION: The Xingnao Kaiqiao needling method is effective and safe for acute ischemic stroke. However, there was selective bias in this study, and the likelihood of measurement bias is high. Thus, more high-quality randomized controlled trials are needed to provide reliable evidence of the efficacy and safety of Xingnao Kaiqiao acupuncture in the treatment of acute ischemic stroke. Related Articles | Metrics

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Association and differences in genetic polymorphisms in PCSK9 gene in subjects with lacunar infarction in the Han and Uygur populations of Xinjiang Uygur Autonomous Region of China Deng-feng Han, Jian-hua Ma, Chen-guang Hao, Tuerhong•Tuerxun, Lei Du, Xiao-ning Zhang 2017, 12 (8):  1315-1321.  doi: 10.4103/1673-5374.213552 Abstract ( 121 )   PDF (520KB) ( 375 )   Save Polymorphisms in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are associated with severe hypercholesterolemia and stroke. Here, we investigated the relationship between single nucleotide polymorphisms in PCSK9 and stroke in 237 patients with lacunar infarction in the Uygur and Han populations in Xinjiang Uygur Autonomous Region of China. Using the SNaPshot single-base terminal extension method, four PCSK9 gene polymorphisms were analyzed. We found a significantly strong relationship between the PCSK9 rs17111503 (G > A) polymorphism and increased susceptibility to lacunar infarction by variant homozygote comparison, and using the dominant and recessive models in the Han population but not in the Uygur population. Low triglyceride levels were found in AA carriers (rs17111503, G > A) in the Han population but not in the Uygur population. Association analysis revealed that the rs17111503 (G > A) olymorphism was not significantly associated with smoking, alcohol drinking, history of hypertension or diabetes in the Han or Uygur lacunar infarction patients. rs11583680, rs483462 and rs505151 were not associated with risk of lacunar infarction in the Han or Uygur populations. Our findings suggest that the PCSK9 rs17111503 (G > A) polymorphism is associated with susceptibility to lacunar infarction in the Han population but not in the Uygur population. Related Articles | Metrics

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Cold water swimming pretreatment reduces cognitive deficits in a rat model of traumatic brain injury Zi-wei Zhou, Ya-dan Li, Wei-wei Gao, Jie-li Chen, Shu-yuan Yue, Jian-ning Zhang 2017, 12 (8):  1322-1328.  doi: 10.4103/1673-5374.213553 Abstract ( 231 )   PDF (850KB) ( 374 )   Save A moderate stress such as cold water swimming can raise the tolerance of the body to potentially injurious events. However, little is  known about the mechanism of beneficial effects induced by moderate stress. In this study, we used a classic rat model of traumatic brain injury to test the hypothesis that cold water swimming preconditioning improved the recovery of cognitive functions and explored the mechanisms. Results showed that after traumatic brain injury, pre-conditioned rats (cold water swimming for 3 minutes at 4°C) spent a significantly higher percent of times in the goal quadrant of cold water swim, and escape latencies were shorter than for non-pretreated rats. The number of circulating endothelial progenitor cells was significantly higher in pre-conditioned rats than those without pretreatment at 0, 3, 6 and 24 hours after traumatic brain injury. Immunohistochemical staining and Von Willebrand factor staining demonstrated that the number of CD34+ stem cells and new blood vessels in the injured hippocampus tissue increased significantly in pre-conditioned rats. These data suggest that pretreatment with cold water swimming could promote the proliferation of endothelial progenitor cells and angiogenesis in the peripheral blood and hippocampus. It also ameliorated cognitive deficits caused by experimental traumatic brain injury. Related Articles | Metrics

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Dexmedetomidine mitigates isoflurane-induced neurodegeneration in fetal rats during the second trimester of pregnancy Zhi-yuan Su, Qing Ye, Xian-bao Liu, Yu-zhong Chen, Hong Zhan, Shi-yuan Xu 2017, 12 (8):  1329-1337.  doi: 10.4103/1673-5374.213554 Abstract ( 221 )   PDF (1528KB) ( 327 )   Save Dexmedetomidine has significant neuroprotective effects. However, whether its protective effects can reduce neurotoxicity caused by isoflurane in fetal brain during the second trimester of pregnancy remains unclear. In this study, timed-pregnancy rats at gestational day 14 spontaneously inhaled 1.5% isoflurane for 4 hours, and were intraperitoneally injected with dexmedetomidine at dosages of 5, 10, 20, and 20 μg/kg 15 minutes before inhalation and after inhalation for 2 hours. Our results demonstrate that 4 hours after inhaling isoflurane, 20 μg/kg dexmedetomidine visibly mitigated isoflurane-induced neuronal apoptosis, reversed downregulation of brain-derived neurotrophic factor expression, and lessened decreased spatial learning and memory ability in adulthood in the fetal rats. Altogether, these findings indicate that dexmedetomidine can reduce neurodegeneration induced by isoflurane in fetal rats during the second trimester of pregnancy. Further, brain-derived neurotrophic factor participates in this process. Related Articles | Metrics

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Dried Rehmannia root protects against glutamateinduced cytotoxity to PC12 cells through energy metabolism-related pathways Yong Liu, Lei Liu, Xi-xiang Ying, Wen-juan Wei, Chao Han, Yang Liu, Chun-hui Han, Ai-jing Leng, Jing-yun Ma, Jing Liu 2017, 12 (8):  1338-1346.  doi: 10.4103/1673-5374.213556 Abstract ( 136 )   PDF (1608KB) ( 705 )   Save Rehmannia has been shown to be clinically effective in treating neurodegenerative diseases; however, the neuroprotective mechanisms  remain unclear. In this study, we established a model of neurodegenerative disease using PC12 cytotoxic injury induced by glutamate. The cells were treated with 20 mM glutamate in the absence or presence of water extracts of dried Rehmannia root of varying concentrations (70%, 50% and 30%). The different concentrations of Rehmannia water extract significantly increased the activity of glutamate-injured cells, reduced the release of lactate dehydrogenase, inhibited apoptosis, increased the concentrations of NADH, NAD and ATP in cells, ameliorated mitochondrial membrane potential, and reduced the levels of light chain 3. Taken together, our findings demonstrate that Rehmannia water extracts exert a cytoprotective effect against glutamate-induced PC12 cell injury via energy metabolism-related pathways. Related Articles | Metrics

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Impact of Pitx3 gene knockdown on glial cell line-derived neurotrophic factor transcriptional activity in dopaminergic neurons Jing Chen, Xiao-yu Kang, Chuan-xi Tang, Dian-shuai Gao 2017, 12 (8):  1347-1351.  doi: 10.4103/1673-5374.213557 Abstract ( 276 )   PDF (1035KB) ( 326 )   Save Pitx3 is strongly associated with the phenotype, differentiation, and survival of dopaminergic neurons. The relationship between Pitx3 and glial cell line-derived neurotrophic factor (GDNF) in dopaminergic neurons remains poorly understood. The present investigation sought to construct and screen a lentivirus expression plasmid carrying a rat Pitx3 short hairpin (sh)RNA and to assess the impact of Pitx3 gene knockdown on GDNF transcriptional activity in MES23.5 dopaminergic neurons. Three pairs of interference sequences were designed and separately ligated into GV102 expression vectors. These recombinant plasmids were transfected into MES23.5 cells and western blot assays were performed to detect Pitx3 protein expression. Finally, the most effective Pitx3 shRNA and a dual-luciferase reporter gene plasmid carrying the GDNF promoter region (GDNF-luciferase) were cotransfected into MES23.5 cells. Sequencing showed that the synthesized sequences were identical to the three Pitx3 interference sequences. Inverted fluorescence microscopy revealed that the lentivirus expression plasmids carrying Pitx3-shRNA had 40–50% transfection efficiency. Western blot assay confirmed that the corresponding Pitx3 of the third knockdown sequence had the lowest expression level. Dual-luciferase reporter gene results showed that the GDNF transcriptional activity in dopaminergic cells cotransfected with both plasmids was decreased compared with those transfected with GDNF-luciferase alone. Together, the results showed that the designed Pitx3-shRNA interference sequence decreased Pitx3 protein expression, which decreased GDNF transcriptional activity. Related Articles | Metrics

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Optical coherence tomography and T cell gene expression analysis in patients with benign multiple sclerosis John Soltys, Qin Wang, Yang Mao-Draayer 2017, 12 (8):  1352-1356.  doi: 10.4103/1673-5374.213558 Abstract ( 136 )   PDF (497KB) ( 987 )   Save Benign multiple sclerosis is a retrospective diagnosis based primarily on a lack of motor symptom progression. Recent findings that suggest patients with benign multiple sclerosis experience non-motor symptoms highlight the need for a more prospective means to diagnose benign multiple sclerosis early in order to help direct patient care. In this study, we present optical coherence tomography and T cell neurotrophin gene analysis findings in a small number of patients with benign multiple sclerosis. Our results demonstrated that retinal nerve fiber layer was mildly thinned, and T cells had a distinct gene expression profile that included upregulation of interleukin 10 and leukemia inhibitory factor, downregulation of interleukin 6 and neurotensin high affinity receptor 1 (a novel neurotrophin receptor). These findings add evidence for further investigation into optical coherence tomography and mRNA profiling in larger cohorts as a potential means to diagnose benign multiple sclerosis in a more prospective manner. Related Articles | Metrics

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A novel triple immunoenzyme staining enables simultaneous identification of all muscle fiber types on a single skeletal muscle cryosection from normal, denervated or reinnervated rats Peng Wu, Shuya Zhang, Robert J. Spinner, Michael Torres Lizardi, Yudong Gu, Cong Yu, Michael J. Yaszemski, Anthony J. Windebank, Huan Wang 2017, 12 (8):  1357-1364.  doi: 10.4103/1673-5374.213560 Abstract ( 213 )   PDF (2282KB) ( 331 )   Save Triple immunofluorescence staining has recently been developed to simultaneously identify all muscle fibers on a single cryosection which is helpful for clinical and basic research, but it has disadvantages such as fast photobleaching and unclear outlines of muscle fibers. Triple immunoenzyme staining (TIE) is likely to avoid these disadvantages. In this study, we aimed to establish a sensitive and specific TIE technique to identify fiber types in normal, denervated, and reinnervated rat muscles, and to develop a systematic sampling method for muscle fiber quantification. Tibialis anterior and soleus from normal, denervated, and reinnervated Lewis rat hind limbs were used. Five consecutive cryosections were cut from each muscle, including one for TIE and four for single immunoenzyme staining (SIE). The TIE was performed using the polymerized reporter enzyme staining system for the first two antigens (A4.74 for MyHC-IIA, BA-F8 for MyHC-I) and alkaline phosphatase staining system for the third antigen (BF-F3 for MyHC-IIB), followed by corresponding detective systems and respective chromogens. The type of muscle fibers was quantified by systematic sampling at 12.5%, 25%, 33% and 50% of all muscle fibers, and was compared with that acquired from counting all the fibers (100%). All muscle fiber phenotypes, including pure and hybrid, could be simultaneously identified on a single TIE cryosection with clear outlines. The fiber types on TIE slides matched well with their respective counterpart on the consecutive SIE slides with a 95% match rate. Systematic sampling of 12.5% fibers could represent the true fiber type distribution of the entire muscle section. Our results suggest that novel TIE can effectively visualize fiber types in normal, denervated or reinnervated rat muscles. Related Articles | Metrics

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A progressive compression model of thoracic spinal cord injury in mice: function assessment and pathological changes in spinal cord Guo-dong Sun, Yan Chen, Zhi-gang Zhou, Shu-xian Yang, Cheng Zhong, Zhi-zhong Li 2017, 12 (8):  1365-1374.  doi: 10.4103/1673-5374.213693 Abstract ( 224 )   PDF (2798KB) ( 387 )   Save Non-traumatic injury accounts for approximately half of clinical spinal cord injury, including chronic spinal cord compression. However,previous rodent spinal cord compression models are mainly designed for rats, few are available for mice. Our aim is to develop a thoracic progressive compression mice model of spinal cord injury. In this study, adult wild-type C57BL/6 mice were divided into two groups: in the surgery group, a screw was inserted at T9 lamina to compress the spinal cord, and the compression was increased by turning it further into the canal (0.2 mm) post-surgery every 2 weeks up to 8 weeks. In the control group, a hole was drilled into the lamina without inserting a screw. The results showed that Basso Mouse Scale scores were lower and gait worsened. In addition, the degree of hindlimb dysfunction in mice was consistent with the degree of spinal cord compression. The number of motor neurons in the anterior horn of the spinal cord was reduced in all groups of mice, whereas astrocytes and microglia were gradually activated and proliferated. In conclusion, this progressive compression of thoracic spinal cord injury in mice is a preferable model for chronic progressive spinal cord compression injury. Related Articles | Metrics

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Naringin as a beneficial natural product against degeneration of the nigrostriatal dopaminergic projection in the adult brain Sang Ryong Kim 2017, 12 (8):  1375-1376.  doi: 10.4103/1673-5374.213694 Abstract ( 118 )   PDF (131KB) ( 311 )   Save Related Articles | Metrics