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15 March 2018, Volume 13 Issue 3 Previous Issue    Next Issue

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Cerebral ischemia and neuroregeneration Reggie H. C. Lee, Michelle H. H. Lee, Celeste Y. C. Wu, Alexandre Couto e Silva, Harlee E. Possoit, Tsung-Han Hsieh,Alireza Minagar, Hung Wen Lin 2018, 13 (3):  373-385.  doi: 10.4103/1673-5374.228711 Abstract ( 226 )   PDF (297KB) ( 229 )   Save Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke (a form of cerebral ischemia)-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics (i.e., tissue plasminogen activator) and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies again st stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism(s) underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies (i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells) as it relates to cerebral ischemia. Related Articles | Metrics

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SNARE complex in axonal guidance and neuroregeneration Fausto Ulloa, Tiziana Cotrufo, Delia Ricolo, Eduardo Soriano, Sofia J. Araújo 2018, 13 (3):  386-392.  doi: 10.4103/1673-5374.228710 Abstract ( 136 )   PDF (338KB) ( 163 )   Save Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration. Related Articles | Metrics

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Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage Nicole J. Scott-Hewitt, Christopher J. Folts, Mark D. Noble 2018, 13 (3):  393-401.  doi: 10.4103/1673-5374.228712 Abstract ( 134 )   PDF (903KB) ( 656 )   Save This review addresses two puzzling findings related to mutations in galactocerebrosidase (GALC) that cause Krabbe disease (KD), a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis (MS), another disease characterized by extensive myelin damage. What explains these correlations? In studies on cuprizone-induced myelin damage in heterozygous (GALC+/–) mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC+/– and wild-type (WT) mice. In contrast, GALC+/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up-regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher (GALC+/–) mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair. Related Articles | Metrics

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The relaxin peptide family – potential future hope for neuroprotective therapy? A short review Marius Nistor, Martin Schmidt, René Schiffner 2018, 13 (3):  402-405.  doi: 10.4103/1673-5374.228713 Abstract ( 117 )   PDF (152KB) ( 164 )   Save  Since its discovery in the 1920’s the relaxin peptide hormone family has not only grown in number to now seven members (relaxin-1, relaxin-2, relaxin-3, insulin-like peptide (INSL) 3, INSL4, INSL5 and INSL6), but ever more effects, suchs as vasodilatory, angiogenic, anti-apoptopic, anti-fibriotic and anti-inflammatory, have been linked to them. While relaxin-2 has mainly been investigated in the context of cardiac protection, most comprehensively in the RELAX-AHF and RELAX AHF2 studies, a small number of studies have furthermore assessed the potential neuroprotective effects of especially relaxin-2 and other members of the relaxin family. In this short review we summarise and discuss recent efforts to utilize relaxin hormones for neuroprotection and point out potential future fields of research and translational applications. While many questions still need to be answered, the promising results of the available studies definitely warrant future well-designed studies on neuroprotection by relaxin peptides. Related Articles | Metrics

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Roles of neural regeneration in memory pharmacology Miao-Kun Sun 2018, 13 (3):  406-407.  doi: 10.4103/1673-5374.228714 Abstract ( 130 )   PDF (253KB) ( 135 )   Save Neural regeneration, or neuroregeneration, is a brain mechanism essential for rescuing cognitive functions pharmacologically against memory disorders and aging-related memory abnormality.In this short Perspective article, we intend to briefly present the essential roles of neuroregeneration and neural plasticity in learning and memory, memory disorders, and critical involvement in an effective treatment of memory disorders. Related Articles | Metrics

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Towards frequency adaptation for delayed feedback deep brain stimulations Mohammad Daneshzand, Miad Faezipour, Buket D. Barkana 2018, 13 (3):  408-409.  doi: 10.4103/1673-5374.228715 Abstract ( 141 )   PDF (181KB) ( 146 )   Save In neurodegenerative disorders such as Parkinson’s disease (PD), deep brain stimulation (DBS) is a desirable approach when the medication is less effective for treating the symptoms. DBS incorporates transferring electrical pulses to a specific tissue of the central nervous system, obtaining therapeutic results by modulating the neuronal activity of that region. DBS has certain advantages such as reversibility and adjustability features over medication, since the neuronal firing patterns can be recorded and used to alter the parameters of the DBS signal (Benabid et al., 2009). One of the DBS indications is its ability to suppress the abnormal neuronal activity to treat symptoms like tremor, akinesia and dystonia. Although the mechanism of DBS is not fully understood, the inhibition of neurons, entrainment of bursting neurons and activation of axons has been associated with DBS therapy (Chiken and Nambu, 2016). Electric fields induced by DBS generally disrupt any abnormal information flow coming from the cortex to the basal ganglia neurons. DBS signals also increase and regularize the neuronal firing rates by direct activation of the axons of the stimulated neuron. This regularization of neuronal firing rate prohibits the oscillatory and bursting abnormalities of the basal ganglia neurons, leading to highly therapeutic results in PD. The therapeutic effects of DBS are enhanced once it is used in a closed loop paradigm. The cortical and pallidal discharge patterns of neurons are more improved by closed loop DBS rather than traditional open loop stimulations (Rosin et al., 2011). DBS is mainly targeted at subthalamic nucleus (STN) or globus pallidus externa (GPe) cells to disrupt the thalamo-cortical synchronizations seen in PD. Therefore,the local field potential (LFP) recorded from a population of the STN cells is often used as the feedback variable for DBS parametrization.Retrospective studies mainly focused on adjusting the stimulation amplitude based on the recorded LFP (Popovych et al., 2017). However, adapting the frequency of stimulation might provide superior results in desynchronizing the coupling patterns of STN-GPe. In addition, high frequency stimulation (HFS)typically used in DBS, significantly increases the device battery usage. In contrast, adapting the frequency of stimulation to a protocol where HFS is only used when high desynchronization is needed, can expand the battery lifespan and reduces the necessity of costly battery replacement surgeries (Lyons et al., 2004). Related Articles | Metrics

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Linking axon transport to regeneration using in vitro laser axotomy Bart Nieuwenhuis, Richard Eva 2018, 13 (3):  410-412.  doi: 10.4103/1673-5374.228716 Abstract ( 128 )   PDF (916KB) ( 126 )   Save Spinal cord injury has devastating consequences because adult central nervous system (CNS) neurons do not regenerate their axons after injury. Two key reasons for axon regeneration failure are extrinsic inhibitory factors and a low intrinsic capacity for axon regrowth. Research has therefore focused on overcoming extrinsic growth inhibition, and enhancing intrinsic regeneration capacity. Both of these issues will need to be addressed to enable optimal repair of the injured spinal cord. Related Articles | Metrics

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Targeting microthrombosis and neuroinflammation with vepoloxamer for therapeutic neuroprotection after traumatic brain injury Ye Xiong, Li Zhang, Zheng Gang Zhang, Asim Mahmood, Michael Chopp 2018, 13 (3):  413-414.  doi: 10.4103/1673-5374.228717 Abstract ( 108 )   PDF (163KB) ( 142 )   Save Traumatic brain injury (TBI): Despite improved supportive and rehabilitative care of TBI patients, TBI remains a leading cause of death and disability worldwide. To date, no effective pharmacological treatments are available for TBI. The mechanisms underlying brain damage and repair following TBI are complex and not completely understood. Coagulopathy after TBI is frequent and an independent prognostic factor for unfavorable outcome and prognosis (Stein and Smith, 2004). It may be amenable to treatment,and effective management of coagulopathy may protect from secondary injury and poor outcomes. Although the main challenge for TBI management is to address the risk of hypocoagulopathy with prolonged bleeding and progression of hemorrhagic lesions, the risk of hypercoagulopathy with an increased microthrombosis formation warrants investigation to reduce neurological deficits after TBI. Related Articles | Metrics

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Drugging SUMOylation for neuroprotection and oncotherapy Joshua D. Bernstock, Daniel G. Ye, Yang-ja Lee, Florian Gessler, Gregory K. Friedman, Wei Zheng, John M. Hallenbeck 2018, 13 (3):  415-416.  doi: 10.4103/1673-5374.228718 Abstract ( 128 )   PDF (308KB) ( 474 )   Save Recently there have been exciting research advances in neuroprotective therapies for ischemic stroke. In the past, the search for neuroprotective agents has been fraught with failure at the clinical trials stage due to numerous factors, including subject heterogeneity and improper therapeutic windows (Tymianski, 2017). Moreover, it is becoming clearer that the complex and evolving pathobiology of stroke requires multimodal therapeutic approaches capable of modulating the numerous axes that contribute to ischemia/reperfusion damage,rather than targeting a single axis (Bernstock et al., 2018a). With the success of recent endovascular thrombectomy (EVT) trials, it has been suggested that clinical trials of EVT with adjunct neuroprotection can overcome past difficulties and maximize the effect size by using imaging to reduce patient heterogeneity (i.e., selecting those with large vessel occlusions, small ischemic cores, and good collateral circulation),restoring perfusion using better EVT devices, and enrolling patients in the correct therapeutic window (i.e., when they still have salvageable brain tissue) (Tymianski, 2017). Considering the opportunity that this represents for new, better clinical trials of neuroprotective agents, the search is on for high-potential compounds that may be investigated in these future studies. Related Articles | Metrics

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Metabolism, neurodegeneration and epigenetics: emerging role of Sirtuins Dafne M. Silberman 2018, 13 (3):  417-418.  doi: 10.4103/1673-5374.228719 Abstract ( 132 )   PDF (154KB) ( 156 )   Save Along with the progressive aging of the population, the prevalence of obesity, metabolic diseases and neurodegenerative disorders continues to grow. Moreover, increasing evidence suggests that metabolic alterations strongly influence the initiation and progression of neurodegenerative disorders. Accordingly, brain aging is accompanied by metabolic, morphological and neurophysiological changes leading to the development of neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and multiple sclerosis (Procaccini et al., 2016). Since each of these disorders involve impaired energy metabolism and/or adverse changes in the cerebral vasculature, a reduction in energy availability to neurons may contribute to increased vulnerability of the brain to develop neurodegenerative processes (Camandola and Mattson, 2017). Related Articles | Metrics

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Melastatin-related transient receptor potential 2 channel in Aβ42-induced neuroinflammation: implications to Alzheimer’s disease mechanism and development of therapeutics Linyu Wei, Sharifah Alawieyah Syed Mortadza, Lin-Hua Jiang 2018, 13 (3):  419-420.  doi: 10.4103/1673-5374.228720 Abstract ( 135 )   PDF (297KB) ( 137 )   Save Alzheimer’s disease (AD) is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β (Aβ) peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies (Selkoe and Hardy, 2016). However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction. Related Articles | Metrics

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Microcebus murinus: a novel promising non-human primate model of spinal cord injury Gaëtan Poulen, Florence Evelyne Perrin 2018, 13 (3):  421-422.  doi: 10.4103/1673-5374.228721. Abstract ( 181 )   PDF (235KB) ( 144 )   Save The number of people affected by spinal cord injuries (SCI) ranges from 2.5 to 4 million worldwide. Traumatic SCI induces a primary injury due to initial mechanical impact that causes focal cellular and blood-spinal cord barrier damages. Subsequently, secondary injuries resulting from infiltration of peripheral monocytes, ischemia, edema,inflammation, glial scar and cystic cavities formation as well as excitotoxicity trigger cellular demise and prevent spontaneous axonal regrowth. Secondary damages, including aggregation of extracellular matrix protein at the lesion epicenter, thus greatly amplify impairments induced by the initial mechanical damage. Related Articles | Metrics

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Immunomodulation as a neuroprotective strategy after spinal cord injury Susana Monteiro, António J. Salgado, Nuno A. Silva 2018, 13 (3):  423-424.  doi: 10.4103/1673-5374.228722 Abstract ( 116 )   PDF (325KB) ( 164 )   Save The initial trauma to the spinal cord is just the starting point for a cascade of endogenous events that will collectively determine the injury extension.These secondary events include, but are not limited to: glutamate excitoxicity,induction of apoptotic pathways, ionic imbalances and the development of a strong and dysfunctional inflammatory response. The secondary injury is associated to an aggravation of neuronal damage increasing the extent of neurological deficits (Ek et al., 2010). Related Articles | Metrics

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Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis Rodolfo Gabriel Gatto 2018, 13 (3):  425-426.  doi: 10.4103/1673-5374.228723 Abstract ( 113 )   PDF (617KB) ( 168 )   Save The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis (ALS): ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord (SC), where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis (mSOD1) and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging (DTI) has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS. Related Articles | Metrics

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The protocadherin alpha cluster is required for axon extension and myelination in the developing central nervous system Wen-cheng Lu, Yu-xiao Zhou, Ping Qiao, Jin Zheng, Qiang Wu, Qiang Shen 2018, 13 (3):  427-433.  doi: 10.4103/1673-5374.228724 Abstract ( 164 )   PDF (1746KB) ( 179 )   Save In adult mammals, axon regeneration after central nervous system injury is very poor, resulting in persistent functional loss. Enhancing the ability of axonal outgrowth may be a potential treatment strategy because mature neurons of the adult central nervous system may retain the intrinsic ability to regrow axons after injury. The protocadherin (Pcdh) clusters are thought to function in neuronal morphogenesis and in the assembly of neural circuitry in the brain. We cultured primary hippocampal neurons from E17.5 Pcdhα deletion (del-α) mouse embryos. After culture for 1 day, axon length was obviously shorter in del-α neurons compared with wild-type neurons. RNA sequencing of hippocampal E17.5 RNA showed that expression levels of BDNF, Fmod, Nrp2, OGN, and Sema3d, which are associated with axon extension, were significantly down-regulated in the absence of the Pcdhα gene cluster. Using transmission electron microscopy, the ratio of myelinated nerve fibers in the axons of del-α hippocampal neurons was significantly decreased; myelin sheaths of P21 Pcdhα-del mice showed lamellar disorder, discrete appearance, and vacuoles. These results indicate that the Pcdhα cluster can promote the growth and myelination of axons in the neurodevelopmental stage. Related Articles | Metrics

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Progesterone modulates mTOR in the hippocampus of mice after traumatic brain injury Richard Justin Garling, Lora Talley Watts, Shane Sprague, Murat Digicaylioglu 2018, 13 (3):  434-439.  doi: 10.4103/1673-5374.228725 Abstract ( 122 )   PDF (918KB) ( 179 )   Save The mechanistic target of rapamycin (mTOR) is an intracellular protein kinase that functions as an energy and nutrient sensor in the cellular microenvironment of neurons. Modulation of mTOR is vital when nutrient and energy sources become limited. Hypoxia, traumatic brain injury, cellular energy states, and growth factors all regulate the phosphorylation and total levels of mTOR in cells. Alterations in the microenvironment induce transduction of signals to downstream proteins by mTOR allowing for cells to make the necessary adjustments to counteract stressors and survive. Progesterone, a hydrophobic steroid hormone, has been shown in studies of non-neural tissue to be a suppressor of mTOR and modulator of mTOR phosphorylation. Our study tested the effects of progesterone on mTOR expression following traumatic brain injury. C57BL/6 mice were treated with progesterone (8 mg/kg) at 1 (intraperitoneal), 6 (subcutaneous), 24 (subcutaneous), and 48 (subcutaneous) hours post closed skull traumatic brain injury.The hippocampus was then harvested 72 hours post injury and prepared for western blot analysis. We found that progesterone significantly decreased total mTOR levels in all groups compared to sham treated with vehicle. This was further confirmed by immunostaining showing decreased cytoplasmic mTOR levels compared to sham. Our study shows progesterone Related Articles | Metrics

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Effect of tibolone pretreatment on kinases and phosphatases that regulate the expression and phosphorylation of Tau in the hippocampus of rats exposed to ozone Rodolfo Pinto-Almazán,Julia J. Segura-Uribe, Marvin A. Soriano-Ursúa, Eunice D. Farfán-García, Juan M. Gallardo, Christian Guerra-Araiza 2018, 13 (3):  440-448.  doi: 10.4103/1673-5374.228726 Abstract ( 122 )   PDF (1120KB) ( 185 )   Save Oxidative stress (OS) is a key process in the development of many neurodegenerative diseases, memory disorders, and other pathological processes related to aging. Tibolone (TIB), a synthetic hormone used as a treatment for menopausal ymptoms, decreases lipoperoxidation levels, prevents memory impairment and learning disability caused by ozone (O3) exposure. However, it is not clear if TIB could prevent the increase in phosphorylation induced by oxidative stress of the microtubule-associated protein Tau. In this study, the effects of TIB at different times of administration on the phosphorylation of Tau, the activation of glycogen synthase kinase-3β (GSK3β), and the inactivation of Akt and phosphatases PP2A and PTEN induced by O3 exposure were assessed in adult male Wistar rats. Rats were divided into 10 groups: control group (ozone-free air plus vehicle [C]), control + TIB group (ozone-free air plus TIB 1 mg/kg [C + TIB]); 7,15, 30, and 60 days of ozone exposure groups [O3] and 7, 15, 30, and 60 days of TIB 1 mg/kg before ozone exposure groups [O3 + TIB]. The effects of O3 exposure and TIB administration were assessed by western blot analysis of total and phosphorylated Tau, GSK3β, Akt, PP2A, and PTEN proteins and oxidative stress marker nitrotyrosine, and superoxide dismutase activity and lipid peroxidation of malondialdehyde by two different spectrophotometric methods (Marklund and TBARS, respectively). We observed that O3 exposure increases Tau phosphorylation, which is correlated with decreased PP2A and PTEN protein levels, diminished Akt protein levels, and increased GSK3β protein levels in the hippocampus of adult male rats. The effects of O3 exposure were prevented by the long-term treatment (over 15 days) with TIB. Malondialdehyde and nitrotyrosine levels increased from 15 to 60 days of exposure to O3 in comparison to C group, and superoxide dismutase activity decreased. Furthermore, TIB administration limited the changes induced by O3 exposure. Our results suggest a beneficial use of hormone replacement therapy with TIB to prevent neurodegeneration caused by O3 exposure in rats. Related Articles | Metrics

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Quinacrine pretreatment reduces microwave-induced neuronal damage by stabilizing the cell membrane Xue-feng Ding, Yan Wu, Wen-rui Qu, Ming Fan, Yong-qi Zhao 2018, 13 (3):  449-455.  doi: 10.4103/1673-5374.228727 Abstract ( 122 )   PDF (733KB) ( 192 )   Save Quinacrine, widely used to treat parasitic diseases, binds to cell membranes. We previously found that quinacrine pretreatment reduced microwave radiation damage in rat hippocampal neurons, but the molecular mechanism remains poorly understood. Considering the thermal effects of microwave radiation and the protective effects of quinacrine on heat damage in cells, we hypothesized that quinacrine would prevent microwave radiation damage to cells in a mechanism associated with cell membrane stability. To test this, we used retinoic acid to induce PC12 cells to differentiate into neuron-like cells. We then pretreated the neurons with quinacrine (20 and 40 mM) and irradiated them with 50 mW/cm2 microwaves for 3 or 6 hours. Flow cytometry, atomic force microscopy and western blot assays revealed that irradiated cells pretreated with quinacrine showed markedly less apoptosis, necrosis, and membrane damage, and greater expression of heat shock protein 70, than cells exposed to microwave irradiation alone. These results suggest that quinacrine stabilizes the neuronal membrane structure by upregulating the expression of heat shock protein 70, thus reducing neuronal injury caused by microwave radiation.   Related Articles | Metrics

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In vivo observation of cerebral microcirculation after experimental subarachnoid hemorrhage in mice Xiao-mei Yang, Xu-hao Chen, Jian-fei Lu, Chang-man Zhou, Jing-yan Han, Chun-hua Chen 2018, 13 (3):  456-462.  doi: 10.4103/1673-5374.228728 Abstract ( 127 )   PDF (1862KB) ( 141 )   Save Acute brain injury caused by subarachnoid hemorrhage is the major cause of poor prognosis. The pathology of subarachnoid hemorrhage likely involves major morphological changes in the microcirculation. However, previous studies primarily used fixed tissue or delayed injury models. Therefore, in the present study, we used in vivo imaging to observe the dynamic changes in cerebral microcirculation after subarachnoid hemorrhage. Subarachnoid hemorrhage was induced by perforation of the bifurcation of the middle cerebral and anterior cerebral arteries in male C57/BL6 mice. The diameter of pial arterioles and venules was measured by in vivo fluorescence microscopy at different time points within 180 minutes after subarachnoid hemorrhage. Cerebral blood flow was examined and leukocyte adhesion/albumin extravasation was determined at different time points before and after subarachnoid hemorrhage. Cerebral pial microcirculation was abnormal and cerebral blood flow was reduced after subarachnoid hemorrhage. Acute vasoconstriction occurred predominantly in the arterioles instead of the venules. A progressive increase in the number of adherent leukocytes in venules and substantial albumin extravasation were observed between 10 and 180 minutes after subarachnoid hemorrhage. These results show that major changes in microcirculation occur in the early stage of subarachnoid hemorrhage. Our findings may promote the development of novel therapeutic strategies for the early treatment of subarachnoid hemorrhage. Related Articles | Metrics

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Associations between thromboxane A synthase 1 gene polymorphisms and the risk of ischemic stroke in a Chinese Han population Lei Li, Zhi-yi He, Yan-zhe Wang, Xu Liu, Li-ying Yuan 2018, 13 (3):  463-469.  doi: 10.4103/1673-5374.228729 Abstract ( 179 )   PDF (309KB) ( 149 )   Save Thromboxane A synthase 1 (TBXAS1) catalyses the synthesis of thromboxane A2 (TXA2), which plays an important role in the pathogenesis of ischemic stroke. Thus, the TBXAS1 gene was investigated as a candidate gene involved in the formation of atherosclerosis. This case-control study collected peripheral blood specimens and clinical data of 370 ischemic stroke patients and 340 healthy controls in the Northern Chinese Han population from October 2010 to May 2011. Two TBXAS1 single-nucleotide polymorphisms, rs2267682 and rs10487667, were analyzed using a SNaPshot Multiplex sequencing assay to explore the relationships between the single-nucleotide polymorphisms in TBXAS1 and ischemic stroke. The TT genotype frequency and T allele frequency of rs2267682 in the patients with ischemic stroke were significantly higher than those in the controls (P < 0.01 and P = 0.02). Furthermore, compared with the GG + GT genotype, the TT rs2267682 genotype was associated with increased risk of ischemic stroke (odds ratio (OR) = 1.80, 95% confidence interval (CI): 1.16–2.79, P < 0.01). Multivariate logistic analysis with adjustments for confounding factors revealed that rs2267682 was still associated with ischemic stroke (OR = 1.94,95% CI : 1.13–3.33, P = 0.02). The frequency of the T-G haplotype in the patients was significantly higher than that in the controls according haplotype analysis (OR = 1.49, 95% CI: 1.10–2.00, P < 0.01). These data reveal that the rs2267682 TBXAS1 polymorphism is associated with ischemic stroke. The TT genotype of TBXAS1 and T allele of rs2267682 increase susceptibility to ischemic stroke in this Northern Chinese Han population. The protocol has been registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559). Related Articles | Metrics

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Evaluation of nerve transfer options for treating total brachial plexus avulsion injury: a retrospective study of 73 participants Kai-ming Gao, Jing-jing Hu, Jie Lao, Xin Zhao 2018, 13 (3):  470-476.  doi: 10.4103/1673-5374.228730 Abstract ( 199 )   PDF (887KB) ( 207 )   Save Despite recent great progress in diagnosis and microsurgical repair, the prognosis in total brachial plexus-avulsion injury remains unfavorable.Insufficient number of donors and unreasonable use of donor nerves might be key factors. To identify an optimal treatment strategy for this condition, we conducted a retrospective review. Seventy-three patients with total brachial plexus avulsion injury were followed up for an average of 7.3 years. Our analysis demonstrated no significant difference in elbow-flexion recovery between phrenic nerve-transfer (25 cases), phrenic nerve-graft (19 cases), intercostal nerve (17 cases), or contralateral C7-transfer (12 cases) groups. Restoration of shoulder function was attempted through anterior accessory nerve (27 cases), posterior accessory nerve (10 cases), intercostal nerve (5 cases), or accessory + intercostal nerve transfer (31 cases). Accessory nerve + intercostal nerve transfer was the most effective method. A significantly greater amount of elbow extension was observed in patients with intercostal nerve transfer (25 cases) than in those with contralateral C7 transfer (10 cases). Recovery of median nerve function was noticeably better for those who received entire contralateral C7 transfer (33 cases) than for those who received partial contralateral C7 transfer (40 cases). Wrist and finger extension were reconstructed by intercostal nerve transfer (31 cases). Overall, the recommended surgical treatment for total brachial plexus-avulsion injury is phrenic nerve transfer for elbow flexion, accessory nerve + intercostal nerve transfer for shoulder function, intercostal nerves transfer for elbow extension, entire contralateral C7 transfer for median nerve function, and intercostal nerve transfer for finger extension. The trial was registered at Clinical-Trials.gov (identifier: NCT03166033). Related Articles | Metrics

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Electroacupuncture and moxibustion promote regeneration of injured sciatic nerve through Schwann cell proliferation and nerve growth factor secretion Lin-na Hu, Jin-xin Tian Wei Gao, Jing Zhu, Fang-fang Mou, Xiao-chun Ye, Yu-pu Liu, Ping-ping Lu, Shui-jin Shao,Hai-dong Guo 2018, 13 (3):  477-483.  doi: 10.4103/1673-5374.228731 Abstract ( 218 )   PDF (1281KB) ( 103 )   Save Using electroacupuncture and moxibustion to treat peripheral nerve injury is highly efficient with low side effects. However, the electroacupuncture-and moxibustion-based mechanisms underlying nerve repair are still unclear. Here, in vivo and in vitro experiments uncovered one mechanism through which electroacupuncture and moxibustion affect regeneration after peripheral nerve injury. We first established rat models of sciatic nerve injury using neurotomy. Rats were treated with electroacupuncture or moxibustion at acupoints Huantiao (GB30) and Zusanli (ST36). Each treatment lasted 15 minutes, and treatments were given six times a week for 4 consecutive weeks. Behavioral testing was used to determine the sciatic functional index. We used electrophysiological detection to measure sciatic nerve conduction velocity and performed hematoxylin-eosin staining to determine any changes in the gastrocnemius muscle. We used immunohistochemistry to observe changes in the expression of S100—a specific marker for Schwann cells—and an enzyme-linked immunosorbent assay to detect serum level of nerve growth factor. Results showed that compared with the model-only group, sciatic functional index, recovery rate of conduction velocity, diameter recovery of the gastrocnemius muscle fibers, number of S100-immunoreactive cells,and level of nerve growth factor were greater in the electroacupuncture and moxibustion groups. The efficacy did not differ between treatment groups. The serum from treated rats was collected and used to stimulate Schwann cells cultured in vitro. Results showed that the viability of Schwann cells was much higher in the treatment groups than in the model group at 3 and 5 days after treatment. These findings indicate that electroacupuncture and moxibustion promoted nerve regeneration and functional recovery; its mechanism might be associated with the enhancement of Schwann cell proliferation and upregulation of nerve growth factor. Related Articles | Metrics

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Acetyl-11-keto-β-boswellic acid extracted from Boswellia serrata promotes Schwann cell proliferation and sciatic nerve function recovery Xiao-wen Jiang, Bin-qing Zhang, Lu Qiao, Lin Liu, Xue-wei Wang, Wen-hui Yu 2018, 13 (3):  484-491.  doi: 10.4103/1673-5374.228732 Abstract ( 192 )   PDF (1760KB) ( 221 )   Save Frankincense can promote blood circulation. Acetyl-11-keto-β-boswellic acid (AKBA) is a small molecule with anti-inflammatory properties that is derived from Boswellia serrata. Here, we hypothesized that it may promote regeneration of injured sciatic nerve. To address this hypothesis, we established a rat model of sciatic nerve injury using a nerve clamping method. Rats were administered AKBA once every 2 days at doses of 1.5, 3, and 6 mg/kg by intraperitoneal injection for 30 days from the 1st day after injury. Sciatic nerve function was evaluated using the sciatic functional index. Degree of muscle atrophy was measured using the triceps surae muscle Cuadros index.Neuropathological changes were observed by hematoxylin-eosin staining. Western blot analysis was used to detect expression of phospho-extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) in injured nerve. S100 immunoreactivity in injured nerve was detected by immunohistochemistry. In vivo experiments showed that 3 and 6 mg/kg AKBA significantly increased sciatic nerve index, Cuadros index of triceps muscle, p-ERK1/2 expression, and S100 immunoreactivity in injured sciatic nerve of sciatic nerve injury model rats. Furthermore,for in vitro experiments, Schwann cells were treated with AKBA at 0–20 μg/mL. Proliferation of Schwann cells was detected by Cell Counting Kit-8 colorimetry assay. The results showed that 2 μg/mL AKBA is the optimal therapeutic concentration. In addition, ERK phosphorylation levels increased following 2 μg/mL AKBA treatment. In the presence of the ERK1/2 inhibitor, PD98059 (2.5 μL/mL), the AKBA-induced increase in p-ERK1/2 protein expression was partially abrogated. In conclusion, our study shows that AKBA promotes peripheral nerve regeneration with ERK protein phosphorylation playing a key role in this process. Related Articles | Metrics

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Neuroprotective effect of ischemic postconditioning on sciatic nerve transection Xiao-bin Zhou, Na Liu, Dong Wang, De-xin Zou, Chang-wei Wei, Jun-lin Zhou 2018, 13 (3):  492-496.  doi: 10.4103/1673-5374.228733 Abstract ( 113 )   PDF (680KB) ( 148 )   Save Ischemic preconditioning or postconditioning has been shown to have neuroprotective effect on cerebral ischemia, but it has not been studied in peripheral nerve injury. In this study, a rat model of sciatic nerve transection was established, and subjected to three cycles of ischemia for 10 minutes + reperfusion for 10 minutes, once a day. After ischemic postconditioning, serum insulin-like growth factor 1 expression increased; sciatic nerve Schwann cell myelination increased; sensory function and motor function were restored. These findings indicate that ischemic postconditioning can effectively protect injured sciatic nerve. The protective effect is possibly associated with upregulation of insulin-like growth factor 1. Related Articles | Metrics

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Cell proliferation during hair cell regeneration induced by Math1 in vestibular epithelia in vitro Yi-bo Huang, Rui Ma, Juan-mei Yang, Zhao Han, Ning Cong, Zhen Gao, Dongdong Ren, Jing Wang,Fang-lu Chi 2018, 13 (3):  497-501.  doi: 10.4103/1673-5374.228734 Abstract ( 153 )   PDF (1185KB) ( 152 )   Save Hair cell regeneration is the fundamental method of correcting hearing loss and balance disorders caused by hair cell damage or loss. How to promote hair cell regeneration is a hot focus in current research. In mammals, cochlear hair cells cannot be regenerated and few vestibular hair cells can be renewed through spontaneous regeneration. However, Math1 gene transfer allows a few inner ear cells to be transformed into hair cells in vitro or in vivo. Hair cells can be renewed through two possible means in birds: supporting cell differentiation and transdifferentiation with or without cell division. Hair cell regeneration is strongly associated with cell proliferation. Therefore, this study explored the relationship between Math1-induced vestibular hair cell regeneration and cell division in mammals. The mouse vestibule was isolated to harvest vestibular epithelial cells. Ad-Math1-enhanced green fluorescent protein (EGFP) was used to track cell division during hair cell transformation.5-Bromo-2′-deoxyuridine (BrdU) was added to track cell proliferation at various time points. Immunocytochemistry was utilized to determine cell differentiation and proliferation. Results demonstrated that when epithelial cells were in a higher proliferative stage, more of these cells differentiated into hair cells by Math1 gene transfer. However, in the low proliferation stage, no BrdU-positive cells were seen after Math1 gene transfer. Cell division always occurred before Math1 transfection but not during or after Math1 transfection, when cells were labeled with BrdU before and after Ad-Math1-EGFP transfection. These results confirm that vestibular epithelial cells with high proliferative potential can differentiate into new hair cells by Math1 gene transfer, but this process is independent of cell proliferation. Related Articles | Metrics

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Efficacy of chitosan and sodium alginate scaffolds for repair of spinal cord injury in rats Zi-ang Yao, Feng-jia Chen, Hong-li Cui, Tong Lin, Na Guo, Hai-ge Wu 2018, 13 (3):  502-509.  doi: 10.4103/1673-5374.228756 Abstract ( 199 )   PDF (2528KB) ( 226 )   Save Spinal cord injury results in the loss of motor and sensory pathways and spontaneous regeneration of adult mammalian spinal cord neurons is limited. Chitosan and sodium alginate have good biocompatibility, biodegradability, and are suitable to assist the recovery of damaged tissues, such as skin, bone and nerve. Chitosan scaffolds, sodium alginate scaffolds and chitosan-sodium alginate scaffolds were separately transplanted into rats with spinal cord hemisection. Basso-Beattie-Bresnahan locomotor rating scale scores and electrophysiological results showed that chitosan scaffolds promoted recovery of locomotor capacity and nerve transduction of the experimental rats.Sixty days after surgery, chitosan scaffolds retained the original shape of the spinal cord. Compared with sodium alginate scaffolds- and chitosan-sodium alginate scaffolds-transplanted rats, more neurofilament-H-immunoreactive cells (regenerating nerve fibers) and less glial fibrillary acidic protein-immunoreactive cells (astrocytic scar tissue) were observed at the injury site of experimental rats in chitosan scaffold-transplanted rats. Due to the fast degradation rate of sodium alginate, sodium alginate scaffolds and composite material scaffolds did not have a supporting and bridging effect on the damaged tissue. Above all, compared with sodium alginate and composite material scaffolds, chitosan had better biocompatibility, could promote the regeneration of nerve fibers and prevent the formation of scar tissue,and as such, is more suitable to help the repair of spinal cord injury. Related Articles | Metrics

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Delayed xenon post-conditioning mitigates spinal cord ischemia/reperfusion injury in rabbits by regulating microglial activation and inflammatory factors Yan-wei Yang, Yun-lu Wang, Jia-kai Lu, Lei Tian, Mu Jin, Wei-ping Cheng 2018, 13 (3):  510-517.  doi: 10.4103/1673-5374.228757 Abstract ( 187 )   PDF (1129KB) ( 166 )   Save The neuroprotective effect against spinal cord ischemia/reperfusion injury in rats exerted by delayed xenon post-conditioning is stronger than that produced by immediate xenon post-conditioning. However, the mechanisms underlying this process remain unclear. Activated microglia are the main inflammatory cell type in the nervous system. The release of pro-inflammatory factors following microglial activation can lead to spinal cord damage, and inhibition of microglial activation can relieve spinal cord ischemia/reperfusion injury. To investigate how xenon regulates microglial activation and the release of inflammatory factors, a rabbit model of spinal cord ischemia/reperfusion injury was induced by balloon occlusion of the infrarenal aorta. After establishment of the model, two interventions were given: (1) immediate xenon post-conditioning—after reperfusion, inhalation of 50% xenon for 1 hour, 50% N2/50%O2 for 2 hours; (2) delayed xenon post-conditioning—after reperfusion, inhalation of 50% N2/50%O2 for 2 hours, 50% xenon for 1 hour. At 4, 8, 24, 48 and 72 hours after reperfusion, hindlimb locomotor function was scored using the Jacobs locomotor scale. At 72 hours after reperfusion, interleukin 6 and interleukin 10 levels in the spinal cord of each group were measured using western blot assays. Iba1 levels were determined using immunohistochemistry and a western blot assay. The number of normal neurons at the injury site was quantified using hematoxylin-eosin staining. At 72 hours after reperfusion, delayed xenon post-conditioning remarkably enhanced hindlimb motor function, increased the number of normal neurons at the injury site, decreased Iba1 levels, and inhibited interleukin-6 and interleukin-10 levels in the spinal cord.Immediate xenon post-conditioning did not noticeably affect the above-mentioned indexes. These findings indicate that delayed xenon post-conditioning after spinal cord injury improves the recovery of neurological function by reducing microglial activation and the release of interleukin-6 and interleukin-10. Related Articles | Metrics

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Cell cycle and complement inhibitors may be specific for treatment of spinal cord injury in aged and young mice: transcriptomic analyses Ming Hao, Xin-ran Ji, Hua Chen, Wei Zhang, Li-cheng Zhang, Li-hai Zhang, Pei-fu Tang, Ning Lu 2018, 13 (3):  518-527.  doi: 10.4103/1673-5374.226405 Abstract ( 124 )   PDF (1954KB) ( 306 )   Save Previous studies have reported age-specific pathological and functional outcomes in young and aged patients suffering spinal cord injury,but the mechanisms remain poorly understood. In this study, we examined mice with spinal cord injury. Gene expression profiles from the Gene Expression Omnibus database (accession number GSE93561) were used, including spinal cord samples from 3 young injured mice (2–3-months old, induced by Impactor at Th9 level) and 3 control mice (2–3-months old, no treatment), as well as 2 aged injured mice (15–18-months old, induced by Impactor at Th9 level) and 2 control mice (15–18-months old, no treatment). Differentially expressed genes (DEGs) in spinal cord tissue from injured and control mice were identified using the Linear Models for Microarray data method,with a threshold of adjusted P < 0.05 and |logFC(fold change)| > 1.5. Protein–protein interaction networks were constructed using data from the STRING database, followed by module analysis by Cytoscape software to screen crucial genes. Kyoto encyclopedia of genes and genomes pathway and Gene Ontology enrichment analyses were performed to investigate the underlying functions of DEGs using Database for Annotation, Visualization and Integrated Discovery. Consequently, 1,604 and 1,153 DEGs were identified between injured and normal control mice in spinal cord tissue of aged and young mice, respectively. Furthermore, a Venn diagram showed that 960 DEGs were shared among aged and young mice, while 644 and 193 DEGs were specific to aged and young mice, respectively. Functional enrichment indicates that shared DEGs are involved in osteoclast differentiation, extracellular matrix–receptor interaction, nuclear factor-kappa B signaling pathway, and focal adhesion. Unique genes for aged and young injured groups were involved in the cell cycle (upregulation of PLK1) and complement (upregulation of C3) activation, respectively. These findings were confirmed by functional analysis of genes in modules (common, 4; aged, 2; young, 1) screened from protein–protein interaction networks. Accordingly, cell cycle and complement inhibitors may be specific treatments for spinal cord injury in aged and young mice, respectively. Related Articles | Metrics

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DTI and pathological changes in a rabbit model of radiation injury to the spinal cord after 125I radioactive seed implantation Xia Cao, Le Fang, Chuan-yu Cui, Shi Gao, Tian-wei Wang 2018, 13 (3):  528-535.  doi: 10.4103/1673-5374.228758 Abstract ( 123 )   PDF (981KB) ( 167 )   Save Excessive radiation exposure may lead to edema of the spinal cord and deterioration of the nervous system. Magnetic resonance imaging can be used to judge and assess the extent of edema and to evaluate pathological changes and thus may be used for the evaluation of spinal cord injuries caused by radiation therapy. Radioactive 125I seeds to irradiate 90% of the spinal cord tissue at doses of 40–100 Gy (D90) were implanted in rabbits at T10 to induce radiation injury, and we evaluated their safety for use in the spinal cord. Diffusion tensor imaging showed that with increased D90, the apparent diffusion coefficient and fractional anisotropy values were increased. Moreover, pathological damage of neurons and microvessels in the gray matter and white matter was aggravated. At 2 months after implantation, obvious pathological injury was visible in the spinal cords of each group. Magnetic resonance diffusion tensor imaging revealed the radiation injury to the spinal cord, and we quantified the degree of spinal cord injury through apparent diffusion coefficient and fractional anisotropy. Related Articles | Metrics

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Endoplasmic reticulum stress transducer old astrocyte specifically induced substance contributes to astrogliosis after spinal cord injury Atsushi Takazawa, Naosuke Kamei, Nobuo Adachi, Mitsuo Ochi 2018, 13 (3):  536-540.  doi: 10.4103/1673-5374.228759 Abstract ( 117 )   PDF (1253KB) ( 190 )   Save Old astrocyte specifically induced substance (OASIS) is an endoplasmic reticulum (ER) stress transducer specifically expressed in astrocytes and osteoblasts. OASIS regulates the differentiation of neural precursor cells into astrocytes in the central nervous system. This study aimed to elucidate the involvement of ER stress responses stimulated via OASIS in astrogliosis following spinal cord injury. In a mouse model of spinal cord contusion injury, OASIS mRNA and protein expression were evaluated at days 7 and 14. A significant increase in OASIS mRNA on day 7 and an increase in protein on days 7 and 14 was observed in injured spinal cords. Immunostaining on day 7 revealed co-localization of OASIS and astrocytes in the periphery of the injury site. Furthermore, anti-OASIS small interfering RNA (siRNA) was injected at the injury sites on day 5 to elucidate the function of OASIS. Treatment with anti-OASIS siRNA caused a significant decrease in OASIS mRNA on day 7 and protein on days 7 and 14, and was associated with the inhibition of astrogliosis and hindlimb motor function recovery. Results of our study show that OASIS expression synchronizes with astrogliosis and is functionally associated with astrogliosis after spinal cord injury. Related Articles | Metrics

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Combined acupuncture and HuangDiSan treatment affects behavior and synaptophysin levels in the hippocampus of senescence-accelerated mouse prone 8 after neural stem cell transplantation Chun-lei Zhou, Lan Zhao,Hui-yan Shi, Jian-wei Liu, Jiang-wei Shi, Bo-hong Kan, Zhen Li, Jian-chun Yu, Jing-xian Han 2018, 13 (3):  541-548.  doi: 10.4103/1673-5374.228760 Abstract ( 145 )   PDF (494KB) ( 180 )   Save Sanjiao acupuncture and HuangDiSan can promote the proliferation, migration and differentiation of exogenous neural stem cells in senescence-accelerated mouse prone 8 (SAMP8) mice and can improve learning and memory impairment and behavioral function in dementia-model mice. Thus, we sought to determine whether Sanjiao acupuncture and HuangDiSan can elevate the effect of neural stem cell transplantation in Alzheimer’s disease model mice. Sanjiao acupuncture was used to stimulate Danzhong (CV17), Zhongwan (CV12),Qihai (CV6), bilateral Xuehai (SP10) and bilateral Zusanli (ST36) 15 days before and after implantation of neural stem cells (5 × 105) into the hippocampal dentate gyrus of SAMP8 mice. Simultaneously, 0.2 mL HuangDiSan, containing Rehmannia Root and Chinese Angelica,was intragastrically administered. Our results demonstrated that compared with mice undergoing neural stem cell transplantation alone,learning ability was significantly improved and synaptophysin mRNA and protein levels were greatly increased in the hippocampus of mice undergoing both Sanjiao acupuncture and intragastric administration of HuangDiSan. We conclude that the combination of Sanjiao acupuncture and HuangDiSan can effectively improve dementia symptoms in mice, and the mechanism of this action might be related to the regulation of synaptophysin expression. Related Articles | Metrics

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The ROCK pathway inhibitor Y-27632 mitigates hypoxia and oxidative stress-induced injury to retinal Müller cells Xiao-hui Zhang, Zhao-hui Feng, Xiao-yu Wang 2018, 13 (3):  549-555.  doi: 10.4103/1673-5374.228761 Abstract ( 146 )   PDF (2633KB) ( 242 )   Save Rho kinase (ROCK) was the first downstream Rho effector found to mediate RhoA-induced actin cytoskeletal changes through effects on myosin light chain phosphorylation. There is abundant evidence that the ROCK pathway participates in the pathogenesis of retinal endothelial injury and proliferative epiretinal membrane traction. In this study, we investigated the effect of the ROCK pathway inhibitor Y-27632 on retinal Müller cells subjected to hypoxia or oxidative stress. Müller cells were subjected to hypoxia or oxidative stress by exposure to CoCl2 or H2O2. After a 24-hour treatment with Y-27632, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to assess the survival of Müller cells. Hoechst 33258 was used to detect apoptosis, while 2′,7′-dichlorodihydrofluorescein diacetate was used to measure reactive oxygen species generation. A transwell chamber system was used to examine the migration ability of Müller cells. Western blot assay was used to detect the expression levels of α-smooth muscle actin, glutamine synthetase and vimentin. After treatment with Y-27632, Müller cells subjected to hypoxia or oxidative stress exhibited a morphology similar to control cells. Y-27632 reduced apoptosis, α-smooth muscle actin expression and reactive oxygen species generation under oxidative stress, and it reduced cell migration under hypoxia. Y-27632 also upregulated glutamine synthetase expression under hypoxia but did not impact vimentin expression. These findings suggest that Y-27632 protects Müller cells against cellular injury caused by oxidative stress and hypoxia by inhibiting the ROCK pathway. Related Articles | Metrics

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Regulatory role of calpain in neuronal death Si-ying Cheng, Shu-chao Wang, Ming Lei, Zhen Wang, Kun Xiong 2018, 13 (3):  556-562.  doi: 10.4103/1673-5374.228762 Abstract ( 275 )   PDF (350KB) ( 354 )   Save Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly (ADP-ribose)polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases. Related Articles | Metrics

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Optic radiation injury in patients with aneurismal subarachnoid hemorrhage: a preliminary diffusion tensor imaging report Sung Ho Jang, Chul Hoon Chang, Young Jin Jung, Seong Ho Kim, Jeong Pyo Seo 2018, 13 (3):  563-566.  doi: 10.4103/1673-5374.228763 Abstract ( 113 )   PDF (564KB) ( 146 )   Save Visual field defect is one of the various clinical manifestations in patients with subarachnoid hemorrhage(SAH). Little is known about the pathogenic mechanism of visual field defect in SAH. In the current study,we investigated the diffusion tensor imaging (DTI) finding of the optic radiation in patients with SAH following rupture of a cerebral artery aneurysm. We recruited 21 patients with aneurismal SAH (12 males, 9 females, mean age, 52.67 years; range, 41–68 years) who showed no definite lesion along the visual pathway.Twenty-one age-and sex-matched normal control subjects were also recruited. DTI data were acquired at an average of 5.9 weeks (range: 3–12 weeks) after onset and reconstruction of the optic radiation was performed using DTI-Studio software. The fractional anisotropy value, apparent diffusion coefficient value,and fiber number of the optic radiation were measured. The fractional anisotropy value of the optic radiation was significantly decreased, and the apparent diffusion coefficient value was significantly increased, in patients with aneurismal SAH than in normal control subjects. However, there was no significant difference in the fiber number of the optic radiation between patients with aneurismal SAH and normal control subjects. The decrement of fractional anisotropy value and increment of apparent diffusion coefficient value of the optic radiation in patients with aneurismal SAH suggest optic radiation injury. Therefore, we recommend a thorough evaluation for optic radiation injury in patient with aneurismal SAH. Related Articles | Metrics

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The biological clock: future of neurological disorders therapy Sagar Gaikwad 2018, 13 (3):  567-568.  doi: 10.4103/1673-5374.228764 Abstract ( 150 )   PDF (838KB) ( 172 )   Save The seminal, discoveries by Jeffrey Connor Hall, Michael Rosbash and Michael Warren Young have earned the Nobel Prize in Physiology and Medicine 2017 for revealing a crucial physiological mechanism explaining biological clock, with important implications for human health and diseases. The work explains the interplay between the biological clock, the transcriptional feedback loop, and neuroscience, where they identified genes and proteins that work together both in humans and other animals.This article describes the link between biological clock disruption and consequent neurodegeneration and also highlights the significance of biological clock modulators for possible clinical interventions in neurological disorders. Related Articles | Metrics