Table of Content

15 June 2020, Volume 15 Issue 6 Previous Issue    Next Issue

For Selected:

Download Citations EndNote Reference Manager ProCite BibTeX RefWorks

Toggle Thumbnails

Select

Adult neurogenesis from reprogrammed astrocytes Brian B. Griffiths, Anvee Bhutani, Creed M. Stary 2020, 15 (6):  973-979.  doi: 10.4103/1673-5374.270292 Abstract ( 124 )   PDF (1080KB) ( 212 )   Save The details of adult neurogenesis, including environmental triggers, region specificity, and species homology remain an area of intense investigation. Slowing or halting age-related cognitive dysfunction, or restoring neurons lost to disease or injury represent just a fraction of potential therapeutic applications. New neurons can derive from stem cells, pluripotent neural progenitor cells, or non-neuronal glial cells, such as astrocytes. Astrocytes must be epigenetically “reprogrammed” to become neurons, which can occur both naturally in vivo, and via artificial exogenous treatments. While neural progenitor cells are localized to a few neurogenic zones in the adult brain, astrocytes populate almost every brain structure. In this review, we will summarize recent research into neurogenesis that arises from conversion of post-mitotic astrocytes, detail the genetic and epigenetic pathways that regulate this process, and discuss the possible clinical relevance in supplementing stem-cell neurogenic therapies. Related Articles | Metrics

Select

Astrocytic modulation of potassium under seizures Fushun Wang, Xiaoming Qi, Jun Zhang, Jason H. Huang 2020, 15 (6):  980-987.  doi: 10.4103/1673-5374.270295 Abstract ( 120 )   PDF (832KB) ( 201 )   Save The contribution of an impaired astrocytic K+ regulation system to epileptic neuronal hyperexcitability has been increasingly recognized in the last decade. A defective K+ regulation leads to an elevated extracellular K+ concentration ([K+]o). When [K+]o reaches peaks of 10–12 mM, it is strongly associated with seizure initiation during hypersynchronous neuronal activities. On the other hand, reactive astrocytes during a seizure attack restrict influx of K+ across the membrane both passively and actively. In addition to decreased K+ buffering, aberrant Ca2+ signaling and declined glutamate transport have also been observed in astrogliosis in epileptic specimens, precipitating an increased neuronal discharge and induction of seizures. This review aims to provide an overview of experimental findings that implicated astrocytic modulation of extracellular K+ in the mechanism of epileptogenesis. Related Articles | Metrics

Select

Type XIX collagen: a promising biomarker from the basement membranes Ana C. Calvo, Laura Moreno, Leticia Moreno, Janne M. Toivonen, Raquel Manzano, Nora Molina, Miriam de la Torre, Tresa López, Francisco J. Miana-Mena, María J. Muñoz, Pilar Zaragoza, Pilar Larrodé, Alberto García-Redondo, Rosario Osta 2020, 15 (6):  988-995.  doi: 10.4103/1673-5374.270299 Abstract ( 196 )   PDF (1334KB) ( 231 )   Save Among collagen members in the collagen superfamily, type XIX collagen has raised increasing interest in relation to its structural and biological roles. Type XIX collagen is a Fibril-Associated Collagen with Interrupted Triple helices member, one main subclass of collagens in this superfamily. This collagen contains a triple helix composed of three polypeptide segments aligned in parallel and it is associated with the basement membrane zone in different tissues. The molecular structure of type XIX collagen consists of five collagenous domains, COL1 to COL5, interrupted by six non-collagenous domains, NC1 to NC6. The most relevant domain by which this collagen exerts its biological roles is NC1 domain that can be cleavage enzymatically to release matricryptins, exerting anti-tumor and anti-angiogenic effect in murine and human models of cancer. Under physiological conditions, type XIX collagen expression decreases after birth in different tissues although it is necessary to keep its basal levels, mainly in skeletal muscle and hippocampal and telencephalic interneurons in brain. Notwithstanding, in amyotrophic lateral sclerosis, altered transcript expression levels show a novel biological effect of this collagen beyond its structural role in basement membranes and its anti-tumor and anti-angiogenic properties. Type XIX collagen can exert a compensatory effect to ameliorate the disease progression under neurodegenerative conditions specific to amyotrophic lateral sclerosis in transgenic SOD1G93A mice and amyotrophic lateral sclerosis patients. This novel biological role highlights its nature as prognostic biomarker of disease progression in and as promising therapeutic target, paving the way to a more precise prognosis of amyotrophic lateral sclerosis. Related Articles | Metrics

Select

Heterogeneity in the regenerative abilities of central nervous system axons within species: why do some neurons regenerate better than others? William Rodemer, Jianli Hu, Michael E. Selzer, Michael I. Shifman 2020, 15 (6):  996-1005.  doi: 10.4103/1673-5374.270298 Abstract ( 148 )   PDF (1240KB) ( 259 )   Save Some neurons, especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system (CNS) regenerate after axotomy, while most mammalian CNS neurons fail to regenerate. There is an emerging consensus that neurons have different intrinsic regenerative capabilities, which theoretically could be manipulated therapeutically to improve regeneration. Population-based comparisons between “good regenerating” and “bad regenerating” neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret. At least in part, this reflects the great diversity of cells in the mammalian CNS. Using mammalian nervous system imposes several methodical limitations. First, the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ones. Second, the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron, and therefore, to dissect the molecular mechanisms of regeneration on the level of single neurons. This review will survey the reported responses to axon injury and the determinants of axon regeneration, emphasizing non-mammalian model organisms, which are often under-utilized, but in which the data are especially easy to interpret. Related Articles | Metrics

Select

Locus coeruleus-norepinephrine: basic functions and insights into Parkinson’s disease Bilal Abdul Bari, Varun Chokshi, Katharina Schmidt 2020, 15 (6):  1006-1013.  doi: 10.4103/1673-5374.270297 Abstract ( 264 )   PDF (600KB) ( 246 )   Save The locus coeruleus is a pontine nucleus that produces much of the brain’s norepinephrine. Despite its small size, the locus coeruleus is critical for a myriad of functions and is involved in many neurodegenerative and neuropsychiatric disorders. In this review, we discuss the physiology and anatomy of the locus coeruleus system and focus on norepinephrine’s role in synaptic plasticity. We highlight Parkinson’s disease as a disorder with motor and neuropsychiatric symptoms that may be understood as aberrations in the normal functions of locus coeruleus. Related Articles | Metrics

Select

Stroke gets in your eyes: stroke-induced retinal ischemia and the potential of stem cell therapy Chase Kingsbury, Matt Heyck, Brooke Bonsack, Jea-Young Lee, Cesar V. Borlongan 2020, 15 (6):  1014-1018.  doi: 10.4103/1673-5374.270293 Abstract ( 151 )   PDF (791KB) ( 179 )   Save Stroke persists as a global health and economic crisis, yet only two interventions to reduce stroke-induced brain injury exist. In the clinic, many patients who experience an ischemic stroke often further suffer from retinal ischemia, which can inhibit their ability to make a functional recovery and may diminish their overall quality of life. Despite this, no treatments for retinal ischemia have been developed. In both cases, ischemia-induced mitochondrial dysfunction initiates a cell loss cascade and inhibits endogenous brain repair. Stem cells have the ability to transfer healthy and functional mitochondria not only ischemic neurons, but also to similarly endangered retinal cells, replacing their defective mitochondria and thereby reducing cell death. In this review, we encapsulate and assess the relationship between cerebral and retinal ischemia, recent preclinical advancements made using in vitro and in vivo retinal ischemia models, the role of mitochondrial dysfunction in retinal ischemia pathology, and the therapeutic potential of stem cell-mediated mitochondrial transfer. Furthermore, we discuss the pitfalls in classic rodent functional assessments and the potential advantages of laser Doppler as a metric of stroke progression. The studies evaluated in this review highlight stem cell-derived mitochondrial transfer as a novel therapeutic approach to both retinal ischemia and stroke. Furthermore, we posit the immense correlation between cerebral and retinal ischemia as an underserved area of study, warranting exploration with the aim of these treating injuries together. Related Articles | Metrics

Select

Using our mini-brains: cerebral organoids as an improved cellular model for human prion disease Bradley R. Groveman, Ryan Walters, Cathryn L. Haigh 2020, 15 (6):  1019-1020.  doi: 10.4103/1673-5374.270300 Abstract ( 134 )   PDF (677KB) ( 216 )   Save Neurodegenerative diseases are an ever-increasing burden in an aging society. Currently no cure is available for any of these diseases and treatment is based on managing symptoms. Despite many candidate therapeutics demonstrating promise in animal models, none has yet shown efficacy in human trials. It is self-evident that humans are different from the animals used to model our diseases, especially models that have been highly manipulated to generate a disease in an animal that does not naturally have such a disease. These differences are likely the reason for the failures of drug candidates in human trials but, until recently, human models of neurodegenerative diseases were lacking. The development of the human cerebral organoid model, by differentiating three-dimensional human neuronal tissue from pluripotent stem cells, represents a significant advance in studying human brain diseases. Cerebral organoids have been used to model Alzheimer’s disease, Parkinson’s disease, Down’s syndrome dementia and we have now shown they can be infected with human prions creating a new model of human prion diseases. Related Articles | Metrics

Select

Harnessing the stem cell properties of pericytes to repair the brain Jo-Maree Courtney, Brad A. Sutherland 2020, 15 (6):  1021-1022.  doi: 10.4103/1673-5374.270301 Abstract ( 130 )   PDF (357KB) ( 149 )   Save Over the last ten years or so, it has become apparent that pericytes have the potential to differentiate into other cell types which may help in the repair and regeneration of tissue after injury. In fact, pericytes have been described as a precursor to mesenchymal stem cells. Their location at the interface between the microvasculature and the brain parenchyma means they are ideally positioned to initiate repair and regeneration in response to various factors. In this perspective, we will highlight how pericytes have stem cell potential alongside their role in regulating processes, such as angiogenesis and inflammation, and discuss how pericytes could be harnessed to promote tissue repair in the brain. Related Articles | Metrics

Select

Exosome-mediated crosstalk between microglia and neural stem cells in the repair of brain injury Bo-Ru Hou, Cheng Jiang, Ze-Ning Wang, Hai-Jun Ren 2020, 15 (6):  1023-1024.  doi: 10.4103/1673-5374.270302 Abstract ( 136 )   PDF (649KB) ( 211 )   Save Brain injury, especially that caused by stroke, is a leading cause of morbidity and mortality worldwide. Numerous studies on the neuroprotective effects of neural stem cells (NSCs) after brain injury have shown that crosstalk among neural cells, including neuron–glial, glial–glial, NSC–neuronal and NSC–glial communication, plays a major role in post-injury repair. Therefore, a better understanding of the factors involved in the interactions between NSCs and other neural cells should advance the development of therapeutic strategies for brain injury. In this article, we discuss the role of exosomes in the crosstalk between NSCs and microglia, focusing on key exosomal proteins and microRNAs in brain injury progression and repair. Related Articles | Metrics

Select

The extended renin-angiotensin system: a promising target for traumatic brain injury therapeutics Zachary C. Janatpour, Aviva J. Symes 2020, 15 (6):  1025-1026.  doi: 10.4103/1673-5374.270304 Abstract ( 111 )   PDF (456KB) ( 224 )   Save Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Global assessments estimate that over 27 million cases of TBI occur annually, resulting in over 8 million years lived with disability (GBD 2016 Dementia Collaborators, 2019). Over 30 clinical trials have failed to show efficacy in TBI, and patients are currently left without any promising therapeutic options (Villapol et al., 2015). The pathophysiology of TBI is commonly divided into primary and secondary injuries. Primary injury refers to the parenchymal damage that occurs as an immediate consequence of acute kinetic energy transfer to the brain (i.e., membrane rupture, hemorrhage, axotomy, etc.). Secondary injury encompasses the deleterious molecular and cellular responses that occur in response to the primary injury in the minutes, hours or days following. The search for therapeutics that mitigate the effects of the secondary injury and/or assist endogenous repair processes remains a large focus of TBI research (Umschweif et al., 2014; Villapol et al., 2015; Janatpour et al., 2019). Related Articles | Metrics

Select

A human translational model based on neuroplasticity for pharmacological agents potentially effective in Treatment-Resistant Depression: focus on dopaminergic system Ginetta Collo, Emilio Merlo Pich 2020, 15 (6):  1027-1029.  doi: 10.4103/1673-5374.270305 Abstract ( 115 )   PDF (843KB) ( 190 )   Save Major depressive disorder (MDD) is a common psychiatric condition characterized by two main symptoms, low mood and anhedonia. About 15–30% of people suffering from MDD do not respond to standard-of-care antidepressants, e.g., the serotonin re-uptake inhibitors (SSRI), and are considered affected by Treatment-Resistant Depression (TRD). The neurobiology of this condition is presently unknown. Recent attempts of developing novel treatments for TRD have been driven by four major breakthroughs: (1) Increasing dopaminergic neurotransmission improves TRD symptoms; (2) Anhedonia occurs when central dopaminergic neurotransmission is low; (3) Enhanced neuroplasticity is critical for the action of antidepressants; (4) Ketamine shows antidepressant properties in TRD patients and triggers neuroplasticity in preclinical animal models. These breakthroughs are at the basis of a putative human translational cellular model for antidepressant agents that we are proposing in this article. The rationale is briefly described here. Related Articles | Metrics

Select

Vascular dysfunction in Alzheimer’s disease: a biomarker of disease progression and a potential therapeutic target Karan Govindpani, Chitra Vinnakota, Henry J. Waldvogel, Richard L. Faull, Andrea Kwakowsky 2020, 15 (6):  1030-1032.  doi: 10.4103/1673-5374.270306 Abstract ( 114 )   PDF (575KB) ( 156 )   Save Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the predominant form of dementia. Since its initial description by Alois Alzheimer in 1906, several advances have been made in our understanding of the progression of the disease and its clinical consequences, yet the underlying etiology remains contentious. Given the stereotyped patterns of cortical and hippocampal neuronal loss and the progressive degeneration of key neurotransmitter pathways, research has traditionally been focused on factors affecting neuronal viability, including the contribution of glial dysfunction to neuronal degeneration. From a clinical perspective, the fruits of this work have been underwhelming. Key pathological markers of the disease, including β-amyloid (Aβ) plaque formation and tau hyperphosphorylation, have yielded no effective therapies, highlighted by the recent discontinuations of several high profile Aβ immunotherapy trials. The few current symptomatic therapies for AD are predicated on the amelioration of cholinergic or glutamatergic dysfunction. Aside from underscoring the inadequacy of current therapeutic approaches, this also points to the importance of alternative contributors to AD pathogenesis. In recent years, there has been a growing appreciation for the multimodal and multifactorial nature of the condition; the case for combinatorial therapies is thus strong. Related Articles | Metrics

Select

Remote ischemic conditioning approach for the treatment of ischemic stroke Seyed Mohammad Seyedsaadat, David F. Kallmes, Waleed Brinjikji 2020, 15 (6):  1033-1034.  doi: 10.4103/1673-5374.270303 Abstract ( 129 )   PDF (621KB) ( 199 )   Save Stroke is the leading cause of disability and death in North America. There has been growing interest in identifying neuroprotective strategies to reduce ischemic burden in patients with acute ischemic stroke. However, despite extensive clinical trials, no neuroprotective agent has been found for prevention of ischemic damage. Remote ischemic preconditioning (RIC) is a promising non-invasive strategy that has been proven to provide renal and cardioprotection and has recently found to have a potential broad application in the treatment of neurovascular disease, which has bee linked to its possible effects on the release and activation of endogenous neuroprotective substances against the ischemia/reperfusion injuries in experimental studies. This endogenous neuroprotection might vaccinate neural tissues against effects of acute IR following primary infarction insult. Regardless of the method of RIC administration, through manual or automated blood pressure cuff, RIC procedure is inexpensive and easy to use. Based on the experimental and clinical data, application of RIC avoids possible adverse effects and interactions associated with chemical pharmacological agents. In previous clinical studies RIC was safe and associated with only minor transient adverse effects in few cases, including petechia and minor limb pain, which were mostly resolved shortly after completing the treatment. RIC involves between three to five cycles of 5 minutes blood pressure cuff inflation and 5 minutes of deflation on the upper or lower extremity. RIC can be applied before (Pre-RIC), during (Per-RIC) and after (Post-RIC) infarction and can be safely continued for a prolonged period of time in human. Related Articles | Metrics

Select

Abscisic acid, a promising therapeutic molecule to prevent Alzheimer’s and neurodegenerative diseases Ana María Sánchez-Pérez 2020, 15 (6):  1035-1036.  doi: 10.4103/1673-5374.270307 Abstract ( 122 )   PDF (322KB) ( 170 )   Save Neuroinflammatory processes induce neuronal damage and underlie the onset of neurodegenerative pathologies, including Alzheimer’s disease (AD) (Calsolaro and Edison, 2016). Several conditions, ranging from emotional stress to metabolic syndrome, including traumatic brain injury, chronic infections or gut microbiota disruption can cause or aggravate neuroinflammation. Moreover, aging is the major factor associated with neurodegenerative diseases. Related Articles | Metrics

Select

Leaky gut, dysbiosis, and enteric glia activation: the trilogy behind the intestinal origin of Parkinson’s disease Luisa Seguella, Giovanni Sarnelli, Giuseppe Esposito 2020, 15 (6):  1037-1038.  doi: 10.4103/1673-5374.270308 Abstract ( 139 )   PDF (573KB) ( 311 )   Save PD is a neurodegenerative disease characterized by motor dysfunctions (tremor, rigidity, bradykinesia and impaired posture/ balance) elicited by selective depletion of dopaminergic (DA) neurons in substantia nigra pars compacta. DA neuron loss is associated with neuronal inclusions of the phosphorylated α-synuclein protein called Lewy body (Shults, 2006). Although the underlying neurodegenerative process is not affected, the management of PD patients has been revolutionized with the introduction of levodopa and DA drugs in the routine therapy, which ensures initial symptomatic relief of motor functions through the DA supply in the nigrostriatal circuit. These drugs are currently the best option for treating PD, although their chronic use is associated with progressive dopamine resistance and loss of effectiveness in the recovery of motor dysfunctions. Alternative therapeutic strategies, including agonists of DA receptors, monoamine oxide B inhibitors, and even deep brain stimulation techniques have been developed to overcome these clinical limitations. Unfortunately, these therapeutic approaches cannot restore PD-compromised functions, as irreversible DA neurodegeneration has occurred in substantia nigra pars compacta when first motor symptoms appear. The nigrostriatal system is traditionally considered as the first region affected by neuronal impairment in Parkinsonisms; however, α-synuclein aggregation appears in a pre-motor stage of the disease in the enteric nervous system (ENS), strongly highlighting an extra-central nervous system (CNS) origin for this neurodegenerative disorder and completely overturning the concept of PD as a central disease. The “ability” of the gut to show the pre-symptomatic evolution of PD is a very fascinating hypothesis to anticipate PD diagnosis and develop more efficient anti-Parkinsonian drugs. In this perspective article, we summarize recent evidence showing enteric glia involvement triggering intestinal neuroinflammation in the asymptomatic stage of PD and improvements in the therapeutic approach that we could achieve by targeting these glial cells. Related Articles | Metrics

Select

Orexin/hypocretinin in multiple sclerosis and experimental autoimmune encephalomyelitis Jean Pierre Pallais, Catherine M. Kotz, Milos Stanojlovic 2020, 15 (6):  1039-1040.  doi: 10.4103/1673-5374.270310 Abstract ( 129 )   PDF (1007KB) ( 167 )   Save Multiple sclerosis (MS) is a T-cell-mediated autoimmune disease of the central nervous system (CNS). Worldwide, more than 2.3 million people are diagnosed with MS. Since its clinical manifestations appear typically in the third and fourth decades of life, MS is a major cause of neurological disability in young adults and has wide health, psychological, economic, and social consequences. There are three key pathological features of MS: inflammation; demyelination and oligodendrocyte loss; axonal loss and neurodegeneration. There are two main hypotheses regarding mechanisms of MS pathology. The “outside-in” concept is an older, widely recognized hypothesis that describes neurodegeneration as a consequence of inflammatory induced demyelination, which is caused by immune system activation (Lassmann et al., 2012). Mechanisms of T-cell mediated myelin destruction are extensively studied, but the manner by which the immune system perceives myelin as foreign, and induces an autoimmune response is still unknown. The newer, “inside- out” hypothesis considers MS to be a primary degenerative disorder, which initiates in oligodendrocytes and results in neuroinflammation that leads to demyelination (Stys et al., 2012). As one of the main pathological features of MS-pathology, induced neurodegenerative processes are present in different brain regions, including the hypothalamus (Hyp). Related Articles | Metrics

Select

Novel small molecule TRVA242 targets neuromuscular junction in amyotrophic lateral sclerosis Poulomee Bose 2020, 15 (6):  1041-1042.  doi: 10.4103/1673-5374.270309 Abstract ( 150 )   PDF (531KB) ( 198 )   Save Research over the past decade has enabled a deeper understanding of the pathophysiology of amyotrophic lateral sclerosis (ALS). While 10% of all ALS cases have been reported to be familial with a clear Mendelian inheritance, clinically, sporadic and familial forms of ALS cannot be distinguished (Robberecht and Philips, 2013). Presently there are only two Food and Drug Administration approved treatment options for ALS - riluzole and radicava (also known as edavarone). Riluzole is mostly known to delay the onset of ventilator dependence and extends the life span by 2–3 months; edavarone on the other hand has been reported slow disease progression at all stages in ALS (Jaiswal, 2019). However, given the multifaceted nature of ALS, there is an urgent need to identify more molecules with a strong therapeutic potential. Related Articles | Metrics

Select

Human endogenous retroviruses: ammunition for myeloid cells in neurodegenerative diseases? Joel Gruchot, David Kremer, Patrick Küry 2020, 15 (6):  1043-1044.  doi: 10.4103/1673-5374.270311 Abstract ( 123 )   PDF (471KB) ( 141 )   Save While the exact causes of neurological diseases such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS) are still elusive, there is evidence of a new category of pathogenic elements called human endogenous retroviruses (HERVs) which seem to contribute to their evolution and progression by exerting inflammatory and degenerative effects (Küry et al., 2018). HERVs are ancient retroviral elements which account for up to 8% of the human genome and it is known that environmental factors can trigger their (re-)expression (Küry et al., 2018). The resulting production of viral particles and/or proteins, especially from members of the HERV-W and HERV-K family, is strongly correlated with the onset and progression of neurological diseases, such as MS and ALS Related Articles | Metrics

Select

Modified constraint-induced movement therapy alters synaptic plasticity of rat contralateral hippocampus following middle cerebral artery occlusion Bei-Yao Gao, Dong-Sheng Xu, Pei-Le Liu, Ce Li, Liang Du, Yan Hua, Jian Hu, Jia-Yun Hou, Yu-Long Bai 2020, 15 (6):  1045-1057.  doi: 10.4103/1673-5374.270312 Abstract ( 177 )   PDF (3314KB) ( 383 )   Save Modified constraint-induced movement therapy is an effective treatment for neurological and motor impairments in patients with stroke by increasing the use of their affected limb and limiting the contralateral limb. However, the molecular mechanism underlying its efficacy remains unclear. In this study, a middle cerebral artery occlusion (MCAO) rat model was produced by the suture method. Rats received modified constraint-induced movement therapy 1 hour a day for 14 consecutive days, starting from the 7th day after middle cerebral artery occlusion. Day 1 of treatment lasted for 10 minutes at 2 r/min, day 2 for 20 minutes at 2 r/min, and from day 3 onward for 20 minutes at 4 r/min. CatWalk gait analysis, adhesive removal test, and Y-maze test were used to investigate motor function, sensory function as well as cognitive function in rodent animals from the 1st day before MCAO to the 21st day after MCAO. On the 21st day after MCAO, the neurotransmitter receptor-related genes from both contralateral and ipsilateral hippocampi were tested by micro-array and then verified by western blot assay. The glutamate related receptor was shown by transmission electron microscopy and the glutamate content was determined by high-performance liquid chromatography. The results of behavior tests showed that modified constraint-induced movement therapy promoted motor and sensory functional recovery in the middle cerebral artery-occluded rats, but had no effect on cognitive function. The modified constraint-induced movement therapy upregulated the expression of glutamate ionotropic receptor AMPA type subunit 3 (Gria3) in the hippocampus and downregulated the expression of the beta3-adrenergic receptor gene Adrb3 and arginine vasopressin receptor 1A, Avpr1a in the middle cerebral artery-occluded rats. In the ipsilateral hippocampus, only Adra2a was downregulated, and there was no significant change in Gria3. Transmission electron microscopy revealed a denser distribution the more distribution of postsynaptic glutamate receptor 2/3, which is an α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor, within 240 nm of the postsynaptic density in the contralateral cornu ammonis 3 region. The size and distribution of the synaptic vesicles within 100 nm of the presynaptic active zone were unchanged. Western blot analysis showed that modified constraint-induced movement therapy also increased the expression of glutamate receptor 2/3 and brain-derived neurotrophic factor in the hippocampus of rats with middle cerebral artery occlusion, but had no effect on Synapsin I levels. Besides, we also found modified constraint-induced movement therapy effectively reduced glutamate content in the contralateral hippocampus. This study demonstrated that modified constraint-induced movement therapy is an effective rehabilitation therapy in middle cerebral artery-occluded rats, and suggests that these positive effects occur via the upregulation of the postsynaptic membrane α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor expression. This study was approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval No. 201802173S) on March 3, 2018. Related Articles | Metrics

Select

A mimetic peptide of α2,6-sialyllactose promotes neuritogenesis Shuang-Xi Chen, Jia-Hui He, Yong-Jian Mi, Hui-Fan Shen, Melitta Schachner, Wei-Jiang Zhao 2020, 15 (6):  1058-1065.  doi: 10.4103/1673-5374.270313 Abstract ( 196 )   PDF (1338KB) ( 227 )   Save Oxidative stress contributes to the pathogenesis of neurodegenerative diseases. With the aim to find reagents that reduce oxidative stress, a phage display library was screened for peptides mimicking α2,6-sialyllactose (6′-SL), which is known to beneficially influence neural functions. Using Sambucus nigra lectin, which specifically binds to 6′-SL, we screened a phage display library and found a peptide comprising identical sequences of 12 amino acids. Mimetic peptide, reverse peptide and scrambled peptide were tested for inhibition of 6′-SL binding to the lectin. Indeed, lectin binding to 6′-SL was inhibited by the most frequently identified mimetic peptide, but not by the reverse or scrambled peptides, showing that this peptide mimics 6′-SL. Functionally, mimetic peptide, but not the reverse or scrambled peptides, increased viability and expression of neural cell adhesion molecule L1 in SK-N-SH human neuroblastoma cells, and promoted survival and neurite outgrowth of cultured mouse cerebellar granule neurons challenged by H2O2-induced oxidative stress. The combined results indicate that the 6′-SL mimetic peptide promotes neuronal survival and neuritogenesis, thus raising hopes for the treatment of neurodegenerative diseases. This study was approved by the Medical Ethics Committee of Shantou University Medical College, China (approval No. SUMC 2014-004) on February 20, 2014. Related Articles | Metrics

Select

Proprotein convertase 1/3-mediated down-regulation of brain-derived neurotrophic factor in cortical neurons induced by oxygen-glucose deprivation Xiang-Yang Zhang, Feng Liu, Yan Chen, Wei-Chun Guo, Zhao-Hui Zhang 2020, 15 (6):  1066-1070.  doi: 10.4103/1673-5374.270314 Abstract ( 148 )   PDF (748KB) ( 155 )   Save Brain-derived neurotrophic factor (BDNF) has robust effects on synaptogenesis, neuronal differentiation and synaptic transmission and plasticity. The maturation of BDNF is a complex process. Proprotein convertase 1/3 (PC1/3) has a key role in the cleavage of protein precursors that are directed to regulated secretory pathways; however, it is not clear whether PC1/3 mediates the change in BDNF levels caused by ischemia. To clarify the role of PC1/3 in BDNF maturation in ischemic cortical neurons, primary cortical neurons from fetal rats were cultured in a humidified environment of 95% N2 and 5% CO2 in a glucose-free Dulbecco’s modified Eagle’s medium at 37°C for 3 hours. Enzyme-linked immunosorbent assays and western blotting showed that after oxygen-glucose deprivation, the secreted and intracellular levels of BDNF were significantly reduced and the intracellular level of PC1/3 was decreased. Transient transfection of cortical neurons with a PC1/3 overexpression plasmid followed by oxygen-glucose deprivation resulted in increased PC1/3 levels and increased BDNF levels. When levels of the BDNF precursor protein were reduced, the concentration of BDNF in the culture medium was increased. These results indicate that PC1/3 cleavage of BDNF is critical for the conversion of pro-BDNF in rat cortical neurons during ischemia. The study was approved by the Animal Ethics Committee of Wuhan University School of Basic Medical Sciences. Related Articles | Metrics

Select

Outgrowth endothelial cells form a functional cerebral barrier and restore its integrity afer damage Rais Reskiawan Abdulkadir, Mansour Alwjwaj, Othman Ahmad Othman, Kamini Rakkar, Ulvi Bayraktutan 2020, 15 (6):  1071-1078.  doi: 10.4103/1673-5374.269029 Abstract ( 198 )   PDF (6310KB) ( 211 )   Save Breakdown of blood-brain barrier, formed mainly by brain microvascular endothelial cells (BMECs), rep- resents the major cause of mortality during early phases of ischemic strokes. Hence, discovery of novel agents that can efectively replace dead or dying endothelial cells to restore blood-brain barrier integrity is of paramount importance in stroke medicine. Although endothelial progenitor cells (EPCs) represent one such agents, their rarity in peripheral blood severely limits their adequate isolation and therapeutic use for acute ischemic stroke which necessitate their ex vivo expansion and generate early EPCs and outgrowth endothelial cells (OECs) as a result. Functional analyses of these cells, in the present study, demonstrated that only OECs endocytosed DiI-labelled acetylated low-density lipoprotein and formed tubules on matri- gel, prominent endothelial cell and angiogenesis markers, respectively. Further analyses by fow cytometry demonstrated that OECs expressed specifc markers for stemness (CD34), immaturity (CD133) and endo- thelial cells (CD31) but not for hematopoietic cells (CD45). Like BMECs, OECs established an equally tight in vitro model of human BBB with astrocytes and pericytes, suggesting their capacity to form tight junc- tions. Ischemic injury mimicked by concurrent deprivation of oxygen and glucose (4 hours) or deprivation of oxygen and glucose followed by reperfusion (20 hours) afected both barrier integrity and function in a similar fashion as evidenced by decreases in transendothelial electrical resistance and increases in para- cellular fux, respectively. Wound scratch assays comparing the vasculoreparative capacity of cells revealed that, compared to BMECs, OECs possessed a greater proliferative and directional migratory capacity. In a triple culture model of BBB established with astrocytes, pericytes and BMEC, exogenous addition of OECs effectively repaired the damage induced on endothelial layer in serum-free conditions. Taken together, these data demonstrate that OECs may efectively home to the site of vascular injury and repair the damage to maintain (neuro)vascular homeostasis during or afer a cerebral ischemic injury Related Articles | Metrics

Select

Efects of CXCR7-neutralizing antibody on neurogenesis in the hippocampal dentate gyrus and cognitive function in the chronic phase of cerebral ischemia Bing-Chao Dong , Mei-Xuan Li , Xiao-Yin Wang , Xi Cheng , Yu Wang , Ting Xiao , Jukka Jolkkonen , Chuan-Sheng Zhao, Shan-Shan Zhao 2020, 15 (6):  1079-1085.  doi: 10.4103/1673-5374.270416 Abstract ( 146 )   PDF (3847KB) ( 188 )   Save Stromal cell-derived factor-1 and its receptor CXCR4 are essential regulators of the neurogenesis that occurs in the adult hippocampal dentate gyrus. However, the efects of CXCR7, a new atypical receptor of stromal cell-derived factor-1, on hippocampal neurogenesis afer a stroke remain largely unknown. Our study is the frst to investigate the efect of a CXCR7-neutralizing antibody on neurogenesis in the dentate gyrus and the associated recovery of cognitive function of rats in the chronic stage of cerebral ischemia. Te rats were randomly divided into sham, sham + anti-CXCR7, ischemia and ischemia + anti-CXCR7 groups. Endothelin-1 was injected in the ipsilateral motor cortex and striatum to induce focal cerebral ischemia. Sham group rats were injected with saline instead of endothelin-1 via intracranial in- jection. Both sham and ischemic rats were treated with intraventricular infusions of CXCR7-neutralizing antibodies for 6 days 1 week afer surgery. Immunofuorescence staining with doublecortin, a marker for neuronal precursors, was performed to assess the neurogenesis in the dentate gyrus. We found that anti-CXCR7 antibody infusion enhanced the proliferation and dendritic development of doublecortin-la- beled cells in the dentate gyrus in both ischemic and sham-operated rats. Spatial learning and memory functions were assessed by Morris water maze tests 30–32 days afer ischemia. CXCR7-neutralizing antibody treatment signifcantly reduced the escape latency of the spatial navigation trial and increased the time spent in the target quadrant of spatial probe trial in animals that received ischemic insult, but not in sham operated rats. Tese results suggest that CXCR7-neutralizing antibody enhances the neurogenesis in the dentate gyrus and improves the cognitive function afer cerebral ischemia in rats. All animal experimental protocols and procedures were approved by the Institutional Animal Care and Use Committee of China Medical University (CMU16089R) on December 8, 2016. Related Articles | Metrics

Select

Achyranthes bidentata polypeptides prevent apoptosis by inhibiting the glutamate current in cultured hippocampal neurons Rong-Lu Pan, Wen-Qing Hu, Jie Pan, Li Huang, Cheng-Cheng Luan, Hong-Mei Shen 2020, 15 (6):  1086-1093.  doi: 10.4103/1673-5374.270317 Abstract ( 155 )   PDF (1573KB) ( 179 )   Save Glutamate-induced excitotoxicity plays a critical role in the neurological impairment caused by middle cerebral artery occlusion. Achyran- thes bidentata polypeptides have been shown to protect against neurological functional damage caused by middle cerebral artery occlusion, but the underlying neuroprotective mechanisms and the relationship to glutamate-induced excitotoxicity remain unclear. Therefore, in the current study, we investigated the protective effects of Achyranthes bidentata polypeptides against glutamate-induced excitotoxicity in cultured hippocampal neurons. Hippocampal neurons were treated with Mg 2+ -free extracellular solution containing glutamate (300 µM) for 3 hours as a model of glutamate-mediated excitotoxicity (glutamate group). In the normal group, hippocampal neurons were incu- bated in Mg 2+ -free extracellular solution. In the Achyranthes bidentata polypeptide group, hippocampal neurons were incubated in Mg 2+ - free extracellular solution containing glutamate (300 µM) and Achyranthes bidentata polypeptide at different concentrations. At 24 hours after exposure to the agents, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Hoechst 33258 staining were used to assess neuronal viability and nuclear morphology, respectively. Caspase-3 expression and activity were evaluated using western blot assay and colorimetric enzymatic assay, respectively. At various time points after glutamate treatment, reactive oxygen species in cells were detected by H2DCF-DA, and mitochondrial membrane potential was detected by rhodamine 123 staining. To examine the effect of Achy- ranthes bidentata polypeptides on glutamate receptors, electrophysiological recording was used to measure the glutamate-induced inward current in cultured hippocampal neurons. Achyranthes bidentata polypeptide decreased the percentage of apoptotic cells and reduced the changes in caspase-3 expression and activity induced by glutamate. In addition, Achyranthes bidentata polypeptide attenuated the ampli- tude of the glutamate-induced current. Furthermore, the glutamate-induced increase in intracellular reactive oxygen species and reduction in mitochondrial membrane potential were attenuated by Achyranthes bidentata polypeptide treatment. These findings collectively suggest that Achyranthes bidentata polypeptides exert a neuroprotective effect in cultured hippocampal neurons by suppressing the overactivation of glutamate receptors and inhibiting the caspase-3-dependent mitochondrial apoptotic pathway. All animal studies were approved by the Animal Care and Use Committee, Nantong University, China (approval No. 20120216-001) on February 16, 2012. Related Articles | Metrics

Select

Photoacoustic treatment mitigates cognitive dysfunction in a model of sleep-wake rhythm disturbance Fang Xing, Xin Fang, Xiang-Dan Gong, Xin Zhao, Ying Du, Zheng-Liang Ma, Xiao-Ping Gu, Tian-Jiao Xia 2020, 15 (6):  1094-1101.  doi: 10.4103/1673-5374.270415 Abstract ( 296 )   PDF (1617KB) ( 244 )   Save Sleep-wake rhythm disturbances, which are characterized by abnormal sleep timing or duration, are associated with cognitive dysfunction. Photoacoustic treatments including light and sound stimulation have been found to be effective in modulating sleep patterns and improv- ing cognitive behavior in abnormal sleep-wake pattern experiments. In this study, we examined whether light and sound interventions could reduce sleep-wake pattern disturbances and memory deficits in a sleep rhythm disturbance model. We established a model of sleep rhythm disturbance in C57BL/6J mice via a sleep deprivation method involving manual cage tapping, cage jostling, and nest disturbance. We used a Mini Mitter radio transmitter device to monitor motor activity in the mice and fear conditioning tests to assess cognitive func- tion. Our results indicated that an intervention in which the mice were exposed to blue light (40-Hz flickering frequency) for 1 hour during their subjective daytime significantly improved the 24-hour-acrophase shift and reduced the degree of memory deficit induced by sleep deprivation. However, interventions in which the mice were exposed to a 40-Hz blue light at offset time or subjective night time points, as well as 2 Hz-blue light at 3 intervention time points (subjective day time, subjective night time, and offset time points), had no positive effects on circadian rhythm shift or memory deficits. Additionally, a 2000-Hz sound intervention during subjective day time attenuated the 24-hour-acrophase shift and memory decline, while 440-Hz and 4000-Hz sounds had no effect on circadian rhythms. Overall, these results demonstrate that photoacoustic treatment effectively corrected abnormal sleep-wake patterns and cognitive dysfunction associated with sleep-deprivation-induced disturbances in sleep-wake rhythm. All animal experiments were approved by the Experimental Animal Ethics Committee of Drum Tower Hospital Affiliated to the Medical College of Nanjing University, China (approval No. 20171102) on November 20, 2017. Related Articles | Metrics

Select

Comparative proteomes change and possible role in different pathways of microRNA-21a-5p in a mouse model of spinal cord injury Almaghalsa-Ziad Mohammed, Hong-Xia Du, Hong-Liang Song, Wei-Ming Gong, Bin Ning, Tang-Hong Jia 2020, 15 (6):  1102-1110.  doi: 10.4103/1673-5374.270418 Abstract ( 147 )   PDF (2884KB) ( 320 )   Save Our previous study found that microRNA-21a-5p (miR-21a-5p) knockdown could improve the recovery of motor function after spinal cord injury in a mouse model, but the precise molecular mechanism remains poorly understood. In this study, a modified Allen’s weight drop was used to establish a mouse model of spinal cord injury. A proteomics approach was used to understand the role of differential protein expression with miR-21a-5p knockdown, using a mouse model of spinal cord injury without gene knockout as a negative control group. We found that after introducing miR-21a-5p knockdown, proteins that played an essential role in the regulation of inflammatory processes, cell protection against oxidative stress, cell redox homeostasis, and cell maintenance were upregulated compared with the nega- tive control group. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified enriched pathways in both groups, such as the oxidative phosphorylation pathway, which is relevant to Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and cardiac muscle contraction. We also found that miR-21a-5p could be a potential biomarker for amyotrophic lateral sclerosis, as miR-21a- 5p becomes deregulated in this pathway. These results indicate successful detection of some important proteins that play potential roles in spinal cord injury. Elucidating the relationship between these proteins and the recovery of spinal cord injury will provide a reference for future research of spinal cord injury biomarkers. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Shandong University of China on March 5, 2014. Related Articles | Metrics

Select

Jidong cognitive impairment cohort study: objectives, design, and baseline screening Dai-Yu Song, Xian-Wei Wang, Sa Wang, Si-Qi Ge, Guo-Yong Ding, Xue-Yu Chen, Yan-Ru Chen, Hua-Min Liu, Xiao-Mei Xie, Wei-Jia Xing, Dong Li, Yong Zhou 2020, 15 (6):  1111-1119.  doi: 10.4103/1673-5374.266070 Abstract ( 425 )   PDF (505KB) ( 317 )   Save The risk of dementia increases in patients with cognitive impairment. However, it is not clear what factors contribute to the onset of de- mentia in those with cognitive impairment. In this prospective cohort study, we will investigate the every-five-year incidence of cognitive impairment and prognostic factors for cognitive impairment. The Jidong cognitive impairment cohort was established from April 2012 to August 2015, during which we recruited 5854 healthy participants (55.1% male) older than 45 years (mean, 57 years). Participants re- ceived a health examination in the Staff Hospital, Jidong Oilfield Branch, China National Petroleum Corporation. Baseline data and blood samples were collected. Cognitive impairment was evaluated using the Mini-Mental State Examination, and was defined as a Mini-Mental State Examination score of less than 24. Dementia was assessed using the criteria of Diagnostic and Statistical Manual of Mental Disorders (Fourth edition), the International Working Group criteria, and the Mini-Mental State Examination score. The follow-up will continue until December 2024, during which a prognostic model will be constructed. The primary outcome is the presence/absence of dementia and the secondary outcome is quality of life. Baseline screening results showed the following: (1) Cognitive impairment was apparent in 320 participants (5.5%). These participants will be excluded from the Jidong cohort study, and the remaining participants will be followed up. (2) Of the 320 participants with cognitive impairment, there was a significantly higher prevalence of illiteracy than other education levels (35.9%, P < 0.05). Age, arterial hypertension, alcohol consumption, and passive smoking differed significantly between the cognitive impairment and healthy groups (P < 0.05). Multivariate logistic regression models showed that age (odds ratio [OR] = 1.059, 95% confidence interval [CI]: 1.044–1.074) and arterial hypertension (OR = 1.665, 95% CI: 1.143–2.427) were risk factors for mild cognitive impairment. With the increase of educational level (illiteracy, primary school, junior high school, high school, university, and above), cognitive impairment gradually decreased (OR < 1, P < 0.05). (3) This cohort study has initially screened for several risk factors for cognitive impairment at base- line, and subsequent prospective data will further describe, validate, and evaluate the effects of these risk factors on cognitive impairment and dementia. These results can provide clinical evidence for the early prevention of cognitive impairment and dementia. The study was approved by the Ethics Committee of Kailuan General Hospital of Tangshan City and the Medical Ethics Committee, Staff Hospital, Jidong Oilfield Branch, China National Petroleum Corporation on July 12, 2013 (approval No. 2013 YILUNZI 1). Related Articles | Metrics

Select

Therapeutic effect of regulating autophagy in spinal cord injury: a network meta-analysis of direct and indirect comparisons Duo Zhang, Di Zhu, Fang Wang, Ji-Chao Zhu, Xu Zhai, Yuan Yuan, Chen-Xi Li 2020, 15 (6):  1120-1132.  doi: 10.4103/1673-5374.270419 Abstract ( 164 )   PDF (4013KB) ( 203 )   Save Objective: An increasing number of studies indicate that autophagy plays an important role in the patho- genesis of spinal cord injury, and that regulating autophagy can enhance recovery from spinal cord injury. However, the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear. Therefore, in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison, in an effort to provide a basis for further re- search. Data source: Relevant literature published from inception to February 1, 2018 were included by searching Wanfang, CNKI, Web of Science, MEDLINE (OvidSP), PubMed and Google Scholar in English and Chi- nese. The keywords included “autophagy”, “spinal cord injury”, and “rat”. Data selection: The literature included in vivo experimental studies on autophagy regulation in the treat- ment of spinal cord injury (including intervention pre- and post-spinal cord injury). Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy, and subgroup analyses were also conducted. Outcome measure: Basso, Beattie, and Bresnahan scores. Results: Of the 622 studies, 33 studies of median quality were included in the analyses. Basso, Beattie, and Bresnahan scores were higher at 1 day (MD = 1.80, 95% CI: 0.81–2.79, P = 0.0004), 3 days (MD = 0.92, 95% CI: 0.72–1.13, P < 0.00001), 1 week (MD = 2.39, 95% CI: 1.85–2.92, P < 0.00001), 2 weeks (MD = 3.26, 95% CI: 2.40–4.13, P < 0.00001), 3 weeks (MD = 3.13, 95% CI: 2.51–3.75, P < 0.00001) and 4 weeks (MD = 3.18, 95% CI: 2.43–3.92, P < 0.00001) after spinal cord injury with upregulation of autophagy compared with the control group (drug solvent control, such as saline group). Basso, Beattie, and Bresnahan scores were higher at 1 day (MD = 6.48, 95% CI: 5.83–7.13, P < 0.00001), 2 weeks (MD = 2.43, 95% CI: 0.79–4.07, P = 0.004), 3 weeks (MD = 2.96, 95% CI: 0.09–5.84, P = 0.04) and 4 weeks (MD = 4.41, 95% CI: 1.08–7.75, P = 0.01) after spinal cord injury with downregulation of autophagy compared with the control group. Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso, Beattie, and Bresnahan scores at 1 day (MD = −4.68, 95% CI: –5.840 to −3.496, P = 0.94644), 3 days (MD = −0.28, 95% CI: −2.231–1.671, P = 0.99448), 1 week (MD = 1.83, 95% CI: 0.0076–3.584, P = 0.94588), 2 weeks (MD = 0.81, 95% CI: −0.850–2.470, P = 0.93055), 3 weeks (MD = 0.17, 95% CI: −2.771–3.111, P = 0.99546) or 4 weeks (MD = –1.23, 95% CI: −4.647–2.187, P = 0.98264) compared with the control group. Conclusion: Regulation of autophagy improves neurological function, whether it is upregulated or down- regulated. There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury. The variability in results among the studies may be associated with differences in research methods, the lack of clearly defined autophagy characteristics after spinal cord injury, and the lim- ited autophagy monitoring techniques. Thus, methods should be standardized, and the dynamic regulation of autophagy should be examined in future studies. Related Articles | Metrics

Select

Role of miR-124 in the regulation of retinoic acid-induced Neuro-2A cell diferentiation Qun You, Qiang Gong, Yu-Qiao Han, Rou Pi, Yi-Jie Du, Su-Zhen Dong 2020, 15 (6):  1133-1139.  doi: 10.4103/1673-5374.270417 Abstract ( 221 )   PDF (4477KB) ( 283 )   Save Retinoic acid can cause many types of cells, including mouse neuroblastoma Neuro-2A cells, to diferentiate into neurons. However, it is still unknown whether microRNAs (miRNAs) play a role in this neuronal diferentiation. To address this issue, real-time polymerase chain reaction assays were used to detect the expression of several diferentiation-related miRNAs during the diferentiation of retinoic ac- id-treated Neuro-2A cells. Te results revealed that miR-124 and miR-9 were upregulated, while miR-125b was downregulated in retinoic acid-treated Neuro-2A cells. To identify the miRNA that may play a key role, miR-124 expression was regulated by transfection of miRNA mimics or inhibitors. Morphological analysis results showed that inhibition of miR-124 expression reversed the efects of retinoic acid on neurite outgrowth. Moreover, miR-124 overexpression alone caused Neuro-2A cells to diferentiate into neurons, and its inhibitor could block this efect. Tese results suggest that miR-124 plays an important role in retinoic acid-induced diferentiation of Neuro-2A cells. Related Articles | Metrics

Select

Adenylate cyclase activator forskolin alleviates intracerebroventricular propionic acid-induced mitochondrial dysfunction of autistic rats Sidharth Mehan, Saloni Rahi, Aarti Tiwari, Tarun Kapoor, Kajal Rajdev, Ramit Sharma, Himanshi Khera, Sourabh Kosey, Umesh Kukkar, Rajesh Dudi 2020, 15 (6):  1140-1149.  doi: 10.4103/1673-5374.270316 Abstract ( 196 )   PDF (1476KB) ( 239 )   Save Neuronal mitochondrial dysfunction increases inflammatory mediators and leads to free radical genera- tion and anti-oxidant enzymatic alterations, which are major neuropathological hallmarks responsible for autism. Mitochondrial dysfunction in autism is associated with decreased ATP levels due to reduced levels of cyclic adenosine monophosphate. Rat models of autism were established by intracerebroventricular in- jection of propionic acid. These rat models had memory dysfunction, decreased muscle coordination and gait imbalance. Biochemical estimation of propionic acid-treated rats showed changes in enzyme activity in neuronal mitochondrial electron transport chain complexes and increases in pro-inflammatory cyto- kines, oxidative stress and lipid biomarkers. Oral administration of 10, 20 and 30 mg/kg adenylate cyclase activator forskolin for 15 days reversed these changes in a dose-dependent manner. These findings suggest that forskolin can alleviate neuronal mitochondrial dysfunction and improve neurological symptoms of rats with autism. This study was approved by the RITS/IAEC, SIRSA, HARYANA on March 3, 2014 (approval No. RITS/IAEC/2014/03/03). Related Articles | Metrics

Select

Dynamic changes of behaviors, dentate gyrus neurogenesis and hippocampal miR-124 expression in rats with depression induced by chronic unpredictable mild stress Yun-Ling Huang, Ning-Xi Zeng, Jie Chen, Jie Niu, Wu-Long Luo, Ping Liu, Can Yan, Li-Li Wu 2020, 15 (6):  1150-1159.  doi: 10.4103/1673-5374.270414 Abstract ( 281 )   PDF (5000KB) ( 275 )   Save The depression-like behavior phenotype, neurogenesis in the dentate gyrus and miR-124 expression in the hippocampus are the focus of current research on the pathogenesis of depression and antidepressant therapy. The present study aimed to clarify the dynamic changes of depression-like behavior, dentate gyrus neurogenesis and hippocampal miR-124 expression during depression induced by chronic stress to reveal pathological features at different stages of depression and to further provide insight into depression treatment. Chronic unpre- dictable mild stress depression models were established by exposing Sprague-Dawley rats to various mild stressors, including white noise, thermal swimming, stroboscopic illumination, soiled cages, pairing with three other stressed animals, cold swimming, tail pinch, restraint and water and food deprivation. Chronic unpredictable mild stress model rats underwent dynamic observation from 1 to 8 weeks and were compared with a control group (normal feeding without any stressors). To observe changes in the depression-like behavior phenotype during chronic unpredictable mild stress-induced depression, a sucrose preference test was used to evaluate the degree of anhedonia. An open-field test was used to evaluate locomotor activity and anxiety status. Compared with the control group, chronic unpredictable mild stress rats lost weight but did not have a depression-like behavioral phenotype at 1–4 weeks. Chronic unpredictable mild stress rats pre- sented decreased sucrose preference and locomotor activity at 5–8 weeks. In addition, chronic unpredictable mild stress rats did not have significant anxiety-like behavior during 1–8 weeks of modeling. To observe neurogenesis dysfunctions and changes in neuronal number in the dentate gyrus during chronic unpredictable mild stress-induced depression, markers (DCX and DCX/BrdU) of neural proliferation and differentiation and the neuronal marker NeuN were assessed by immunofluorescence. Compared with the control group, neurogen- esis and the neuronal number in the dentate gyrus did not change from 2 to 6 weeks; however, neural proliferation and differentiation in the dentate gyrus decreased, and the number of neurons decreased until the eighth week in the chronic unpredictable mild stress group. Real-time quantitative reverse transcription polymerase chain reaction assays and fluorescence in situ hybridization were used to measure the expression of hippocampal miR-124 during chronic unpredictable mild stress-induced depression. The results showed that the expres- sion of hippocampal miR-124 was unchanged during the first 4 weeks but increased from 5 to 6 weeks and decreased from 7 to 8 weeks compared with the control group. These findings indicate that during chronic unpredictable mild stress-induced depression, the behavioral phenotype, miR-124 expression in the hippocampus, neurogenesis in the dentate gyrus and neuronal numbers showed dynamic changes, which suggested that various pathological changes occur at different stages of depression. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2015. Related Articles | Metrics

Select

Time course analysis of sensory axon regeneration in vivo by directly tracing regenerating axons Yan Gao, Yi-Wen Hu, Run-Shan Duan, Shu-Guang Yang, Feng-Quan Zhou, Rui-Ying Wang 2020, 15 (6):  1160-1165.  doi: 10.4103/1673-5374.270315 Abstract ( 189 )   PDF (4139KB) ( 226 )   Save Most current studies quantify axon regeneration by immunostaining regeneration-associated proteins, representing indirect measure- ment of axon lengths from both sensory neurons in the dorsal root ganglia and motor neurons in the spinal cord. Our recently developed method of in vivo electroporation of plasmid DNA encoding for enhanced green fluorescent protein into adult sensory neurons in the dorsal root ganglia provides a way to directly and specifically measure regenerating sensory axon lengths in whole-mount nerves. A mouse model of sciatic nerve compression was established by squeezing the sciatic nerve with tweezers. Plasmid DNA carrying enhanced green fluorescent protein was transfected by ipsilateral dorsal root ganglion electroporation 2 or 3 days before injury. Fluorescence distribution of dorsal root or sciatic nerve was observed by confocal microscopy. At 12 and 18 hours, and 1, 2, 3, 4, 5, and 6 days of injury, lengths of regenerated axons after sciatic nerve compression were measured using green fluorescence images. Apoptosis-related protein caspase-3 expression in dorsal root ganglia was determined by western blot assay. We found that in vivo electroporation did not affect caspase-3 ex- pression in dorsal root ganglia. Dorsal root ganglia and sciatic nerves were successfully removed and subjected to a rapid tissue clearing technique. Neuronal soma in dorsal root ganglia expressing enhanced green fluorescent protein or fluorescent dye-labeled microRNAs were imaged after tissue clearing. The results facilitate direct time course analysis of peripheral nerve axon regeneration. This study was approved by the Institutional Animal Care and Use Committee of Guilin Medical University, China (approval No. GLMC201503010) on March 7, 2014. Related Articles | Metrics

Select

Pazopanib-induced posterior reversible encephalopathy syndrome with possible syndrome of inappropriate secretion of antidiuretic hormone: an incidental or pathophysiological association? Jonathan Wong So, Bérenger Largeau, Frédérique Beau-Salinas, Stephan Ehrmann, Christophe Magni, Jérôme Meunier 2020, 15 (6):  1166-1168.  doi: 10.4103/1673-5374.270420 Abstract ( 125 )   PDF (1048KB) ( 373 )   Save Pazopanib is an oral protein kinase inhibitor (PKI) that targets vascular endothelial growth factor (VEGF) receptors, fibroblastic growth factor receptors, platelet-derived growth factor receptors, and stem cell factor that inhibits VEGF-induced cellular proliferation. Pazopanib is approved for use in advanced renal cell carcinoma and subtypes of advanced soft-tissue sarcoma (Deguchi et al., 2018). Major adverse drug reactions of pazopanib include hyper- tension, high-grade hyponatremia and posterior reversible encepha- lopathy syndrome (PRES) (Berardi et al., 2016; Deguchi et al., 2018). In clinical trials, few investigations have been conducted to deter- mine the aetiology of PKI-associated hyponatremia, the mechanism remains therefore unknown. Only rare cases of PKI-induced syn- drome of inappropriate secretion of antidiuretic hormone (SIADH) (Largeau et al., 2019), and none with pazopanib, have been reported. PRES is a clinical and radiological entity where a bilateral white mat- ter oedema, occurring predominantly in the posterior occipital and parietal lobes, is associated with several neurologic symptoms. Inter- estingly, a recent review suggests that SIADH could be a symptom of PRES (Largeau et al., 2019). To our knowledge, this is the first case published where pazopanib-induced PRES occurs contemporane- ously with possible SIADH. Related Articles | Metrics