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   Table of Contents - Current issue
Coverpage
June 2022
Volume 17 | Issue 6
Page Nos. 1165-1392

Online since Friday, November 12, 2021

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REVIEWS  

The importance of fasciculation and elongation protein zeta-1 in neural circuit establishment and neurological disorders p. 1165
Rafhanah Banu Bte Abdul Razar, Yinghua Qu, Saravanan Gunaseelan, John Jia En Chua
DOI:10.4103/1673-5374.327327  PMID:34782550
The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly. These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions. Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders. Supporting this notion, efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation, maturation, synaptogenesis and synaptic function. Fasciculation and elongation protein zeta-1, a Kinesin-1 adapter, has emerged as a key central player involved in many of these processes. Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment. Furthermore, it acts downstream of guidance cue pathways to regulate axo-dendritic development. Significantly, perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system. Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders. Moreover, altered phosphorylation of the protein contributes to neurodegenerative disorders. Together, these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.
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Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling Highly accessed article p. 1172
Bart Nieuwenhuis, Richard Eva
DOI:10.4103/1673-5374.327324  PMID:34782551
Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system. Axons in the central nervous system fail to regenerate, meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences. In 2008, genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve. PTEN is a phosphatase that opposes the actions of PI3-kinase, a family of enzymes that function to generate the membrane phospholipid PIP3 from PIP2 (phosphatidylinositol (3,4,5)-trisphosphate from phosphatidylinositol (4,5)-bisphosphate). Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase, and was initially demonstrated to promote axon regeneration by signaling through mTOR. More recently, additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability. This review describes neuronal signaling pathways downstream of PI3-kinase and PIP3, and considers them in relation to both developmental and regenerative axon growth. We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability, and describe how these are affected by signaling through PI3-kinase. We highlight the recent finding of a developmental decline in the generation of PIP3 as a key reason for regenerative failure, and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system. Finally, we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.
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Microglial voltage-gated proton channel Hv1 in spinal cord injury p. 1183
Jiaying Zheng, Madhuvika Murugan, Lingxiao Wang, Long-Jun Wu
DOI:10.4103/1673-5374.327325  PMID:34782552
After spinal cord injury, microglia as the first responders to the lesion display both beneficial and detrimental characteristics. Activated microglia phagocyte and eliminate cell debris, release cytokines to recruit peripheral immune cells to the injury site. Excessively activated microglia can aggravate the secondary damage by producing extravagant reactive oxygen species and pro-inflammatory cytokines. Recent studies demonstrated that the voltage-gated proton channel Hv1 is selectively expressed in microglia and regulates microglial activation upon injury. In mouse models of spinal cord injury, Hv1 deficiency ameliorates microglia activation, resulting in alleviated production of reactive oxygen species and pro-inflammatory cytokines. The reduced secondary damage subsequently decreases neuronal loss and correlates with improved locomotor recovery. This review provides a brief historical perspective of advances in investigating voltage-gated proton channel Hv1 and home in on microglial Hv1. We discuss recent studies on the roles of Hv1 activation in pathophysiological activities of microglia, such as production of NOX-dependent reactive oxygen species, microglia polarization, and tissue acidosis, particularly in the context of spinal cord injury. Further, we highlight the rationale for targeting Hv1 for the treatment of spinal cord injury and related disorders.
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Liposome based drug delivery as a potential treatment option for Alzheimer’s disease p. 1190
Carely Hernandez, Surabhi Shukla
DOI:10.4103/1673-5374.327328  PMID:34782553
Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions. Alzheimer’s disease is associated with dementia and a progressive decline in memory, thinking, and social skills, eventually leading to a point that the individual can no longer perform daily activities independently. Currently available drugs on the market temporarily alleviate the symptoms, however, they are not successful in slowing down the progression of Alzheimer’s disease. Treatment and cures have been constricted due to the difficulty of drug delivery to the blood-brain barrier. Several studies have led to identification of vesicles to transport the necessary drugs through the blood-brain barrier that would typically not achieve the targeted area through systemic delivered medications. Recently, liposomes have emerged as a viable drug delivery agent to transport drugs that are not able to cross the blood-brain barrier. Liposomes are being used as a component of nanoparticle drug delivery; due to their biocompatible nature; and possessing the capability to carry both lipophilic and hydrophilic therapeutic agents across the blood brain barrier into the brain cells. Studies indicate the importance of liposomal based drug delivery in treatment of neurodegenerative disorders. The idea is to encapsulate the drugs inside the properly engineered liposome to generate a response of treatment. Liposomes are engineered to target specific diseased moieties and also several surface modifications of liposomes are under research to create a clinical path to the management of Alzheimer’s disease. This review deals with Alzheimer’s disease and emphasize on challenges associated with drug delivery to the brain, and how liposomal drug delivery can play an important role as a drug delivery method for the treatment of Alzheimer’s disease. This review also sheds some light on variation of liposomes. Additionally, it emphasizes on the liposomal formulations which are currently researched or used for treatment of Alzheimer’s disease and also discusses the future prospect of liposomal based drug delivery in Alzheimer’s disease.
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Retinal regeneration requires dynamic Notch signaling p. 1199
Leah J Campbell, Jaclyn L Levendusky, Shannon A Steines, David R Hyde
DOI:10.4103/1673-5374.327326  PMID:34782554
Retinal damage in the adult zebrafish induces Müller glia reprogramming to produce neuronal progenitor cells that proliferate and differentiate into retinal neurons. Notch signaling, which is a fundamental mechanism known to drive cell-cell communication, is required to maintain Müller glia in a quiescent state in the undamaged retina, and repression of Notch signaling is necessary for Müller glia to reenter the cell cycle. The dynamic regulation of Notch signaling following retinal damage also directs proliferation and neurogenesis of the Müller glia-derived progenitor cells in a robust regeneration response. In contrast, mammalian Müller glia respond to retinal damage by entering a prolonged gliotic state that leads to additional neuronal death and permanent vision loss. Understanding the dynamic regulation of Notch signaling in the zebrafish retina may aid efforts to stimulate Müller glia reprogramming for regeneration of the diseased human retina. Recent findings identified DeltaB and Notch3 as the ligand-receptor pair that serves as the principal regulators of zebrafish Müller glia quiescence. In addition, multi-omics datasets and functional studies indicate that additional Notch receptors, ligands, and target genes regulate cell proliferation and neurogenesis during the regeneration time course. Still, our understanding of Notch signaling during retinal regeneration is limited. To fully appreciate the complex regulation of Notch signaling that is required for successful retinal regeneration, investigation of additional aspects of the pathway, such as post-translational modification of the receptors, ligand endocytosis, and interactions with other fundamental pathways is needed. Here we review various modes of Notch signaling regulation in the context of the vertebrate retina to put recent research in perspective and to identify open areas of inquiry.
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All roads lead to Rome — a review of the potential mechanisms by which exerkines exhibit neuroprotective effects in Alzheimer’s disease Highly accessed article p. 1210
Yi-Yao Liang, Li-Dan Zhang, Xi Luo, Li-Li Wu, Zhao-Wei Chen, Guang-Hao Wei, Kai-Qing Zhang, Ze-An Du, Ren-Zhi Li, Kwok-Fai So, Ang Li
DOI:10.4103/1673-5374.325012  PMID:34782555
Age-related neurodegenerative disorders such as Alzheimer’s disease (AD) have become a critical public health issue due to the significantly extended human lifespan, leading to considerable economic and social burdens. Traditional therapies for AD such as medicine and surgery remain ineffective, impractical, and expensive. Many studies have shown that a variety of bioactive substances released by physical exercise (called “exerkines”) help to maintain and improve the normal functions of the brain in terms of cognition, emotion, and psychomotor coordination. Increasing evidence suggests that exerkines may exert beneficial effects in AD as well. This review summarizes the neuroprotective effects of exerkines in AD, focusing on the underlying molecular mechanism and the dynamic expression of exerkines after physical exercise. The findings described in this review will help direct research into novel targets for the treatment of AD and develop customized exercise therapy for individuals of different ages, genders, and health conditions.
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SARS-CoV-2 involvement in central nervous system tissue damage Highly accessed article p. 1228
Muhammad Ali Haidar, Zaynab Shakkour, Mohammad Amine Reslan, Nadine Al-Haj, Perla Chamoun, Karl Habashy, Hasan Kaafarani, Shima Shahjouei, Sarah H Farran, Abdullah Shaito, Esber S Saba, Bassam Badran, Mirna Sabra, Firas Kobeissy, Maya Bizri
DOI:10.4103/1673-5374.327323  PMID:34782556
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, it became evident that the SARS-CoV-2 virus infects multiple organs including the brain. Several clinical studies revealed that patients with COVID-19 infection experience an array of neurological signs ranging in severity from headaches to life-threatening strokes. Although the exact mechanism by which the SARS-CoV-2 virus directly impacts the brain is not fully understood, several theories have been suggested including direct and indirect pathways induced by the virus. One possible theory is the invasion of SARS-CoV-2 to the brain occurs either through the bloodstream or via the nerve endings which is considered to be the direct route. Such findings are based on studies reporting the presence of viral material in the cerebrospinal fluid and brain cells. Nevertheless, the indirect mechanisms, including blood-clotting abnormalities and prolonged activation of the immune system, can result in further tissue and organ damages seen during the course of the disease. This overview attempts to give a thorough insight into SARS-CoV-2 coronavirus neurological infection and highlights the possible mechanisms leading to the neurological manifestations observed in infected patients.
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Application of neurotrophic and proangiogenic factors as therapy after peripheral nervous system injury p. 1240
Kamilla Faritovna Idrisova, Alina Kazymovna Zeinalova, Galina Andreevna Masgutova, Alexey Andreevich Bogov, Cinzia Allegrucci, Valeriia Yurievna Syromiatnikova, Ilnur Ildusovich Salafutdinov, Ekaterna Evgenievna Garanina, Dina Ivanovna Andreeva, Adilet Abdullaatovich Kadyrov, Albert Anatolevich Rizvanov, Ruslan Faridovich Masgutov
DOI:10.4103/1673-5374.327329  PMID:34782557
The intrinsic ability of peripheral nerves to regenerate after injury is extremely limited, especially in case of severe injury. This often leads to poor motor function and permanent disability. Existing approaches for the treatment of injured nerves do not provide appropriate conditions to support survival and growth of nerve cells. This drawback can be compensated by the use of gene therapy and cell therapy-based drugs that locally provide an increase in the key regulators of nerve growth, including neurotrophic factors and extracellular matrix proteins. Each growth factor plays its own specific angiotrophic or neurotrophic role. Currently, growth factors are widely studied as accelerators of nerve regeneration. Particularly noteworthy is synergy between various growth factors, that is essential for both angiogenesis and neurogenesis. Fibroblast growth factor 2 and vascular endothelial growth factor are widely known for their proangiogenic effects. At the same time, fibroblast growth factor 2 and vascular endothelial growth factor stimulate neural cell growth and play an important role in neurodegenerative diseases of the peripheral nervous system. Taken together, their neurotrophic and angiogenic properties have positive effect on the regeneration process. In this review we provide an in-depth overview of the role of fibroblast growth factor 2 and vascular endothelial growth factor in the regeneration of peripheral nerves, thus demonstrating their neurotherapeutic efficacy in improving neuron survival in the peripheral nervous system.
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PERSPECTIVES Top

The power of “touch” and early enriched stimulation: neuroplasticity effects in rodents and preterm infants p. 1248
Alberto Fernandez-Teruel
DOI:10.4103/1673-5374.327336  PMID:34782558
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The code of light: do neurons generate light to communicate and repair? p. 1251
Cecile Moro, Ann Liebert, Catherine Hamilton, Nicolas Pasqual, Glen Jeffery, Jonathan Stone, John Mitrofanis
DOI:10.4103/1673-5374.327332  PMID:34782559
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Role of serotonin in modulating the development and function of adult-born neurons in the olfactory bulb p. 1253
Natalie Fomin-Thunemann, Olga Garaschuk
DOI:10.4103/1673-5374.327337  PMID:34782560
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SARS-CoV-2-induced autophagy dysregulation may cause neuronal dysfunction in COVID-19 p. 1255
Madepalli K Lakshmana
DOI:10.4103/1673-5374.327333  PMID:34782561
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Trace amine-associated receptors at the cross-road between innate olfaction of amines, emotions, and adult neurogenesis p. 1257
Evgeniya V Efimova, Nataliia V Katolikova, Evgeny V Kanov, Raul R Gainetdinov
DOI:10.4103/1673-5374.327338  PMID:34782562
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Emerging role of lysosomal calcium store as a hub of neuroprotection p. 1259
Valentina Tedeschi, Agnese Secondo
DOI:10.4103/1673-5374.327340  PMID:34782563
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Preterm neonatal brain injury: are human amnion epithelial stem cells a pan-treatment for neuroprotection and neurorepair? p. 1261
Joanne O Davidson, Simerdeep K Dhillon, Laura Bennet
DOI:10.4103/1673-5374.327339  PMID:34782564
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Mechanosensitivity of N-methyl-D-aspartate receptors (NMDAR) is the key through which amyloid beta oligomers activate them p. 1263
Giulia Fani, Fabrizio Chiti
DOI:10.4103/1673-5374.327341  PMID:34782565
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Non-cell autonomous role of astrocytes in axonal degeneration of cortical projection neurons in hereditary spastic paraplegias p. 1265
Xue-Jun Li
DOI:10.4103/1673-5374.327342  PMID:34782566
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Retinal ganglion cell protection by hop-flower extract as a novel neuroprotective strategy for glaucoma p. 1267
Tomoko Hasegawa, Hanako Ohashi Ikeda
DOI:10.4103/1673-5374.327344  PMID:34782567
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Coordination of Schwann cell myelination and node formation at the transcriptional level p. 1269
Franziska Frob, Michael Wegner
DOI:10.4103/1673-5374.327343  PMID:34782568
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Targeting collective behaviors of transplanted retinal cells as a strategy to improve cellular integration p. 1271
Miles Markey, Maribel Vazquez
DOI:10.4103/1673-5374.327345  PMID:34782569
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Progress in perisynaptic Schwann cell and neuromuscular junction research p. 1273
Chandler L Walker
DOI:10.4103/1673-5374.327334  PMID:34782570
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Guardians of the eye: new tales about retinal microglia and other ocular macrophages p. 1275
Dennis-Dominik Rosmus, Peter Wieghofer
DOI:10.4103/1673-5374.327335  PMID:34782571
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RESEARCH ARTICLES: BRAIN INJURY AND NEURAL REGENERATION Top

L4-to-L4 nerve root transfer for hindlimb hemiplegia after hypertensive intracerebral hemorrhage p. 1278
Teng-Da Qian, Xi-Feng Zheng, Jing Shi, Tao Ma, Wei-Yan You, Jia-Huan Wu, Bao-Sheng Huang, Yi Tao, Xi Wang, Ze-Wu Song, Li-Xin Li
DOI:10.4103/1673-5374.327359  PMID:34782572
There is no effective treatment for hemiplegia after hypertensive intracerebral hemorrhage. Considering that the branches of L4 nerve roots in the lumbar plexus root control the movement of the lower extremity anterior and posterior muscles, we investigated a potential method of nerve repair using the L4 nerve roots. Rat models of hindlimb hemiplegia after a hypertensive intracerebral hemorrhage were established by injecting autogenous blood into the posterior limb of internal capsule. The L4 nerve root on the healthy side of model rats was transferred and then anastomosed with the L4 nerve root on the affected side to drive the extensor and flexor muscles of the hindlimbs. We investigated whether this method can restore the flexible movement of the hindlimbs of paralyzed rats after hypertensive intracerebral hemorrhage. In a beam-walking test and ladder rung walking task, model rats exhibited an initial high number of slips, but improved in accuracy on the paretic side over time. At 17 weeks after surgery, rats gained approximately 58.2% accuracy from baseline performance and performed ankle motions on the paretic side. At 9 weeks after surgery, a retrograde tracing test showed a large number of fluoro-gold-labeled motoneurons in the left anterior horn of the spinal cord that supports the L4-to-L4 nerve roots. In addition, histological and ultramicrostructural findings showed axon regeneration of motoneurons in the anterior horn of the spinal cord. Electromyography and paw print analysis showed that denervated hindlimb muscles regained reliable innervation and walking coordination improved. These findings suggest that the L4-to-L4 nerve root transfer method for the treatment of hindlimb hemiplegia after hypertensive intracerebral hemorrhage can improve the locomotion of hindlimb major joints, particularly of the distal ankle. Findings from study support that the L4-to-L4 nerve root transfer method can effectively repair the hindlimb hemiplegia after hypertensive intracerebral hemorrhage. All animal experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (No. IACUC-1906009) in June 2019.
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Estimation of the density of neural, glial, and endothelial lineage cells in the adult mouse dentate gyrus p. 1286
Joshua D Rieskamp, Patricia Sarchet, Bryon M Smith, Elizabeth D Kirby
DOI:10.4103/1673-5374.327354  PMID:34782573
The dentate gyrus subregion of the mammalian hippocampus is an adult neural stem cell niche and site of lifelong neurogenesis. Hypotheses regarding the role of adult-born neuron synaptic integration in hippocampal circuit function are framed by robust estimations of adult-born versus pre/perinatally-born neuron number. In contrast, the non-neurogenic functions of adult neural stem cells and their immediate progeny, such as secretion of bioactive growth factors and expression of extracellular matrix-modifying proteins, lack similar framing due to few estimates of their number versus other prominent secretory cells. Here, we apply immunohistochemical methods to estimate cell density of neural stem/progenitor cells versus other major classes of glial and endothelial cell types that are potentially secretory in the dentate gyrus of adult mice. Of the cell types quantified, we found that GFAP+SOX2+ stellate astrocytes were the most numerous, followed by CD31+ endothelia, GFAPSOX2+ intermediate progenitors, Olig2+ oligodendrocytes, Iba1+ microglia, and GFAP+SOX2+ radial glia-like neural stem cells. We did not observe any significant sex differences in density of any cell population. Notably, neural stem/progenitor cells were present at a similar density as several cell types known to have potent functional roles via their secretome. These findings may be useful for refining hypotheses regarding the contributions of these cell types to regulating hippocampal function and their potential therapeutic uses. All experimental protocols were approved by the Ohio State University Institutional Animal Care and Use Committee (protocol# 2016A00000068) on July 14, 2016.
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Enriched environment for offspring improves learning and memory impairments induced by sevoflurane exposure during the second trimester of pregnancy p. 1293
Shao-Wei Yin, Yi-Lin Meng, Chuang Li, Yuan Wang
DOI:10.4103/1673-5374.327347  PMID:34782574
Studies in animals indicate that sevoflurane exposure in the second trimester of pregnancy has harmful effects on the learning and memory of offspring. Whether an enriched environment can reverse the damage of sevoflurane exposure in the second trimester of pregnancy on the learning and memory of rat offspring remains unclear. In this study, rats at 14 days of pregnancy were exposed to 3.5% sevoflurane for 2 hours and their offspring were treated with an enriched environment for 20 successive days. We found that the enriched environment for offspring increased nestin and Ki67 levels in hippocampal tissue, increased hippocampal neurogenesis, inhibited glycogen synthase kinase 3β activity, and increased the expression of cell proliferation-related β-catenin and apoptosis-related Bcl-2, indicating that an enriched environment reduces sevoflurane-induced damage by increasing the proliferation of stem cells in the hippocampus. These findings suggest that an enriched environment can reverse the effects of sevoflurane inhaled by rats during the second trimester of pregnancy on learning and memory of offspring. This study was approved by the Animal Ethics Committee of Shengjing Hospital of China Medical University (approval No. 2018PS07K) on January 2, 2018.
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Neuroprotective effects of long noncoding RNAs involved in ischemic postconditioning after ischemic stroke p. 1299
Wei Ma, Chun-Yan Li, Si-Jia Zhang, Cheng-Hao Zang, Jin-Wei Yang, Zhen Wu, Guo-Dong Wang, Jie Liu, Wei Liu, Kuang-Pin Liu, Yu Liang, Xing-Kui Zhang, Jun-Jun Li, Jian-Hui Guo, Li-Yan Li
DOI:10.4103/1673-5374.327346  PMID:34782575
During acute reperfusion, the expression profiles of long noncoding RNAs in adult rats with focal cerebral ischemia undergo broad changes. However, whether long noncoding RNAs are involved in neuroprotective effects following focal ischemic stroke in rats remains unclear. In this study, RNA isolation and library preparation was performed for long noncoding RNA sequencing, followed by determining the coding potential of identified long noncoding RNAs and target gene prediction. Differential expression analysis, long noncoding RNA functional enrichment analysis, and co-expression network analysis were performed comparing ischemic rats with and without ischemic postconditioning rats. Rats were subjected to ischemic postconditioning via the brief and repeated occlusion of the middle cerebral artery or femoral artery. Quantitative real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of differentially expressed long noncoding RNAs after ischemic postconditioning in a rat model of ischemic stroke. The results showed that ischemic postconditioning greatly affected the expression profile of long noncoding RNAs and mRNAs in the brains of rats that underwent ischemic stroke. The predicted target genes of some of the identified long noncoding RNAs (cis targets) were related to the cellular response to ischemia and stress, cytokine signal transduction, inflammation, and apoptosis signal transduction pathways. In addition, 15 significantly differentially expressed long noncoding RNAs were identified in the brains of rats subjected to ischemic postconditioning. Nine candidate long noncoding RNAs that may be related to ischemic postconditioning were identified by a long noncoding RNA expression profile and long noncoding RNA-mRNA co-expression network analysis. Expression levels were verified by quantitative real-time reverse transcription-polymerase chain reaction. These results suggested that the identified long noncoding RNAs may be involved in the neuroprotective effects associated with ischemic postconditioning following ischemic stroke. The experimental animal procedures were approved by the Animal Experiment Ethics Committee of Kunming Medical University (approval No. KMMU2018018) in January 2018.
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Contralateral S1 function is involved in electroacupuncture treatment-mediated recovery after focal unilateral M1 infarction p. 1310
Lu-Lu Yao, Si Yuan, Zhen-Nan Wu, Jian-Yu Luo, Xiao-Rong Tang, Chun-Zhi Tang, Shuai Cui, Neng-Gui Xu
DOI:10.4103/1673-5374.327355  PMID:34782576
Acupuncture at acupoints Baihui (GV20) and Dazhui (GV14) has been shown to promote functional recovery after stroke. However, the contribution of the contralateral primary sensory cortex (S1) to recovery remains unclear. In this study, unilateral local ischemic infarction of the primary motor cortex (M1) was induced by photothrombosis in a mouse model. Electroacupuncture (EA) was subsequently performed at acupoints GV20 and GV14 and neuronal activity and functional connectivity of contralateral S1 and M1 were detected using in vivo and in vitro electrophysiological recording techniques. Our results showed that blood perfusion and neuronal interaction between contralateral M1 and S1 is impaired after unilateral M1 infarction. Intrinsic neuronal excitability and activity were also disturbed, which was rescued by EA. Furthermore, the effectiveness of EA treatment was inhibited after virus-mediated neuronal ablation of the contralateral S1. We conclude that neuronal activity of the contralateral S1 is important for EA-mediated recovery after focal M1 infarction. Our study provides insight into how the S1–M1 circuit might be involved in the mechanism of EA treatment of unilateral cerebral infarction. The animal experiments were approved by the Committee for Care and Use of Research Animals of Guangzhou University of Chinese Medicine (approval No. 20200407009) April 7, 2020.
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RESEARCH ARTICLES: SPINAL CORD INJURY AND NEURAL REGENERATION Top

Oscillating field stimulation promotes axon regeneration and locomotor recovery after spinal cord injury p. 1318
Yi-Xin Wang, Jin-Zhu Bai, Zhen Lyu, Guang-Hao Zhang, Xiao-Lin Huo
DOI:10.4103/1673-5374.327349  PMID:34782577
Oscillating field stimulation (OFS) is a potential method for treating spinal cord injury. Although it has been used in spinal cord injury (SCI) therapy in basic and clinical studies, its underlying mechanism and the correlation between its duration and nerve injury repair remain poorly understood. In this study, we established rat models of spinal cord contusion at T10 and then administered 12 weeks of OFS. The results revealed that effectively promotes the recovery of motor function required continuous OFS for more than 6 weeks. The underlying mechanism may be related to the effects of OFS on promoting axon regeneration, inhibiting astrocyte proliferation, and improving the linear arrangement of astrocytes. This study was approved by the Animal Experiments and Experimental Animal Welfare Committee of Capital Medical University (supplemental approval No. AEEI-2021-204) on July 26, 2021.
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Lithium promotes recovery after spinal cord injury p. 1324
Ying-Jie Zhao, Hao Qiao, Dong-Fan Liu, Jie Li, Jia-Xi Li, Su-E Chang, Teng Lu, Feng-Tao Li, Dong Wang, Hao-Peng Li, Xi-Jing He, Fang Wang
DOI:10.4103/1673-5374.327348  PMID:34782578
Lithium is associated with oxidative stress and apoptosis, but the mechanism by which lithium protects against spinal cord injury remains poorly understood. In this study, we found that intraperitoneal administration of lithium chloride (LiCl) in a rat model of spinal cord injury alleviated pathological spinal cord injury and inhibited expression of tumor necrosis factor α, interleukin-6, and interleukin 1 β. Lithium inhibited pyroptosis and reduced inflammation by inhibiting Caspase-1 expression, reducing the oxidative stress response, and inhibiting activation of the Nod-like receptor protein 3 inflammasome. We also investigated the neuroprotective effects of lithium intervention on oxygen/glucose-deprived PC12 cells. We found that lithium reduced inflammation, oxidative damage, apoptosis, and necrosis and up-regulated nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 in PC12 cells. All-trans retinoic acid, an Nrf2 inhibitor, reversed the effects of lithium. These results suggest that lithium exerts anti-inflammatory, anti-oxidant, and anti-pyroptotic effects through the Nrf2/heme oxygenase-1 pathway to promote recovery after spinal cord injury. This study was approved by the Animal Ethics Committee of Xi’an Jiaotong University (approval No. 2018-2053) on October 23, 2018.
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Identification of key genes involved in recovery from spinal cord injury in adult zebrafish p. 1334
Wen-Yuan Shen, Xuan-Hao Fu, Jun Cai, Wen-Chang Li, Bao-You Fan, Yi-Lin Pang, Chen-Xi Zhao, Muhtidir Abula, Xiao-Hong Kong, Xue Yao, Shi-Qing Feng
DOI:10.4103/1673-5374.327360  PMID:34782579
Zebrafish are an effective vertebrate model to study the mechanisms underlying recovery after spinal cord injury. The subacute phase after spinal cord injury is critical to the recovery of neurological function, which involves tissue bridging and axon regeneration. In this study, we found that zebrafish spontaneously recovered 44% of their swimming ability within the subacute phase (2 weeks) after spinal cord injury. During this period, we identified 7762 differentially expressed genes in spinal cord tissue: 2950 were up-regulated and 4812 were down-regulated. These differentially expressed genes were primarily concentrated in the biological processes of the respiratory chain, axon regeneration, and cell-component morphogenesis. The genes were also mostly involved in the regulation of metabolic pathways, the cell cycle, and gene-regulation pathways. We verified the gene expression of two differentially expressed genes, clasp2 up-regulation and h1m down-regulation, in zebrafish spinal cord tissue in vitro. Pathway enrichment analysis revealed that up-regulated clasp2 functions similarly to microtubule-associated protein, which is responsible for axon extension regulated by microtubules. Down-regulated h1m controls endogenous stem cell differentiation after spinal cord injury. This study provides new candidate genes, clasp2 and h1m, as potential therapeutic intervention targets for spinal cord injury repair by neuroregeneration. All experimental procedures and protocols were approved by the Animal Ethics Committee of Tianjin Institute of Medical & Pharmaceutical Sciences (approval No. IMPS-EAEP-Q-2019-02) on September 24, 2019.
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RESEARCH ARTICLES: PERIPHERAL NERVE INJURY AND NEURAL REGENERATION Top

Myelin-associated glycoprotein combined with chitin conduit inhibits painful neuroma formation after sciatic nerve transection p. 1343
Wei Pi, Ci Li, Meng Zhang, Wei Zhang, Pei-Xun Zhang
DOI:10.4103/1673-5374.327351  PMID:34782580
Studies have shown that myelin-associated glycoprotein (MAG) can inhibit axon regeneration after nerve injury. However, the effects of MAG on neuroma formation after peripheral nerve injury remain poorly understood. In this study, local injection of MAG combined with nerve cap made of chitin conduit was used to intervene with the formation of painful neuroma after sciatic nerve transfection in rats. After 8 weeks of combined treatment, the autotomy behaviors were reduced in rats subjected to sciatic nerve transfection, the mRNA expression of nerve growth factor, a pain marker, in the proximal nerve stump was decreased, the density of regenerated axons was decreased, the thickness of the myelin sheath was increased, and the ratio of unmyelinated to myelinated axons was reduced. Moereover, the percentage of collagen fiber area and the percentage of fibrosis marker alpha-smooth muscle actin positive staining area in the proximal nerve stump were decreased. The combined treatment exhibited superior effects in these measures to chitin conduit treatment alone. These findings suggest that MAG combined with chitin conduit synergistically inhibits the formation of painful neuroma after sciatic nerve transection and alleviates neuropathic pain. This study was approved by the Animal Ethics Committee of Peking University People’s Hospital (approval No. 2019PHE027) on December 5, 2019.
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RESEARCH ARTICLE: NEURAL INJURY AND REGENERATION Top

Optical tissue clearing enables rapid, precise and comprehensive assessment of three-dimensional morphology in experimental nerve regeneration research p. 1348
Simeon C Daeschler, Jennifer Zhang, Tessa Gordon, Gregory H Borschel
DOI:10.4103/1673-5374.329473  PMID:34782581
Morphological analyses are key outcome assessments for nerve regeneration studies but are historically limited to tissue sections. Novel optical tissue clearing techniques enabling three-dimensional imaging of entire organs at a subcellular resolution have revolutionized morphological studies of the brain. To extend their applicability to experimental nerve repair studies we adapted these techniques to nerves and their motor and sensory targets in rats. The solvent-based protocols rendered harvested peripheral nerves and their target organs transparent within 24 hours while preserving tissue architecture and fluorescence. The optical clearing was compatible with conventional laboratory techniques, including retrograde labeling studies, and computational image segmentation, providing fast and precise cell quantitation. Further, optically cleared organs enabled three-dimensional morphometry at an unprecedented scale including dermatome-wide innervation studies, tracing of intramuscular nerve branches or mapping of neurovascular networks. Given their wide-ranging applicability, rapid processing times, and low costs, tissue clearing techniques are likely to be a key technology for next-generation nerve repair studies. All procedures were approved by the Hospital for Sick Children’s Laboratory Animal Services Committee (49871/9) on November 9, 2019.
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RESEARCH ARTICLES: NEURODEGENERATIVE DISEASES AND NEURAL REGENERATION Top

Schwann cells differentiated from skin-derived precursors provide neuroprotection via autophagy inhibition in a cellular model of Parkinson’s disease p. 1357
Jia-Nan Yan, Hai-Ying Zhang, Jun-Rui Li, Ying Chen, Yong-Cheng Jiang, Jia-Bing Shen, Kai-Fu Ke, Xiao-Su Gu
DOI:10.4103/1673-5374.327353  PMID:34782582
Autophagy has been shown to play an important role in Parkinson’s disease. We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy. In this study, 6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells (SKP-SCs). The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine, reduced excessive autophagy, increased tyrosine hydroxylase expression, reduced α-synuclein expression, reduced the autophagosome number, and activated the PI3K/AKT/mTOR pathway. Autophagy activator rapamycin inhibited the effects of SKP-SCs, and autophagy inhibitor 3-methyladenine had the opposite effect. These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy, thereby exhibiting a neuroprotective effect in a cellular model of Parkinson’s disease. This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University (approval No. S20181009-205) on October 9, 2018.
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RESEARCH ARTICLES: OPTIC NERVE INJURY AND NEURAL REGENERATION Top

Maternally expressed gene 3 regulates retinal neovascularization in retinopathy of prematurity p. 1364
Yu Di, Yue Wang, Yue-Xia Wang, Xue Wang, Yuan Ma, Qing-Zhu Nie
DOI:10.4103/1673-5374.327358  PMID:34782583
The mouse model of oxygen induced retinopathy is suitable for the study of various retinal neovascularization diseases, including retinopathy of prematurity. The maternally expressed gene 3 (MEG3) has been demonstrated to have an inhibitory effect on diabetic retinopathy. In this study, we investigated the role of MEG3 overexpression in oxygen-induced retinopathy in mice. The results showed that MEG3 overexpression effectively inhibited the production of retinal neovascularization in oxygen-induced retinopathy mice. It acts by down-regulating the expression of phosphoinositide 3-kinase, serine/threonine kinase, and vascular endothelial growth factor and pro-inflammatory factors. MEG3 overexpression lentivirus has a future as a new method for the clinical treatment of retinopathy of prematurity. The animal experiments were approved by the Animal Ethics Committee of Shengjing Hospital of China Medical University, China (approval No. 2016PS074K) on February 25, 2016.
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RESEARCH ARTICLES: SPINAL CORD INJURY AND NEURAL REGENERATION Top

Leisure-time physical activity, anthropometrics, and body composition as predictors of quality of life domains after spinal cord injury: an exploratory cross-sectional study p. 1369
Melody N Mickens, Paul Perrin, Jacob A Goldsmith, Refka E Khalil, William E Carter III, Ashraf S Gorgey
DOI:10.4103/1673-5374.327356  PMID:34782584
The objective of the current work was to examine the relationships between quality of life (QOL) domains in persons with spinal cord injury (SCI) and their levels of weekly leisure-time physical activity (LTPA), anthropometric variables, and body composition variables. This exploratory cross-sectional study consisted of baseline data collected as part of a randomized clinical trial at a VA Medical Center and SCI center. A convenience sample of 36 community-dwelling persons with SCI participated in the current study. Outcome measures included the World Health Organization Quality of Life Short Form (WHOQOL-BREF), Leisure-Time Physical Activity Questionnaire for People with Spinal Cord Injury (LTPAQ-SCI), anthropomorphic measures (waist, hip, and abdominal circumference), and dual-energy x-ray absorptiometry (DXA) to quantify regional and total body composition. Multiple regression models suggested that engagement in LTPA accounted for 35.7% of the variance in physical health QOL, 33.5% in psychological QOL, 14.2% in social relationships QOL, and 38.2% in environmental QOL. Anthropometric measures accounted for 11.3%, 3.1%, 12.0%, and 6.7% of the variance in these QOL indices, respectively, and DXA indices accounted for 18.7%, 17.5%, 27.4%, and 21.9%. Within these models, the number of minutes of heavy LTPA per day uniquely predicted physical health QOL, the number of mild LTPA days per week uniquely predicted psychological QOL, and the amount of mild LTPA per day uniquely predicted environmental QOL. Bivariate analyses also suggested that android and trunk fat, as well as supine waist and abdominal circumferences, were positively associated with social relationships QOL. Encouraging individuals with SCI to engage in LTPA may robustly enhance multiple aspects of QOL while reducing the risk for cardiovascular and metabolic morbidities associated with SCI. Moreover, this may lead to a further understanding of how QOL may impact longitudinal intervention trials. The study protocol and procedures were reviewed and approved by the McGuire VA Research Institutional Review Board (IRB# 02152, approval date August 9, 2015; IRB# 02375, approval date May 2, 2018).
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Effects of amyloid precursor protein peptide APP96-110, alone or with human mesenchymal stromal cells, on recovery after spinal cord injury p. 1376
Stuart I Hodgetts, Sarah J Lovett, D Baron-Heeris, A Fogliani, Marian Sturm, C Van den Heuvel, Alan R Harvey
DOI:10.4103/1673-5374.327357  PMID:34782585
Delivery of a peptide (APP96-110), derived from amyloid precursor protein (APP), has been shown to elicit neuroprotective effects following cerebral stroke and traumatic brain injury. In this study, the effect of APP96-110 or a mutant version of this peptide (mAPP96-110) was assessed following moderate (200 kdyn, (2 N)) thoracic contusive spinal cord injury (SCI) in adult Nude rats. Animals received a single tail vein injection of APP96-110 or mAPP96-110 at 30 minutes post-SCI and were then assessed for functional improvements over the next 8 weeks. A cohort of animals also received transplants of either viable or non-viable human mesenchymal stromal cells (hMSCs) into the SC lesion site at one week post-injury to assess the effect of combining intravenous APP96-110 delivery with hMSC treatment. Rats were perfused 8 weeks post-SCI and longitudinal sections of spinal cord analyzed for a number of factors including hMSC viability, cyst size, axonal regrowth, glial reactivity and macrophage activation. Analysis of sensorimotor function revealed occasional significant differences between groups using Ladderwalk or Ratwalk tests, however there were no consistent improvements in functional outcome after any of the treatments. mAPP96-110 alone, and APP96-110 in combination with both viable and non-viable hMSCs significantly reduced cyst size compared to SCI alone. Combined treatments with donor hMSCs also significantly increased βIII tubulin+, glial fibrillary acidic protein (GFAP+) and laminin+ expression, and decreased ED1+ expression in tissues. This preliminary study demonstrates that intravenous delivery of APP96-110 peptide has selective, modest neuroprotective effects following SCI, which may be enhanced when combined with hMSC transplantation. However, the effects are less pronounced and less consistent compared to the protective morphological and cognitive impact that this same peptide has on neuronal survival and behaviour after stroke and traumatic brain injury. Thus while the efficacy of a particular therapeutic approach in one CNS injury model may provide justification for its use in other neurotrauma models, similar outcomes may not necessarily occur and more targeted approaches suited to location and severity are required. All animal experiments were approved by The University of Western Australia Animal Ethics Committee (RA3/100/1460) on April 12, 2016.
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Selection of suitable internal controls for gene expression normalization in rats with spinal cord injury p. 1387
Wei Liu, Jie Yu, Yi-Fan Wang, Qian-Qian Shan, Ya-Xian Wang
DOI:10.4103/1673-5374.327350  PMID:34782586
There is a lack of systematic research on the expression of internal control genes used for gene expression normalization in real-time reverse transcription polymerase chain reaction in spinal cord injury research. In this study, we used rat models of spinal cord hemisection to analyze the expression stability of 13 commonly applied reference genes: Actb, Ankrd27, CypA, Gapdh, Hprt1, Mrpl10, Pgk1, Rictor, Rn18s, Tbp, Ubc, Ubxn11, and Ywhaz. Our results show that the expression of Ankrd27, Ubc, and Tbp were stable after spinal cord injury, while Actb was the most unstable internal control gene. Ankrd27, Ubc, Tbp, and Actb were consequently used to investigate the effects of internal control genes with differing stabilities on the normalization of target gene expression. Target gene expression levels and changes over time were similar when Ankrd27, Ubc, and Tbp were used as internal controls but different when Actb was used as an internal control. We recommend that Ankrd27, Ubc, and Tbp are used as internal control genes for real-time reverse transcription polymerase chain reaction in spinal cord injury research. This study was approved by the Administration Committee of Experimental Animals, Jiangsu Province, China (approval No. 20180304-008) on March 4, 2018.
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CORRIGENDA Top

Corrigendum: Effects of delayed repair of peripheral nerve injury on the spatial distribution of motor endplates in target muscle  

DOI:10.4103/1673-5374.324864  PMID:34782587
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Corrigendum: Brain-derived neurotrophic factor and its related enzymes and receptors play important roles after hypoxic-ischemic brain damage  

DOI:10.4103/1673-5374.324865  PMID:34782588
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