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15 April 2019, Volume 14 Issue 4 Previous Issue    Next Issue

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Corneal re-innervation following refractive surgery treatments Francisco Bandeira,Nur Zahira Yusoff,Gary Hin-Fai Yam, Jodhbir Singh Mehta 2019, 14 (4):  557-565.  doi: 10.4103/1673-5374.247421 Abstract ( 113 )   PDF (809KB) ( 270 )   Save  Laser refractive surgery is one of the most performed surgical procedures in the world. Although regarded safe and efficient, it has side effects. All of the laser based refractive surgical procedures invoke corneal nerve injury to some degree. The impact of this denervation can range from mild discomfort to neurotrophic corneas. Currently, three techniques are widely used for laser vision correction: small incision lenticule extraction, laser-assisted keratomileusis in situ and photorefractive keratotomy. Each of these techniques affects corneal innervation differently and has a different pattern of nerve regeneration. The purpose of this review is to summarize the different underlying mechanisms for corneal nerve injury and compare the different patterns of corneal reinnervation. Related Articles | Metrics

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Rabs and axonal regeneration Cheryl Qian Ying Yong,Bor Luen Tang 2019, 14 (4):  566-569.  doi: 10.4103/1673-5374.247422 Abstract ( 117 )   PDF (394KB) ( 232 )   Save Membrane trafficking processes are presumably vital for axonal regeneration after injury, but mechanistic understanding in this regard has been sparse. A recent loss-of-function screen had been carried out for factors important for axonal regeneration by cultured cortical neurons and the results suggested that the activity of a number of Rab GTPases might act to restrict axonal regeneration. A loss of Rab27b, in particular, is shown to enhance axonal regeneration in vitro, as well as in C. elegans and mouse central nervous system injury models in vivo. Possible mechanisms underlying this new finding, which has important academic and translational implication, are discussed. Related Articles | Metrics

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Uncoupling neurotrophic function from nociception of nerve growth factor: what can be learned from a rare human disease? Kijung Sung, Wanlin Yang, Chengbiao Wu 2019, 14 (4):  570-573.  doi: 10.4103/1673-5374.247442 Abstract ( 138 )   PDF (327KB) ( 227 )   Save Nerve growth factor (NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V (HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100th position of mature NGF resulting in a change of residue from arginine to tryptophan (R100W). Although those HSAN V patients associated with the NGFR100W mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGFR100W mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGFR100W provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGFR100W no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGFR100W mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic factor was significantly diminished. The significance of these findings is at least two folds: 1) the NGFR100W mutation can be used as an alternative to the wildtype NGF to treat human conditions without eliciting pain; and 2) the 75 kDa neurotrophic factor may serve as a novel target for pain management. We will discuss all the details in this mini-review. Related Articles | Metrics

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“Teaching old dogs new tricks”: targeting neural extracellular matrix for normal and pathological aging-related cognitive decline Adam D. Richard, Xiao-Hong Lu 2019, 14 (4):  578-581.  doi: 10.4103/1673-5374.247459 Abstract ( 109 )   PDF (474KB) ( 231 )   Save Cognitive decline is a feature of normal and pathological aging. As the proportion of the global aged population continues to grow, it is imperative to understand the molecular and cellular substrates of cognitive aging for therapeutic discovery. This review focuses on the critical role of neural extracellular matrix in the regulation of neuroplasticity underlying learning and memory in another under-investigated “critical period”: the aging process. The fascinating ideas of neural extracellular matrix forming a synaptic cradle in the tetrapartite synapse and possibly serving as a substrate for storage of very long-term memories will be introduced. We emphasize the distinct functional roles of diffusive neural extracellular matrix and perineuronal nets and the advantage of the coexistence of two structures for the adaptation to the ever-changing external and internal environments. Our study of striatal neural extracellular matrix supports the idea that chondroitin sulfate proteoglycan-associated extracellular matrix is restrictive on synaptic neuroplasticity, which plays important functional and pathogenic roles in early postnatal synaptic consolidation and aging-related cognitive decline. Therefore, the chondroitin sulfate proteoglycan-associated neural extracellular matrix can be targeted for normal and pathological aging. Future studies should focus on the cell-type specificity of neural extracellular matrix to identify the endogenous, druggable targets to restore juvenile neuroplasticity and confer a therapeutic benefit to neural circuits affected by aging. Related Articles | Metrics

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Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism? Elisa Piscianz,Liza Vecchi Brumatti,Alberto Tommasini,Annalisa Marcuzzi 2019, 14 (4):  582-587.  doi: 10.4103/1673-5374.247441 Abstract ( 112 )   PDF (573KB) ( 192 )   Save The balance of autophagy, apoptosis and necroptosis is crucial to determine the outcome of the cellular response to cholesterol dysregulation. Cholesterol plays a major role in regulating the properties of cell membranes, especially as regards their fluidity, and the regulation of its biosynthesis influences the shape and functions of these membranes. Whilst dietary cholesterol can easily be distributed to most organs, the central nervous system, whose membranes are particularly rich in cholesterol, mainly relies on de novo synthesis. For this reason, defects in the biosynthesis of cholesterol can variably affect the development of central nervous system. Moreover, defective synthesis of cholesterol and its intermediates may reflect both on structural cell anomalies and on the response to inflammatory stimuli. Examples of such disorders include mevalonate kinase deficiency, and Smith-Lemli-Opitz syndrome, due to deficiency in biosynthetic enzymes, and type C Niemann-Pick syndrome, due to altered cholesterol trafficking across cell compartments. Autophagy, as a crucial pathway dedicated to the degradation of cytosolic proteins and organelles, plays an essential role in the maintenance of homeostasis and in the turnover of the cytoplasmic material especially in the presence of imbalances such as those resulting from alteration of cholesterol metabolism. Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders. Related Articles | Metrics

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Involvement of T-complex protein 1-ring complex/chaperonin containing T-complex protein 1 (TRiC/CCT) in retrograde axonal transport through tau phosphorylation Xu-Qiao Chen 2019, 14 (4):  588-590.  doi: 10.4103/1673-5374.247460 Abstract ( 219 )   PDF (239KB) ( 237 )   Save The cytosolic chaperonin T-complex protein 1-ring complex (TRiC) or chaperonin containing T-complex protein 1 (CCT) is essential in de novo folding of approximately 10% of the eukaryotic, newly translated polypeptides as well as misfolded proteins. There is a close link between the TRiC/CCT cytosolic chaperonin and neurodegenerative diseases. A lot of research suggests that CCT plays neuroprotective roles in neurodegenerative diseases including Huntington’s disease. Either overexpression of a single or all eight subunits (CCT1-8) or treatment of the substrate-binding apical domain of yeast CCT1 (ApiCCT1) prevented mutant Huntingtin aggregation and improved cellular and neuronal functions. Importantly, our recent study has demonstrated that both CCT and ApiCCT could reduce mutant Huntingtin level and enhance both anterograde and retrograde axonal transport of brain-derived neurotrophic factor. These results led to restoration of the trophic status of striatal neurons from a bacterial artificial chromosome transgenic mouse model of Huntington’s disease. Related Articles | Metrics

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Perspectives for the association between olfactory disturbances and depression in Parkinson’s disease Jessica L. Ilkiw, Marcelo M. S. Lima 2019, 14 (4):  591-592.  doi: 10.4103/1673-5374.247461 Abstract ( 122 )   PDF (281KB) ( 256 )   Save Non-motor disturbances in Parkinson’s disease: Globally, population aged 60 or over is growing and considering the World Bank predictions for the next 20 years it is expected that the number of Parkinson’s disease (PD) cases will double at the end of this period thus, reaching an impressive 13–39 million patients worldwide. This scenario is potentially associated with a significant global negative impact on public health systems particularly in countries with increased ageing populations such as the European countries, Asia and Americas. The pathophysiology of PD involves the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) that triggers denervation of the nigrostriatal pathway and consequent significant reduction of dopamine in the dorsal striatum. Such process leads to a critical motor impairment scenario characterized by bradykinesia, rigidity, resting tremor, and postural instability. However, several other non-motor disturbances develop earlier, thus, being considered as prodromal signs of the neurodegeneration. In this sense, the literature is increasingly emphasizing the importance of investigating mood and olfactory disruptions as high sensitive benchmarks of the early-phase disease. In fact, the need for innovative early-phase diagnostic tools, as well as the elucidation of the pathophysiological mechanisms of such disturbances, is essential priority in the field of investigation of PD. Remarkably, in the year of 2015, a woman was known for an intriguing ability of “smell PD”. Her husband had lived with the disease for twenty years and during this process she noticed that his odor slowly changed to a musky smell. Interestingly, this woman could associate this particular smell with PD after meeting different people with this distinct odor in a charity for PD patients. In fact, this clever observation is aligned with studies showing that hyposmia is found decades before the motor onset. Another type of anecdotal story, frequently reported by the patients, is the often cases of burnt food during cooking. They just fail to sense the burnt smell generating a very frustrating feeling of incapacity. Related Articles | Metrics

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Indirect traumatic optic neuropathy: modeling optic nerve injury in the context of closed head trauma Emma G. Burke, Shelby M. Cansler, Nathan K. Evanson 2019, 14 (4):  593-594.  doi: 10.4103/1673-5374.247463 Abstract ( 123 )   PDF (146KB) ( 1275 )   Save Traumatic optic neuropathy: Traumatic brain injury is one of the leading causes of disability and mortality in the United States. It impacts people of all ages and demographics, particularly younger males and members of the military. Vision loss is commonly associated with traumatic brain injuries of all severities and can leave patients permanently disabled. This vision loss can be caused by injury to the visual system at multiple levels, including the eyes, optic nerves, and many different sites in the brain and brainstem. Despite the far-reaching effects of visual impairment after traumatic brain injury, its incidence after traumatic brain injury is not well measured, and few successful treatments have been identified or implemented. Related Articles | Metrics

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Astrocyte syncytium: a functional reticular system in the brain Conrad M. Kiyoshi, Min Zhou 2019, 14 (4):  595-596.  doi: 10.4103/1673-5374.247462 Abstract ( 209 )   PDF (310KB) ( 1031 )   Save In contrary to the discrete neuronal circuits, astrocytes share their cytoplasm through gap junctional coupling into a syncytium. This distinctive difference in neuronal and astrocytic anatomy recalls the historical debate between Camillo Golgi and Ramón y Cajal on the wiring principle of the nervous system over a century ago. At that neuron-centric era, the Cajal advocated the cell theory that considered the nervous system to be made up of discrete individual cells. Golgi on the other hand favored the reticular theory that viewed the nervous system as a singular continuing network system. Nevertheless, regardless of the difference in their viewpoints, both theories were intended to postulate an anatomical blueprint of neural circuitry, with no attention given to neuroglia. It was until the 1950s, the distinct membrane bordersbetween synapses were revealed by electron microscopy, which means that neurons are indeed discrete individual cells. This declared Ramón y Cajal’s cell theory the victor in the debate, while Golgi’s reticular theory was disregarded. However, the existence of a “low-resistance pathway” between neuroglia was soon identified in the optic nerve in the 1960s, which we now know to be gap junction coupling that connects the cytoplasm of astrocyter into a syncytial network. Ever since, decades of studies clearly demonstrated that syncytial coupling into the network is a most prominent feature of astrocytes and these glial networks are intimately interwoven with the neuronal circuits running across the entire central nervous system. Surprisingly, the question of whether a reticular system exists in parallel with the neuronal circuits has received a little research attention to this day. Interestingly, the wiring pattern of astrocyte syncytium is reminiscent of the reticular theory postulated by Golgi. In this perspective, the “revived” use of “reticular theory” is solely dedicated to the brain reticular system established by astrocytes. References | Related Articles | Metrics

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Neuroprotective effects of human bone marrow mesenchymal stem cells against cerebral ischemia are mediated in part by an anti-apoptotic mechanism Yuyang Zhang,Seongjin Yu,Julian P. Tuazon,Jea-Young Lee,Sydney Corey,Lauren Kvederis,Chase Kingsbury,Yuji Kaneko,Cesar V. Borlongan 2019, 14 (4):  597-604.  doi: 10.4103/1673-5374.247464 Abstract ( 127 )   PDF (1034KB) ( 225 )   Save Transplantation of human bone marrow mesenchymal stem cells (hMSCs) stands as a potent stroke therapy, but its exact mechanism remains unknown. This study investigated the anti-apoptotic mechanisms by which hMSCs exert neuroprotective effects on cerebral ischemia. Primary mixed cultures of rat neurons and astrocytes were cultured and exposed to oxygen-glucose deprivation. A two-hour period of “reperfusion” in standard medium and normoxic conditions was allowed and immediately followed by hMSCs and/or Bcl-2 antibody treatment. Cell viability of primary rat neurons and astrocytes was determined by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide and trypan blue exclusion methods. hMSC survival and differentiation were characterized by immunocytochemistry, while the concentration of Bcl-2 in the supernatant was measured by enzyme-linked immunosorbent assay to reveal the secretory anti-apoptotic function of hMSCs. Cultured hMSCs expressed embryonic-like stem cell phenotypic markers CXCR4, Oct4, SSEA4, and Nanog, as well as immature neural phenotypic marker Nestin. Primary rat neurons and astrocytes were protected from oxygen-glucose deprivation by hMSCs, which was antagonized by the Bcl-2 antibody. However, Bcl-2 levels in the supernatants did not differ between hMSC- and non-treated cells exposed to oxygen-glucose deprivation. Neuroprotective effects of hMSCs against cerebral ischemia were partially mediated by the anti-apoptotic mechanisms. However, further studies are warranted to fully elucidate this pathway. Related Articles | Metrics

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Acacetin protects against cerebral ischemia-reperfusion injury via the NLRP3 signaling pathway Juan Bu,Shen Shi,Hui-Qin Wang,Xiao-Shan Niu,Zong-Feng Zhao,Wei-Dong Wu,Xiao-Ling Zhang,Zhi Ma,Yan-Jun Zhang,Hui Zhang,Yi Zhu 2019, 14 (4):  605-612.  doi: 10.4103/1673-5374.247465 Abstract ( 139 )   PDF (1469KB) ( 272 )   Save Acacetin (5,7-dihydroxy-4′-methoxyflavone), a potential neuroprotective agent, has an inhibitory effect on lipopolysaccharide-in¬duced neuroinflammatory reactions. However, whether acacetin has an effect on inflammatory corpuscle 3 (NLRP3) after cerebral ischemia-reperfusion injury has not been fully determined. This study used an improved suture method to establish a cerebral isch¬emia-reperfusion injury model in C57BL/6 mice. After ischemia with middle cerebral artery occlusion for 1 hour, reperfusion with intraperitoneal injection of 25 mg/kg of acacetin (acacetin group) or an equal volume of saline (0.1 mL/10 g, middle cerebral artery occlu¬sion group) was used to investigate the effect of acacetin on cerebral ischemia-reperfusion injury. Infarct volume and neurological function scores were determined by 2,3,5-triphenyltetrazolium chloride staining and the Zea-Longa scoring method. Compared with the middle cerebral artery occlusion group, neurological function scores and cerebral infarction volumes were significantly reduced in the acacetin group. To understand the effect of acacetin on microglia-mediated inflammatory response after cerebral ischemia-reperfusion injury, im¬munohistochemistry for the microglia marker calcium adapter protein ionized calcium-binding adaptor molecule 1 (Iba1) was examined in the hippocampus of ischemic brain tissue. In addition, tumor necrosis factor-α, interleukin-1β, and interleukin-6 expression in ischemic brain tissue of mice was quantified by enzyme-linked immunosorbent assay. Expression of Iba1, tumor necrosis factor-α, interleukin-1β and interleukin-6 was significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Western blot assay results showed that expression of Toll-like receptor 4, nuclear factor kappa B, NLRP3, procaspase-1, caspase-1, pro-interleukin-1β, and interleukin-1β were significantly lower in the acacetin group compared with the middle cerebral artery occlusion group. Our findings indicate that acacetin has a protective effect on cerebral ischemia-reperfusion injury, and its mechanism of action is associated with inhibi¬tion of microglia-mediated inflammation and the NLRP3 signaling pathway. Related Articles | Metrics

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Luteolin induces hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome Wen-Bo Zhou,Zong-Ning Miao, Bin Zhang,Wei Long,Fang-Xiu Zheng,Jing Kong,Bin Yu 2019, 14 (4):  613-620.  doi: 10.4103/1673-5374.248519 Abstract ( 201 )   PDF (1168KB) ( 339 )   Save Studies have shown that the natural flavonoid luteolin has neurotrophic activity. In this study, we investigated the effect of luteolin in a mouse model of Down syndrome. Ts65Dn mice, which are frequently used as a model of Down syndrome, were intraperitoneally injected with 10 mg/kg luteolin for 4 consecutive weeks starting at 12 weeks of age. The Morris water maze test was used to evaluate learning and memory abilities, and the novel object recognition test was used to assess recognition memory. Immunohistochemistry was performed for the neural stem cell marker nestin, the astrocyte marker glial fibrillary acidic protein, the immature neuron marker DCX, the mature neuron marker NeuN, and the cell proliferation marker Ki67 in the hippocampal dentate gyrus. Nissl staining was used to observe changes in morphology and to quantify cells in the dentate gyrus. Western blot assay was used to analyze the protein levels of brain-derived neuro¬trophic factor (BDNF) and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) in the hippocampus. Luteolin improved learning and memory abilities as well as novel object recognition ability, and enhanced the proliferation of neurons in the hippocampal dentate gyrus. Furthermore, luteolin increased expression of nestin and glial fibrillary acidic protein, increased the number of DCX+ neurons in the gran¬ular layer and NeuN+ neurons in the subgranular region of the dentate gyrus, and increased the protein levels of BDNF and p-ERK1/2 in the hippocampus. Our findings show that luteolin improves behavioral performance and promotes hippocampal neurogenesis in Ts65Dn mice. Moreover, these effects might be associated with the activation of the BDNF/ERK1/2 pathway. Related Articles | Metrics

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A mathematical model of synaptotagmin 7 revealing functional importance of short-term synaptic plasticity Yao He, Don Kulasiri,Jingyi Liang 2019, 14 (4):  621-631.  doi: 10.4103/1673-5374.247466 Abstract ( 131 )   PDF (1750KB) ( 197 )   Save Synaptotagmin 7 (Syt7), a presynaptic calcium sensor, has a significant role in the facilitation in short-term synaptic plasticity: Syt7 knock out mice show a significant reduction in the facilitation. The functional importance of short-term synaptic plasticity such as facilitation is not well understood. In this study, we attempt to investigate the potential functional relationship between the short-term synaptic plasticity and postsynaptic response by developing a mathematical model that captures the responses of both wild-type and Syt7 knock-out mice. We then studied the model behaviours of wild-type and Syt7 knock-out mice in response to multiple input action potentials. These behaviors could establish functional importance of short-term plasticity in regulating the postsynaptic response and related synaptic properties. In agreement with previous modeling studies, we show that release sites are governed by non-uniform release probabilities of neurotransmitters. The structure of non-uniform release of neurotransmitters makes short-term synaptic plasticity to act as a high-pass filter. We also propose that Syt7 may be a modulator for the long-term changes of postsynaptic response that helps to train the target frequency of the filter. We have developed a mathematical model of short-term plasticity which explains the experimental data. Related Articles | Metrics

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Expression signatures of long non-coding RNA and mRNA in human traumatic brain injury Li-Xiang Yang,Li-Kun Yang,Jie Zhu,Jun-Hui Chen,Yu-Hai Wang,Kun Xiong 2019, 14 (4):  632-641.  doi: 10.4103/1673-5374.247467 Abstract ( 143 )   PDF (2024KB) ( 366 )   Save Long non-coding RNAs (lncRNAs) play a key role in craniocerebral disease, although their expression profiles in human traumatic brain injury are still unclear. In this regard, in this study, we examined brain injury tissue from three patients of the 101st Hospital of the Peo¬ple’s Liberation Army, China (specifically, a 36-year-old male, a 52-year-old female, and a 49-year-old female), who were diagnosed with traumatic brain injury and underwent brain contusion removal surgery. Tissue surrounding the brain contusion in the three patients was used as control tissue to observe expression characteristics of lncRNAs and mRNAs in human traumatic brain injury tissue. Volcano plot filtering identified 99 lncRNAs and 63 mRNAs differentially expressed in frontotemporal tissue of the two groups (P < 0.05, fold change > 1.2). Microarray analysis showed that 43 lncRNAs were up-regulated and 56 lncRNAs were down-regulated. Meanwhile, 59 mRNAs were up-regulated and 4 mRNAs were down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed 27 signaling pathways associated with target genes and, in particular, legionellosis and influenza A signaling pathways. Subsequently, a lncRNA-gene network was generated, which showed an absolute correlation coefficient value > 0.99 for 12 lncRNA-mR¬NA pairs. Finally, quantitative real-time polymerase chain reaction confirmed different expression of the five most up-regulated mRNAs within the two groups, which was consistent with the microarray results. In summary, our results show that expression profiles of mRNAs and lncRNAs are significantly different between human traumatic brain injury tissue and surrounding tissue, providing novel insight re¬garding lncRNAs’ involvement in human traumatic brain injury. All participants provided informed consent. This research was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-TCC-13004002) and the protocol version number is 1.0. Related Articles | Metrics

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Resting-state network complexity and magnitude changes in neonates with severe hypoxic ischemic encephalopathy Hong-Xin Li,Min Yu,Ai-Bin Zheng,Qin-Fen Zhang,Guo-Wei Hua,Wen-Juan Tu,Li-Chi Zhang 2019, 14 (4):  642-648.  doi: 10.4103/1673-5374.247468 Abstract ( 133 )   PDF (641KB) ( 391 )   Save Resting-state functional magnetic resonance imaging has revealed disrupted brain network connectivity in adults and teenagers with cere¬bral palsy. However, the specific brain networks implicated in neonatal cases remain poorly understood. In this study, we recruited 14 term-born infants with mild hypoxic ischemic encephalopathy and 14 term-born infants with severe hypoxic ischemic encephalopathy from Changzhou Children’s Hospital, China. Resting-state functional magnetic resonance imaging data showed efficient small-world organization in whole-brain networks in both the mild and severe hypoxic ischemic encephalopathy groups. However, compared with the mild hypoxic ischemic encephalopathy group, the severe hypoxic ischemic encephalopathy group exhibited decreased local efficiency and a low clustering coefficient. The distribution of hub regions in the functional networks had fewer nodes in the severe hypoxic ischemic encephalopathy group compared with the mild hypoxic ischemic encephalopathy group. Moreover, nodal efficiency was reduced in the left rolandic operculum, left supramarginal gyrus, bilateral superior temporal gyrus, and right middle temporal gyrus. These results suggest that the topological structure of the resting state functional network in children with severe hypoxic ischemic encephalopathy is clearly distinct from that in children with mild hypoxic ischemic encephalopathy, and may be associated with impaired language, motion, and cognition. These data indicate that it may be possible to make early predictions regarding brain development in children with severe hypoxic ischemic encephalopathy, enabling early interventions targeting brain function. This study was approved by the Regional Ethics Review Boards of the Changzhou Children’s Hospital (approval No. 2013-001) on January 31, 2013. Informed consent was obtained from the family members of the children. The trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800016409) and the protocol version is 1.0. Related Articles | Metrics

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Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer’s disease Xu-Sheng Yan,Zhan-Jun Yang,Jian-Xin Jia,Wei Song, Xin Fang,Zhi-Ping Cai,Dong-Sheng Huo, He Wang 2019, 14 (4):  649-657.  doi: 10.4103/1673-5374.245477 Abstract ( 146 )   PDF (1873KB) ( 463 )   Save Cognitive dysfunction in Alzheimer’s disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxida-tive stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1–42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer’s disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer’s disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocam¬pal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer’s disease is mediated via androgen receptors to scavenge free radicals, thereby en¬hancing synaptic plasticity. Related Articles | Metrics

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Mutations of beta-amyloid precursor protein alter the consequence of Alzheimer’s disease pathogenesis Nuo-Min Li,Ke-Fu Liu,Yun-Jie Qiu,Huan-Huan Zhang,Hiroshi Nakanishi,Hong Qing 2019, 14 (4):  658-665.  doi: 10.4103/1673-5374.247469 Abstract ( 125 )   PDF (2335KB) ( 209 )   Save Alzheimer’s disease is pathologically defined by accumulation of extracellular amyloid-β (Aβ). Approximately 25 mutations in β-amyloid precursor protein (APP) are pathogenic and cause autosomal dominant Alzheimer’s disease. To date, the mechanism underlying the effect of APP mutation on Aβ generation is unclear. Therefore, investigating the mechanism of APP mutation on Alzheimer’s disease may help understanding of disease pathogenesis. Thus, APP mutations (A673T, A673V, E682K, E693G, and E693Q) were transiently co-transfected into human embryonic kidney cells. Western blot assay was used to detect expression levels of APP, beta-secretase 1, and presenilin 1 in cells. Enzyme-linked immunosorbent assay was performed to determine Aβ1–40 and Aβ1–42 levels. Liquid chromatography-tandem mass chromatography was used to examine VVIAT, FLF, ITL, VIV, IAT, VIT, TVI, and VVIA peptide levels. Immunofluorescence staining was performed to measure APP and early endosome antigen 1 immunoreactivity. Our results show that the protective A673T mutation de-creases Aβ42/Aβ40 rate by downregulating IAT and upregulating VVIA levels. Pathogenic A673V, E682K, and E693Q mutations promote Aβ42/Aβ40 rate by increasing levels of CTF99, Aβ42, Aβ40, and IAT, and decreasing VVIA levels. Pathogenic E693G mutation shows no significant change in Aβ42/Aβ40 ratio because of inhibition of γ-secretase activity. APP mutations can change location from the cell surface to early endosomes. Our findings confirm that certain APP mutations accelerate Aβ generation by affecting the long Aβ cleavage pathway and increasing Aβ42/40 rate, thereby resulting in Alzheimer’s disease. Related Articles | Metrics

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Emotion processing in Parkinson’s disease: a blood oxygenation level-dependent functional magnetic resonance imaging study Mohammed Benzagmout,Saïd Boujraf,Badreeddine Alami,Hassane Ali Amadou,Halima El Hamdaoui,Amine Bennani,Mounir Jaafari, Ismail Rammouz,Mustapha Maaroufi,Rabia Magoul,Driss Boussaoud 2019, 14 (4):  666-672.  doi: 10.4103/1673-5374.247470 Abstract ( 114 )   PDF (811KB) ( 278 )   Save Parkinson’s disease is a neurodegenerative disorder caused by loss of dopamine neurons in the substantia nigra pars compacta. Tremor, rigidity, and bradykinesia are the major symptoms of the disease. These motor impairments are often accompanied by affective and emotional dysfunctions which have been largely studied over the last decade. The aim of this study was to investigate emotional processing organization in the brain of patients with Parkinson’s disease and to explore whether there are differences between recognition of different types of emotions in Parkinson’s disease. We examined 18 patients with Parkinson’s disease (8 men, 10 women) with no history of neurological or psychiatric comorbidities. All these patients underwent identical brain blood oxygenation level-dependent functional magnetic resonance imaging for emotion evaluation. Blood oxygenation level-dependent functional magnetic resonance imaging results revealed that the occipito-temporal cortices, insula, orbitofrontal cortex, basal ganglia, and parietal cortex which are involved in emotion processing, were activated during the functional control. Additionally, positive emotions activate larger volumes of the same anatomical entities than neutral and negative emotions. Results also revealed that Parkinson’s disease associated with emotional disorders are increasingly recognized as disabling as classic motor symptoms. These findings help clinical physicians to recognize the emotional dysfunction of patients with Parkinson’s disease. Related Articles | Metrics

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Electroacupuncture promotes peripheral nerve regeneration after facial nerve crush injury and upregulates the expression of glial cell-derived neurotrophic factor Jing Fei,Lin Gao,Huan-Huan Li,Qiong-Lan Yuan,Lei-Ji Li 2019, 14 (4):  673-682.  doi: 10.4103/1673-5374.247471 Abstract ( 219 )   PDF (3501KB) ( 323 )   Save The efficacy of electroacupuncture in the treatment of peripheral facial paralysis is known, but the specific mechanism has not been clar¬ified. Glial cell-derived neurotrophic factor (GDNF) has been shown to protect neurons by binding to N-cadherin. Our previous results have shown that electroacupuncture could increase the expression of N-cadherin mRNA in facial neurons and promote facial nerve re¬generation. In this study, the potential mechanisms by which electroacupuncture promotes nerve regeneration were elucidated through assessing the effects of electroacupuncture on GDNF and N-cadherin expression in facial motoneurons of rabbits with peripheral facial nerve crush injury. New Zealand rabbits were randomly divided into a normal group (normal control, n = 21), injury group (n = 45) and electroacupuncture group (n = 45). Model rabbits underwent facial nerve crush injury only. Rabbits in the electroacupuncture group received facial nerve injury, and then underwent electroacupuncture at Yifeng (TE17), Jiache (ST6), Sibai (ST2), Dicang (ST4), Yangbai (GB14), Quanliao (SI18), and Hegu (LI4; only acupuncture, no electrical stimulation). The results showed that in behavioral assessments, the total scores of blink reflex, vibrissae movement, and position of apex nasi, were markedly lower in the EA group than those in the injury group. Hematoxylin-eosin staining of the right buccinator muscle of each group showed that the cross-sectional area of buccinator was larger in the electroacupuncture group than in the injury group on days 1, 14 and 21 post-surgery. Toluidine blue staining of the right facial nerve tissue of each group revealed that on day 14 post-surgery, there was less axonal demyelination and fewer inflammatory cells in the electroacupuncture group compared with the injury group. Quantitative real time-polymerase chain reaction showed that compared with the injury group, N-cadherin mRNA levels on days 4, 7, 14 and 21 and GDNF mRNA levels on days 4, 7 and 14 were significant¬ly higher in the electroacupuncture group. Western blot assay displayed that compared with the injury group, the expression of GDNF protein levels on days 7, 14 and 21 were significantly upregulated in the electroacupuncture group. The histology with hematoxylin-eosin staining and Nissl staining of brainstem tissues containing facial neurons in the middle and lower part of the pons exhibited that on day 7 post-surgery, there were significantly fewer apoptotic neurons in the electroacupuncture group than in the injury group. By day 21, there was no significantly difference in the number of neurons between the electroacupuncture and normal groups. Taken together, these results have confirmed that electroacupuncture promotes regeneration of peripheral facial nerve injury in rabbits, inhibits neuronal apoptosis, and reduces peripheral inflammatory response, resulting in the recovery of facial muscle function. This is achieved by up-regulating the expression of GDNF and N-cadherin in central facial neurons. Related Articles | Metrics

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Qian-Zheng-San promotes regeneration after sciatic nerve crush injury in rats Zhi-Yong Wang,Li-Hua Qin, Wei-Guang Zhang,Pei-Xun Zhang,Bao-Guo Jiang 2019, 14 (4):  683-691.  doi: 10.4103/1673-5374.247472 Abstract ( 199 )   PDF (3571KB) ( 649 )   Save Qian-Zheng-San, a traditional Chinese prescription consisting of Typhonii Rhizoma, Bombyx Batryticatus, Scorpio, has been found to play an active therapeutic role in central nervous system diseases. However, it is unclear whether Qian-Zheng-San has therapeutic value for peripheral nerve injury. Therefore, we used Sprague-Dawley rats to investigate this. A sciatic nerve crush injury model was induced by clamping the right sciatic nerve. Subsequently, rats in the treatment group were administered 2 mL Qian-Zheng-San (1.75 g/mL) daily as systemic therapy for 1, 2, 4, or 8 weeks. Rats in the control group were not administered Qian-Zheng-San. Rats in sham group did not undergo surgery and systemic therapy. Footprint analysis was used to assess nerve motor function. Electrophysiological experiments were used to detect nerve conduction function. Immunofluorescence staining was used to assess axon counts and morphological analysis. Im¬munohistochemical staining was used to observe myelin regeneration of the sciatic nerve and the number of motoneurons in the anterior horn of the spinal cord. At 2 and 4 weeks postoperatively, the sciatic nerve function index, nerve conduction velocity, the number of dis¬tant regenerated axons and the axon diameter of the sciatic nerve increased in the Qian-Zheng-San treatment group compared with the control group. At 2 weeks postoperatively, nerve fiber diameter, myelin thickness, and the number of motor neurons in the lumbar spinal cord anterior horn increased in the Qian-Zheng-San treatment group compared with the control group. These results indicate that Qian- Zheng-San has a positive effect on peripheral nerve regeneration. Related Articles | Metrics

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Repair of long segmental ulnar nerve defects in rats by several different kinds of nerve transposition Fei Yu,You-Lai Yu, Su-Ping Niu,Pei-Xun Zhang,Xiao-Feng Yin,Na Han,Ya-Jun Zhang, Dian-Ying Zhang,Yu-Hui Kou, Bao-Guo Jiang 2019, 14 (4):  692-698.  doi: 10.4103/1673-5374.247473 Abstract ( 129 )   PDF (1144KB) ( 240 )   Save Multiple regeneration of axonal buds has been shown to exist during the repair of peripheral nerve injury, which confirms a certain repair potential of the injured peripheral nerve. Therefore, a systematic nerve transposition repair technique has been proposed to treat severe peripheral nerve injury. During nerve transposition repair, the regenerated nerve fibers of motor neurons in the anterior horn of the spinal cord can effectively grow into the repaired distal nerve and target muscle tissues, which is conducive to the recovery of motor function. The aim of this study was to explore regeneration and nerve functional recovery after repairing a long-segment peripheral nerve defect by transposition of different donor nerves. A long-segment (2 mm) ulnar nerve defect in Sprague-Dawley rats was repaired by transposition of the musculocutaneous nerve, medial pectoral nerve, muscular branches of the radial nerve and anterior interosseous nerve (pronator quadratus muscle branch). In situ repair of the ulnar nerve was considered as a control. Three months later, wrist flexion function, nerve regeneration and innervation muscle recovery in rats were assessed using neuroelectrophysiological testing, osmic acid staining and hematoxylin-eosin staining, respectively. Our findings indicate that repair of a long-segment ulnar nerve defect with different donor nerve transpositions can reinnervate axonal function of motor neurons in the anterior horn of spinal cord and restore the function of affected limbs to a certain extent. Related Articles | Metrics

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Reinnervation of spinal cord anterior horn cells after median nerve repair using transposition with other nerves Yu-Song Yuan,Su-Ping Niu,You-Lai Yu,Pei-Xun Zhang,Xiao-Feng Yin,Na Han,Ya-Jun Zhang,Dian-Ying Zhang,Hai-Lin Xu,Yu-Hui Kou,Bao-Guo Jiang 2019, 14 (4):  699-705.  doi: 10.4103/1673-5374.247474 Abstract ( 149 )   PDF (1618KB) ( 229 )   Save Our previous studies have confirmed that during nerve transposition repair to injured peripheral nerves, the regenerated nerve fibers of motor neurons in the anterior horn of the spinal cord can effectively repair distal nerve and target muscle tissue and restore muscle motor function. To observe the effect of nerve regeneration and motor function recovery after several types of nerve transposition for median nerve defect (2 mm), 30 Sprague-Dawley rats were randomly divided into sham operation group, epineurial neurorrhaphy group, musculocutaneous nerve transposition group, medial pectoral nerve transposition group, and radial nerve muscular branch transposition group. Three months after nerve repair, the wrist flexion test was used to evaluate the recovery of wrist flexion after regeneration of median nerve in the affected limbs of rats. The number of myelinated nerve fibers, the thickness of myelin sheath, the diameter of axons and the cross-sectional area of axons in the proximal and distal segments of the repaired nerves were measured by osmic acid staining. The ratio of newly produced distal myelinated nerve fibers to the number of proximal myelinated nerve fibers was calculated. Wet weights of the flexor digitorum superficialis muscles were measured. Muscle fiber morphology was detected using hematoxylin-eosin staining. The cross-sectional area of muscle fibers was calculated to assess the recovery of muscles. Results showed that wrist flexion function was restored, and the nerve grew into the distal effector in all three nerve transposition groups and the epineurial neurorrhaphy group. There were differences in the number of myelinated nerve fibers in each group. The magnification of proximal to distal nerves was 1.80, 3.00, 2.50, and 3.12 in epineurial neurorrhaphy group, musculocutaneous nerve transposition group, medial pectoral nerve transposition group, and radial nerve muscular branch transposition group, respectively. Nevertheless, axon diameters of new nerve fibers, cross-sectional areas of axons, thicknesses of myelin sheath, wet weights of flexor digitorum superficialis muscle and cross-sectional areas of muscle fibers of all three groups of donor nerves from different anterior horn motor neurons after nerve transposition were similar to those in the epineurial neurorrhaphy group. Our findings indicate that donor nerve translocation from different anterior horn motor neurons can effectively repair the target organs innervated by the median nerve. The corresponding spinal anterior horn motor neurons obtain functional reinnervation and achieve some degree of motor function in the affected limbs. Related Articles | Metrics

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Repair of peripheral nerve defects by nerve transposition using small gap bio-sleeve suture with different inner diameters at both ends Yu-Hui Kou, You-Lai Yu, Ya-Jun Zhang,Na Han,Xiao-Feng Yin,Yu-Song Yuan,Fei Yu,Dian-Ying Zhang,Pei-Xun Zhang,Bao-Guo Jiang 2019, 14 (4):  706-712.  doi: 10.4103/1673-5374.247475 Abstract ( 146 )   PDF (926KB) ( 288 )   Save During peripheral nerve transposition repair, if the diameter difference between transposed nerves is large or multiple distal nerves must be repaired at the same time, traditional epineurial neurorrhaphy has the problem of high tension at the suture site, which may even lead to the failure of nerve suture. We investigated whether a small gap bio-sleeve suture with different inner diameters at both ends can be used to repair a 2-mm tibial nerve defect by proximal transposition of the common peroneal nerve in rats and compared the results with the repair seen after epineurial neurorrhaphy. Three months after surgery, neurological function, nerve regeneration, and recovery of nerve innervation muscle were assessed using the tibial nerve function index, neuroelectrophysiological testing, muscle biomechanics and wet weight measurement, osmic acid staining, and hematoxylin-eosin staining. There was no obvious inflammatory reaction and neuroma formation in the tibial nerve after repair by the small gap bio-sleeve suture with different inner diameters at both ends. The conduction velocity, muscle strength, wet muscle weight, cross-sectional area of muscle fibers, and the number of new myelinated nerve fibers in the bio-sleeve suture group were similar to those in the epineurial neurorrhaphy group. Our findings indicate that small gap bio-sleeve suture with different inner diameters at both ends can achieve surgical suture between nerves of different diameters and promote regeneration and functional recovery of injured peripheral nerves. Related Articles | Metrics

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Establishment and verification of a surgical prognostic model for cervical spinal cord injury without radiological abnormality Jie Wang,Shuai Guo,Xuan Cai,Jia-Wei Xu,Hao-Peng Li 2019, 14 (4):  713-720.  doi: 10.4103/1673-5374.247480 Abstract ( 144 )   PDF (565KB) ( 205 )   Save Some studies have suggested that early surgical treatment can effectively improve the prognosis of cervical spinal cord injury without radiological abnormality, but no research has focused on the development of a prognostic model of cervical spinal cord injury without radiological abnormality. This retrospective analysis included 43 patients with cervical spinal cord injury without radiological abnormal¬ity. Seven potential factors were assessed: age, sex, external force strength causing damage, duration of disease, degree of cervical spinal stenosis, Japanese Orthopaedic Association score, and physiological cervical curvature. A model was established using multiple binary lo¬gistic regression analysis. The model was evaluated by concordant profiling and the area under the receiver operating characteristic curve. Bootstrapping was used for internal validation. The prognostic model was as follows: logit(P) = −25.4545 + 21.2576VALUE + 1.2160SCORE − 3.4224TIME, where VALUE refers to the Pavlov ratio indicating the extent of cervical spinal stenosis, SCORE refers to the Japanese Or-thopaedic Association score (0–17) after the operation, and TIME refers to the disease duration (from injury to operation). The area under the receiver operating characteristic curve for all patients was 0.8941 (95% confidence interval, 0.7930–0.9952). Three factors assessed in the predictive model were associated with patient outcomes: a great extent of cervical stenosis, a poor preoperative neurological status, and a long disease duration. These three factors could worsen patient outcomes. Moreover, the disease prognosis was considered good when logit(P) ≥ −2.5105. Overall, the model displayed a certain clinical value. This study was approved by the Biomedical Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University, China (approval number: 2018063) on May 8, 2018. Related Articles | Metrics

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Neuroprotective effects of rapamycin on spinal cord injury in rats by increasing autophagy and Akt signaling Xi-Gong Li,Jun-Hua Du, Yang Lu, Xiang-Jin Lin 2019, 14 (4):  721-727.  doi: 10.4103/1673-5374.247476 Abstract ( 144 )   PDF (1439KB) ( 278 )   Save Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuroprotective effects on spinal cord injury by activating Akt phosphorylation. We hypothesized that both effects of rapamycin, the increased autophagy activity and Akt signaling, would contribute to its neuroprotective properties. In this study, a compressive spinal cord injury model of rat was created by an aneurysm clip with a 30 g closing force. Rat models were intraperitoneally injected with rapamycin 1 mg/kg, followed by autophagy inhibitor 3-methyladenine 2.5 mg/kg and Akt inhib¬itor IV 1 μg/kg. Western blot assay, immunofluorescence staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to observe the expression of neuronal autophagy molecule Beclin 1, apoptosis-related molecules Bcl-2, Bax, cytochrome c, casp ase-3 and Akt signaling. Our results demonstrated that rapamycin inhibited the expression of mTOR in injured spinal cord tissue and up-reg¬ulated the expression of Beclin 1 and phosphorylated-Akt. Rapamycin prevented the decrease of bcl-2 expression in injured spinal cord tissue, reduced Bax, cytochrome c and caspase-3 expression levels and reduced the number of apoptotic neurons in injured spinal cord tissue 24 hours after spinal cord injury. 3-Methyladenine and Akt inhibitor IV intervention suppressed the expression of Beclin-1 and phosphorylated-Akt in in¬jured spinal cord tissue and reduced the protective effect of rapamycin on apoptotic neurons. The above results indicate that the neuroprotective effect of rapamycin on spinal cord injury rats can be achieved by activating autophagy and the Akt signaling pathway. Related Articles | Metrics

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Voluntary running delays primary degeneration in rat retinas after partial optic nerve transection Hong-Ying Li,Xi Hong 1,Mi Huang,Kwok-Fai So 2019, 14 (4):  728-734.  doi: 10.4103/1673-5374.247481 Abstract ( 192 )   PDF (1032KB) ( 264 )   Save Running is believed to be beneficial for human health. Many studies have focused on the neuroprotective effects of voluntary running on animal models. There were both primary and secondary degeneration in neurodegenerative diseases, including glaucoma. However, whether running can delay primary or secondary degeneration or both of them was not clear. Partial optic nerve transection model is a valuable glaucoma model for studying both primary and secondary degeneration because it can separate primary (mainly in the superior retina) from secondary (mainly in the inferior retina) degeneration. Therefore, we compared the survival of retinal ganglion cells between Sprague-Dawley rat runners and non-runners both in the superior and inferior retinas. Excitotoxicity, oxidative stress, and apoptosis are involved in the degeneration of retinal ganglion cells in glaucoma. So we also used western immunoblotting to compare the expression of some proteins involved in apoptosis (phospho-c-Jun N-terminal kinases, p-JNKs), oxidative stress (manganese superoxide dismutase, MnSOD) and excitotoxicity (glutamine synthetase) between runners and non-runners after partial optic nerve transection. Results showed that voluntary running delayed the death of retinal ganglion cells vulnerable to primary degeneration but not those to secondary degeneration. In addition, voluntary running decreased the expression of glutamine synthetase, but not the expression of p-JNKs and MnSOD in the superior retina after partial optic nerve transection. These results illustrated that primary degeneration of retinal ganglion cells might be mainly related with excitotoxicity rather than oxidative stress; and the voluntary running could down-regulate excitotoxicity to delay the primary degeneration of retinal ganglion cells after partial optic nerve transection. Related Articles | Metrics

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Human survival and immune mediated mitophagy in neuroplasticity disorders Ian James Martins 2019, 14 (4):  735-735.  doi: 10.4103/1673-5374.247482 Abstract ( 115 )   PDF (168KB) ( 201 )   Save Neurodegenerative diseases are now associated with the global obesity and diabetes epidemic in the developing and developed world. Neurodegenerative diseases are a heterogeneous group of disorders with complex factors such as neurohumoral, endocrine and environmental factors involved in induction of these neurodegenerative diseases. The future of science and medicine in neurodegenerative diseases is now dependent on nutritional genomics with insulin resistance a major factor in the induction of neurodegenerative diseases. Nutritional genomics now involves the anti-aging gene Sirtuin 1 (Sirt 1) that is important to the prevention of insulin resistance with its critical involvement in the immune system. Sirt 1 inactivation leads to toxic immune reactions connected to the acceleration of neuron death in various communities. Appetite control with relevance to immunometabolism has become of critical importance to the treatment of neurodegeneration. Nutritional diets activate the heat shock gene Sirt 1 to prevent the increase in heat shock proteins connected to autoimmune disease, mitophagy and irreversible programmed cell death in global populations. Related Articles | Metrics