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    15 October 2018, Volume 13 Issue 10 Previous Issue    Next Issue
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    The combination of induced pluripotent stem cells and bioscaffolds holds promise for spinal cord regeneration
    Ashley DeBrot, Li Yao
    2018, 13 (10):  1677-1684.  doi: 10.4103/1673-5374.238602
    Abstract ( 111 )   PDF (198KB) ( 164 )   Save

    Spinal cord injuries (SCIs) are debilitating conditions for which no effective treatment currently exists. The damage of neural tissue causes disruption of neural tracts and neuron loss in the spinal cord. Stem cell replacement offers a solution for SCI treatment by providing a source of therapeutic cells for neural function restoration. Induced pluripotent stem cells (iPSCs) have been investigated as a potential type of stem cell for such therapies. Transplantation of iPSCs has been shown to be effective in restoring function after SCIs in animal models while they circumvent ethical and immunological concerns produced by other stem cell types. Another approach for the treatment of SCI involves the graft of a bioscaffold at the site of injury to create a microenvironment that enhances cellular viability and guides the growing axons. Studies suggest that a combination of these two treatment methods could have a synergistic effect on functional recovery post-neural injury. While much progress has been made, more research is needed before clinical trials are possible. This review highlights recent advancements using iPSCs and bioscaffolds for treatment of SCI.

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    Melatonin for the treatment of spinal cord injury
    Yan Zhang, Wen-Xiu Zhang, Yan-Jun Zhang, Ya-Dong Liu, Zong-Jian Liu, Qi-Chao Wu, Yun Guan, Xue-Ming Chen
    2018, 13 (10):  1685-1692.  doi: 10.4103/1673-5374.238603
    Abstract ( 170 )   PDF (363KB) ( 174 )   Save

    Spinal cord injury (SCI) from trauma or disease severely impairs sensory and motor function. Neurore­habilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing damaged connections in the central nervous system. An increasing number of preclinical studies suggest that melatonin may be useful for the treatment of SCI. Melatonin is an indolamine that is primarily secreted by the pineal gland and known to be regulated by photoperiodicity. However, it is also a versatile hormone with antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. Here, we review the neuroprotective properties of melatonin and the potential mechanisms by which it might be beneficial in the treatment of SCI. We also describe therapies that combine melatonin with exercise, oxy­tetracycline, and dexamethasone to attenuate the secondary injury after SCI and limit potential side effects. Finally, we discuss how injury at different spinal levels may differentially affect the secretion of melatonin.

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    Depression following a traumatic brain injury: uncovering cytokine dysregulation as a pathogenic mechanism
    Colleen N. Bodnar, Josh M. Morganti, Adam D. Bachstetter
    2018, 13 (10):  1693-1704.  doi: 10.4103/1673-5374.238604
    Abstract ( 128 )   PDF (1328KB) ( 235 )   Save

    A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury (TBI). Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α (TNFα) and interleukin 1 (IL-1) can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which TNFα and IL-1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.

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    Loss of canonical Wnt signaling is involved in the pathogenesis of Alzheimer’s disease
    Cheril Tapia-Rojas, Nibaldo C. Inestrosa
    2018, 13 (10):  1705-1710.  doi: 10.4103/1673-5374.238606
    Abstract ( 155 )   PDF (412KB) ( 184 )   Save

    Alzheimer’s disease (AD) is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β (Aβ) peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein (APP) processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic (Tg) mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type (WT) mice, contributing to the development of an Alzheimer’s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.

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    The balance between efficient anti-inflammatory treatment and neuronal regeneration in the olfactory epithelium
    Seo Young Chang, Isaias Glezer
    2018, 13 (10):  1711-1714.  doi: 10.4103/1673-5374.238605
    Abstract ( 112 )   PDF (515KB) ( 169 )   Save

    The sense of smell is important for human quality of life. This sophisticated sensorial system relies on the detection of odorant molecules that engage receptors expressed in the cilia of dedicated neurons that constitute the olfactory epithelium (OE). Importantly, the OE is a highly active site of adult neurogenesis where short-lived neurons are efficiently replenished, even after massive neuronal cell loss. It is suggested that the degree of olfactory function recovery after OE injury may depend on the nature of the lesion (traumatic, chemical, infectious or inflammatory), as well on the velocity of cellular regeneration. Topical steroidal anti-inflammatory drugs (SAIDs), such as glucocorticoids, are routinely prescribed for treating upper airway inflammatory conditions, such as chronic rhinosinusitis. While the therapeutic strategy aims to minimize the inflammatory damage and dysfunction to nasal air conduction, new evidences raise concerns if such drugs may impair neuronal regeneration in the OE. In consequence, new directions are necessary in terms of drug development or prescription, in order to preserve olfactory function through lifelong repeated episodes of chronic inflammation in the upper respiratory tract. Here we discuss mechanisms involved in glucocorticoid deleterious effects to OE regeneration and possible therapeutic alternatives considering relevant side-effects.

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    Regeneration of neurotransmission transcriptome in a model of epileptic encephalopathy after antiinflammatory treatment
    Dumitru A. Iacobaş, Libor Velíšek
    2018, 13 (10):  1715-1718.  doi: 10.4103/1673-5374.238607
    Abstract ( 104 )   PDF (1600KB) ( 176 )   Save

    Inflammation is an established etiopathogenesis factor of infantile spasms (IS), a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in rat hypothalamic arcuate nucleus, how they are corrected by antiinflamatory treatments and whether there are sex differences. IS was triggered by repeated intraperitoneal administration of N-methyl-D-aspartic acid (NMDA) following anti-inflammatory treatment (adreno-cortico-tropic-hormone (ACTH) or PMX53) or normal saline vehicle to prenatally exposed to betamethasone young rats. We found that treatments with both ACTH and PMX53 resulted in substantial recovery of the genomic fabrics of all types of synaptic transmission altered by IS. While ACTH represents the first line of treatment for IS, the even higher efficiency of PMX53 (an antagonist of the complement C5a receptor) in restoring the normal transcriptome was not expected. In addition to the childhood epilepsy, the recovery of the neurotransmission genomic fabrics by PMX53 also gives hope for the autism spectrum disorders that share a high comorbidity with IS. Our results revealed significant sex dichotomy in both IS-associated transcriptomic alterations (males more affected) and in the efficiency of PMX53 anti-inflammatory treatment (better for males). Our data further suggest that anti-inflammatory treatments correcting alterations in the inflammatory transcriptome may become successful therapies for refractory epilepsies.

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    Distinguishing normal brain aging from the development of Alzheimer’s disease: inflammation, insulin signaling and cognition
    Paul Denver, Paula L. McClean
    2018, 13 (10):  1719-1730.  doi: 10.4103/1673-5374.238608
    Abstract ( 129 )   PDF (267KB) ( 186 )   Save

    As populations age, prevalence of Alzheimer’s disease (AD) is rising. Over 100 years of research has provided valuable insights into the pathophysiology of the disease, for which age is the principal risk factor. However, in recent years, a multitude of clinical trial failures has led to pharmaceutical corporations becoming more and more unwilling to support drug development in AD. It is possible that dependence on the amyloid cascade hypothesis as a guide for preclinical research and drug discovery is part of the problem. Accumulating evidence suggests that amyloid plaques and tau tangles are evident in non-demented individuals and that reducing or clearing these lesions does not always result in clinical improvement. Normal aging is associated with pathologies and cognitive decline that are similar to those observed in AD, making differentiation of AD-related cognitive decline and neuropathology challenging. In this mini-review, we discuss the difficulties with discerning normal, age-related cognitive decline with that related to AD. We also discuss some neuropathological features of AD and aging, including amyloid and tau pathology, synapse loss, inflammation and insulin signaling in the brain, with a view to highlighting cognitive or neuropathological markers that distinguish AD from normal aging. It is hoped that this review will help to bolster future preclinical research and support the development of clinical tools and therapeutics for AD.

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    By using either endogenous or transplanted stem cells, which could you prefer for neural regeneration?
    Satoru Matsuda, Yukie Nakagawa, Kumi Amano, Yuka Ikeda, Ai Tsuji, Yasuko Kitagishi
    2018, 13 (10):  1731-1732.  doi: 10.4103/1673-5374.238609
    Abstract ( 146 )   PDF (187KB) ( 155 )   Save

    Neural regeneration by stem cells transplantation: Tissue regeneration and homeostasis are principally dependent on tissue stem cells which possess abilities of self-renewal and differentiation into multidirectional specialized cell types. In general,stem cells are critical for normal tissue renewal as well as repair after tissue injury. For example, mesenchymal stromal cells and endothelial progenitor cells identified in bone marrow could express several markers of pluripotent stem cells including Nanog and Oct-4. Such cells are also found in peripheral blood as well as in umbilical cord blood which might contribute to neural tissue-repair. Consequently, stems cells could constitute an asset for neural regeneration. Many studies have engaged different techniques for employing the neural stem cells into specific lineages such as neurons and glial cells, which may promote specific functional recovery through neurogenesis. In addition, preceding studies have revealed the recovery following transplantation of pluripotent stem cells in spinal cord injury models demonstrated the therapeutic potential of this approach, meaning that pluripotent stem cell-derived neural stem cells promote the functional recovery of motor neuron following stem cells transplantation into the damaged neural tissues. Amazingly, the motor function in a non-human primate animal model has been restored by transplanting human stem cells. The functional improvement seems to be associated with the grafted neuronal stem cells. Synaptogenesis between graft-derived neurons and host-derived neurons may be possible contributing to the functional recovery. In addition,re-myelination of the de-myelinated axons is a key mechanism in the regeneration of the injured spinal cord neurons. So, neural stem cells need to primarily differentiate both into neurons and into oligodendrocytes. Axonal growth supported by astrocytes derived from transplanted stem cells may be another foundation for the observed recovery. A previous study had indicated that transplanted stem cells-derived astrocytes in an injured spinal cord promote the outgrowth of serotonergic axon fibers. Oligodendrocytes derived from transplanted stem cells may also play an essential role in promoting the neural recovery by re-myelination of axons.

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    Glial cell line-derived neurotrophic factor as a treatment after spinal cord injury
    Stephen D. Ortmann, Daniel J. Hellenbrand
    2018, 13 (10):  1733-1734.  doi: 10.4103/1673-5374.238610
    Abstract ( 118 )   PDF (173KB) ( 160 )   Save

    Spinal cord injury (SCI) is a devastating trauma that currently affects 54 people out of every million, which is approximately 270,000 people in the United States (National Spinal Cord Injury Statistical Center, 2013). The effects of such an injury can cause a loss of both motor and sensory function below the injury site, normally leaving the patient unable to care for themselves entirely and relying on family and friends to provide personal care. Currently there are no definitive cures to a SCI; however, several potential treatments are currently being researched. One potential treatment would be the use of glial cell line-derived neurotrophic factor (GDNF), a growth factor that affects both neurons and astrocytes, which are support cells that protect neurons and maintain homeostasis. This has been shown to decrease lesion size, reduce allodynia, and regenerate axons in the central nervous system (CNS) and peripheral nervous system (PNS).

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    Developmental dependence for functional eye regrowth in Xenopus laevis
    Cindy X. Kha, Kelly Ai-Sun Tseng
    2018, 13 (10):  1735-1737.  doi: 10.4103/1673-5374.238611
    Abstract ( 132 )   PDF (408KB) ( 144 )   Save

    Introduction: A key challenge in designing tissue repair strategies is knowing whether and how developmental mechanisms are used for successful repair of mature/adult tissues.Although it is known that developmental components are used in repair, it remains mostly unclear which ones are required and whether they act similarly as during development.This issue is further complicated by the fact that it is difficult to assess the similarities and differences between development and the repair of mature tissues, since the two contexts are highly dissimilar. A potentially useful yet underutilized approach is to understand developmental regrowth (defined here as the ability to compensate for missing tissues by restoring normal organ structures and function). An ideal model would have two key features: repair capacity in the organ of interest during development, and well-understood developmental mechanisms. This approach reduces the complexity of comparing mature repair processes to developmental ones.The African clawed frog, Xenopus laevis, has a high capacity to restore lost body structures, including the eye, It can regenerate the retina and lens after injury,and Xenopus eye development is well characterized with known mechanisms.

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    Exploring the use of transcranial photobiomodulation in Parkinson’s disease patients
    Catherine Hamilton, David Hamilton, Frank Nicklason, Nabil El Massri, John Mitrofanis
    2018, 13 (10):  1738-1740.  doi: 10.4103/1673-5374.238613
    Abstract ( 132 )   PDF (363KB) ( 238 )   Save

    Parkinson’s disease is a neurological disorder with distinct motor signs of resting tremor, akinesia and/or lead-pipe rigidity, together with non-motor symptoms of impaired smell, cognition and autonomic function. These manifest after a major degeneration of neurones mainly within the brainstem, particularly among the dopaminergic neurones in the substantia nigra pars compacta, together with their terminations in the striatum. A number of recent studies have shown that photobiomodulation, the use of red to infrared light (λ = 600–1070 nm) on body tissues, has beneficial effects in many animal models of Parkinson’s disease, from flies to monkeys.These benefits include, a restoration of the abnormal neuronal activity in the basal ganglia, an improvement in locomotive behaviour and reduction in clinical signs, as well as an increase in the survival patterns of neurones damaged by either the parkinsonian toxin or the genetic mutation of the model used. This latter neuroprotective disease-modifying effect is particularly relevant because it is the key process in Parkinson’s disease and is currently not addressed by drug and surgical therapies. In this perspective, we will explore several issues associated with the use of photobiomodulation in patients. First,we will consider the early evidence indicating that this therapy is effective in improving the signs and symptoms of the disease, as well as the mechanisms that may underpin these improvements. Second, we discuss how these preliminary reports (and experimental findings) can be developed into a viable treatment option for patients, together with some of the potential issues and/or problems associated with this process.

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    Neuroprotection of the inner retina: Müller cells and lactate
    Rupali Vohra, Miriam Kolko
    2018, 13 (10):  1741-1742.  doi: 10.4103/1673-5374.238612
    Abstract ( 139 )   PDF (221KB) ( 155 )   Save

    Müller cells: The neglected neighbor: Müller cells constitute the majority of retinal glial cells and offer more alternating functions than any other cell of the retina. Uniquely, Müller cells cover the complete thickness of the retina, and their roles therefore differ correspondingly to the retinal segment in which they are located. In the inner retina, Müller cells are crucial in taking up toxic molecules, such as excessive glutamate from the synapses between bipolar cells and retinal ganglion cells (RGCs), thereby preventing glutamate-induced excitoxic RGC death. Additionally, Müller cells are crucial in maintaining ion balances and have also been suggested to secrete essential neuroprotective factors as well as to buffer energy sources to the neighboring cells. Despite being over looked for decades Müller cells have now been proven essential in overall retinal maintenance, and increasing attention and acknowledgement has been attributed to their mere presence and function.

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    Release of interleukin-10 and neurotrophic factors in the choroid plexus: possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia
    Yolanda Cruz, Edna E. García, Jessica V. Gálvez, Stella V. Arias-Santiago, Horacio G. Carvajal, Raúl Silva-García, Herlinda Bonilla-Jaime, Julio Rojas-Castañeda, Antonio Ibarra
    2018, 13 (10):  1743-1752.  doi: 10.4103/1673-5374.238615
    Abstract ( 110 )   PDF (832KB) ( 205 )   Save

    Copolymer-1 (Cop-1) is a peptide with immunomodulatory properties, approved by the Food and Drug Administration of United States in the treatment of multiple sclerosis. Cop-1 has been shown to exert neuroprotective effects and induce neurogenesis in cerebral ischemia models. Nevertheless, the mechanism involved in the neurogenic action of this compound remains unknown. The choroid plexus (CP) is a network of cells that constitute the interphase between the immune and central nervous systems, with the ability to mediate neurogenesis through the release of cytokines and growth factors. Therefore, the CP could play a role in Cop-1-induced neurogenesis. In order to determine the participation of the CP in the induction of neurogenesis after Cop-1 immunization, we evaluated the gene expression of various growth factors (brain-derived neurotrophic factor, insulin-like growth factor 1, neurotrophin-3) and cytokines (tumor necrosis factor alpha, interferon-gamma, interleukin-4 (IL-4), IL-10 and IL-17), in the CP at 14 days after ischemia. Furthermore, we analyzed the correlation between the expression of these genes and neurogenesis. Our results showed that Cop-1 was capable of stimulating an upregulation in the expression of the genes encoding for brain-derived neurotrophic factor, insulin-like growth factor 1, neurotrophin-3 and IL-10 in the CP, which correlated with an increase in neurogenesis in the subventricular and subgranular zone. As well, we observed a downregulation of IL-17 gene expression. This study demonstrates the effect of Cop-1 on the expression of growth factors and IL-10 in the CP, in the same way, presents a possible mechanism involved in the neurogenic effect of Cop-1.

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    Cognitive impairment after traumatic brain injury is associated with reduced long-term depression of excitatory postsynaptic potential in the rat hippocampal dentate gyrus
    Bao-Liang Zhang, Yue-Shan Fan, Ji-Wei Wang, Zi-Wei Zhou, Yin-Gang Wu, Meng-Chen Yang, Dong-Dong Sun, Jian-Ning Zhang
    2018, 13 (10):  1753-1758.  doi: 10.4103/1673-5374.238618
    Abstract ( 139 )   PDF (567KB) ( 176 )   Save

    Traumatic brain injury can cause loss of neuronal tissue, remote symptomatic epilepsy, and cognitive deficits. However, the mechanisms underlying the effects of traumatic brain injury are not yet clear. Hippocampal excitability is strongly correlated with cognitive dysfunction and remote symptomatic epilepsy. In this study, we examined the relationship between traumatic brain injury-induced neuronal loss and subsequent hippocampal regional excitability. We used hydraulic percussion to generate a rat model of traumatic brain injury. At 7 days after injury, the mean modified neurological severity score was 9.5, suggesting that the neurological function of the rats was remarkably impaired. Electrophysiology and immunocytochemical staining revealed increases in the slope of excitatory postsynaptic potentials and long-term depression (indicating weakened long-term inhibition), and the numbers of cholecystokinin and parvalbumin immunoreactive cells were clearly reduced in the rat hippocampal dentate gyrus. These results indicate that interneuronal loss and changes in excitability occurred in the hippocampal dentate gyrus. Thus, traumatic brain injury-induced loss of interneurons appears to be associated with reduced long-term depression in the hippocampal dentate gyrus.

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    Combination of mild therapeutic hypothermia and adipose-derived stem cells for ischemic brain injury
    Kai Zhao, Rui Li, Sheng Bi, Yu Li, Long Liu, Yu-Long Jia, Peng Han, Chang-Cong Gu, Xi-Ze Guo, Wan-Ping Zhang, Chun Wang, Chun-Ying Pei, Lin-Lu Tian, Li-Xian Li
    2018, 13 (10):  1759-1770.  doi: 10.4103/1673-5374.238617
    Abstract ( 105 )   PDF (4891KB) ( 192 )   Save

    Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells,exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia (33°C) was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining.Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining.The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the mRNA expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.

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    Motor imagery training induces changes in brain neural networks in stroke patients
    Fang Li, Tong Zhang, Bing-Jie Li, Wei Zhang, Jun Zhao, Lu-Ping Song
    2018, 13 (10):  1771-1781.  doi: 10.4103/1673-5374.238616
    Abstract ( 125 )   PDF (465KB) ( 209 )   Save

    Motor imagery is the mental representation of an action without overt movement or muscle activation. However, the effects of motor imagery on stroke-induced hand dysfunction and brain neural networks are still unknown. We conducted a randomized controlled trial in the China Rehabilitation Research Center. Twenty stroke patients, including 13 males and 7 females, 32–51 years old, were recruited and randomly assigned to the traditional rehabilitation treatment group (PP group, n = 10) or the motor imagery training combined with traditional rehabilitation treatment group (MP group, n = 10). All patients received rehabilitation training once a day, 45 minutes per session, five times per week, for 4 consecutive weeks. In the MP group, motor imagery training was performed for 45 minutes after traditional rehabilitation training, daily. Action Research Arm Test and the Fugl-Meyer Assessment of the upper extremity were used to evaluate hand functions before and after treatment. Transcranial magnetic stimulation was used to analyze motor evoked potentials in the affected extremity. Diffusion tensor imaging was used to assess changes in brain neural networks. Compared with the PP group, the MP group showed better recovery of hand function, higher amplitude of the motor evoked potential in the abductor pollicis brevis, greater fractional anisotropy of the right dorsal pathway, and an increase in the fractional anisotropy of the bilateral dorsal pathway. Our findings indicate that 4 weeks of motor imagery training combined with traditional rehabilitation treatment improves hand function in stroke patients by enhancing the dorsal pathway. This trial has been registered with the Chinese Clinical Trial Registry (registration number:ChiCTR-OCH-12002238).

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    Relationship of calcitonin gene-related peptide with disease progression and prognosis of patients with severe traumatic brain injury
    Li-Xiong Chen, Wei-Feng Zhang, Ming Wang, Pi-Feng Jia
    2018, 13 (10):  1782-1786.  doi: 10.4103/1673-5374.238619
    Abstract ( 134 )   PDF (566KB) ( 183 )   Save

    Calcitonin gene-related peptide (CGRP) has been implicated in multiple functions across many bioprocesses; however, whether CGRP is associated with severe traumatic brain injury (TBI) remains poorly understood. In this study, 96 adult patients with TBI (enrolled from September 2015 to December 2016) were divided into a mild/moderate TBI group (36 males and 25 females, aged 38 ± 13 years) and severe TBI group (22 males and 13 females, aged 38 ± 11 years) according to Glasgow Coma Scale scores. In addition, 25 healthy individuals were selected as controls (15 males and 10 females, aged 39 ± 13 years). Radioimmunoassay was used to detect serum levels of CGRP and endothelin-1 at admission and at 12, 24, 48, 72 hours, and 7 days after admission. CGRP levels were remarkably lower, but endothelin-1 levels were obviously higher in the severe TBI group compared with mild/moderate TBI and control groups. Levels of CGRP were remarkably lower, but endothelin-1 levels were obviously higher in deceased patients compared with patients who survived. Survival analysis and logistic regression showed that both CGRP and endothelin-1 levels were associated with patient mortality, with each serving as an independent risk factor for 6-month mortality of severe TBI patients. Moreover, TBI patients with lower serum CGRP levels had a higher risk of death. Thus, our retrospective analysis demonstrates the potential utility of CGRP as a new biomarker, monitoring method, and therapeutic target for TBI.

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    Semi-automated segmentation of magnetic resonance images for thigh skeletal muscle and fat using threshold technique after spinal cord injury
    Mina P. Ghatas, Robert M. Lester, M. Rehan Khan, Ashraf S. Gorgey
    2018, 13 (10):  1787-1795.  doi: 10.4103/1673-5374.238623
    Abstract ( 128 )   PDF (1290KB) ( 252 )   Save

    Magnetic resonance imaging is considered the “gold standard” technique for quantifying thigh muscle and fat cross-sectional area. We have developed a semi-automated technique to segment seven thigh compartments in persons with spinal cord injury. Thigh magnetic resonance images from 18 men (18–50 years old) with traumatic motor-complete spinal cord injury were analyzed in a blinded fashion using the threshold technique. The cross-sectional area values acquired by thresholding were compared to the manual tracing technique. The percentage errors for thigh circumference were (threshold: 170.71 ± 38.67; manual: 169.45 ± 38.27 cm2) 0.74%, subcutaneous adipose tissue (threshold: 65.99±30.79; manual: 62.68 ± 30.22) 5.2%, whole muscle (threshold: 98.18 ± 20.19; manual: 98.20 ± 20.08 cm2) 0.13%, femoral bone (threshold: 6.53 ± 1.09;manual: 6.53 ± 1.09 cm2) 0.64%, bone marrow fat (threshold: 3.12 ± 1.12; manual: 3.1 ± 1.11 cm2) 0.36%,knee extensor (threshold: 43.98 ± 7.66; manual: 44.61 ± 7.81 cm2) 1.78% and % intramuscular fat (threshold: 10.45 ± 4.29; manual: 10.92 ± 8.35%) 0.47%. Collectively, these results suggest that the threshold technique provided a robust accuracy in measuring the seven main thigh compartments, while greatly reducing the analysis time.

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    Decellularized sciatic nerve matrix as a biodegradable conduit for peripheral nerve regeneration
    Jongbae Choi, Jun Ho Kim, Ji Wook Jang, Hyun Jung Kim, Sung Hoon Choi, Sung Won Kwon
    2018, 13 (10):  1796-1803.  doi: 10.4103/1673-5374.237126
    Abstract ( 120 )   PDF (1988KB) ( 184 )   Save

    The use of autologous nerve grafts remains the gold standard for treating nerve defects, but current nerve repair techniques are limited by donor tissue availability and morbidity associated with tissue loss. Recently, the use of conduits in nerve injury repair, made possible by tissue engineering, has shown therapeutic potential. We manufactured a biodegradable, collagen-based nerve conduit containing decellularized sciatic nerve matrix and compared this with a silicone conduit for peripheral nerve regeneration using a rat model. The collagen-based conduit contains nerve growth factor, brain-derived neurotrophic factor, and laminin, as demonstrated by enzyme-linked immunosorbent assay. Scanning electron microscopy images showed that the collagen-based conduit had an outer wall to prevent scar tissue infiltration and a porous inner structure to allow axonal growth. Rats that were implanted with the collagen-based conduit to bridge a sciatic nerve defect experienced significantly improved motor and sensory nerve functions and greatly enhanced nerve regeneration compared with rats in the sham control group and the silicone conduit group. Our results suggest that the biodegradable collagen-based nerve conduit is more effective for peripheral nerve regeneration than the silicone conduit.

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    Transcriptome analysis of adherens junction pathway-related genes after peripheral nerve injury
    Sheng Yi, Xing-Hui Wang, Ling-Yan Xing
    2018, 13 (10):  1804-1810.  doi: 10.4103/1673-5374.237127
    Abstract ( 103 )   PDF (1576KB) ( 185 )   Save

    The neural regeneration process is driven by a wide range of molecules and pathways. Adherens junctions are critical cellular junctions for the integrity of peripheral nerves. However, few studies have systematically characterized the transcript changes in the adherens junction pathway following injury. In this study, a rat model of sciatic nerve crush injury was established by forceps. Deep sequencing data were analyzed using comprehensive transcriptome analysis at 0, 1, 4, 7, and 14 days after injury. Results showed that most individual molecules in the adherens junctions were either upregulated or downregulated after nerve injury. The mRNA expression of ARPC1B, ARPC3, TUBA8, TUBA1C, CTNNA2, ACTN3, MET, HGF, NME1 and ARF6, which are involved in the adherens junction pathway and in remodeling of adherens junctions, was analyzed using quantitative real-time polymerase chain reaction. Most of these genes were upregulated in the sciatic nerve stump following peripheral nerve injury, except for CTNNA2, which was downregulated. Our findings reveal the dynamic changes of key molecules in adherens junctions and in remodeling of adherens junctions. These key genes provide a reference for the selection of clinical therapeutic targets for peripheral nerve injury.

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    Comparison of morphological and functional outcomes of mouse sciatic nerve repair with three biodegradable polymer conduits containing poly(lactic acid)
    Fernanda Marques Pestana, Rui C.C. Domingues, Júlia Teixeira Oliveira, Daniela F. P. A. Durço2, 3, Camila Oliveira Goulart, Henrique Rocha Mendonça, Anne Caroline Rodrigues dos Santos, Natália Tavares de Campos, Beatriz Theodoro da Silva, Cristina Cardoso Pereira, Cristiano Piacsek Borges, Ana Maria Blanco Martinez
    2018, 13 (10):  1811-1819.  doi: 10.4103/1673-5374.238712
    Abstract ( 154 )   PDF (4276KB) ( 485 )   Save

    Poly(lactic acid) (PLA)-containing nerve guidance conduits (NGCs) are currently being investigated for nerve repair as an alternative to autograft, which leads to permanent functional impairment in the territory innervated by the removed nerve. Combination of polymers modifies the physical properties of the conduits, altering their nerve-guidance properties. Conduits made from PLA-only or combined with other polymers have been used successfully for nerve repair, but their efficiency has not been compared. We compared the morphological and functional outcomes of peripheral nerve repair by using NGCs made of poly(lactic acid) and combined or not with polycaprolactone (PLA/PCL) or polyvinylpyrrolidone (PLA/PVP). To assess the functional recovery, we employed a mechanical hyperalgesia analysis, sciatic functional index (SFI), and electroneuromyography. The mechanical hyperalgesia analysis showed that the PLA group improved more rapidly than the PLA/PVP and PLA/PCL groups; similarly, in the electroneuromyography assay, the PLA group exhibited higher amplitude than the PLA/PCL and PLA/PVP groups. However, the SFI improvement rates did not differ among the groups. Morphologically, the PLA group showed more vascularization, while the nerve fiber regeneration did not differ among the groups. In conclusion, the PLA-only conduits were superior to the other NGCs tested for nerve repair.

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    Combined VEGF/PDGF improves olfactory regeneration after unilateral bulbectomy in mice
    Kate Beecher, Louise M. Hafner, Jenny Ekberg, James A. St. John, Fatemeh Chehrehasa
    2018, 13 (10):  1820-1826.  doi: 10.4103/1673-5374.238713
    Abstract ( 114 )   PDF (7538KB) ( 134 )   Save

    The olfactory receptor neurons lining the nasal cavity have a remarkable capacity to regenerate throughout life. They are replenished continuously and their axons make new connections within the olfactory bulb.However, some factors such as head trauma and skull base surgery damage the olfactory nerve which lead to olfactory dysfunction. Losing the sense of smell has considerable effects on quality of life and life-expectancy.Therefore, there is a clear need to find a treatment for olfactory dysfunction. One such potential treatment is growth factor therapy which showed promising results in the spinal cord and brain injuries. The aim of the present study was to investigate whether combined delivery of two growth factors, vascular endothelial growth factor and platelet-derived growth factor treatment can improve the olfactory neurons regeneration in mice. The degeneration of the olfactory neurons was induced by unilateral bulbectomy. The treatment group received 1.5 μg of the combined growth factors intranasally, while the control injured group received saline. Growth factor treatment significantly increased the number of immature neurons at 5 and 7 days post injury and also the number of mature olfactory neurons at 10 and 14 days post bulbectomy.Regenerating axons extended over a larger volume in the operated cavity in the treatment group compared to control group at 14 days post bulbectomy. The growth factor treatment also significantly reduced astrocytic glia scar in the operated cavity. The results indicate that the combined delivery of the growth factors has the potential to improve olfactory dysfunction.

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    Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia
    Somayeh Kouhestani, Adele Jafari, Parvin Babaei
    2018, 13 (10):  1827-1832.  doi: 10.4103/1673-5374.238714
    Abstract ( 104 )   PDF (1135KB) ( 224 )   Save

    Alzheimer’s disease (AD) is associated with oxidative stress, and ultimately results in cognitive deficit. Despite existing literature on the pathophysiology of AD, there is currently no cure for AD. The present study investigated the effects of kaempferol (Kmp) isolated from the extract of Mespilus germanica L. (medlar) leaves on cognitive impairment, hippocampal antioxidants, apoptosis, lipid peroxidation and neuro-inflammation markers in ovariectomized (OVX) rat models of sporadic AD. Kaempferol, as the main flavonoid of medlar extract has been previously known for anti-oxidative, anti-inflammatory and anti-neurotoxic effects. Thirty-two female Wistar rats were ovariectomized, and randomly divided into four groups: sham, OVX + saline, OVX + streptozotocin (STZ) + saline, OVX + STZ + Kmp. Animals received intracerebroventricular injection of STZ (3 mg/kg, twice with one day interval) to establish models of sporadic AD. Intraperitoneal injection of Kmp (10 mg/kg) for 21 days was performed in the OVX + STZ + Kmp group. Spatial learning and memory of rats were evaluated using a Morris water maze. Finally, brain homogenates were used for biochemical analysis by enzyme-linked immunosorbent assay. The results showed a significant improvement in spatial learning and memory as evidenced by shortened escape latency and searching distance in Morris water maze in the OVX + STZ + Kmp group compared with the OVX + STZ group. Kmp also exhibited significant elevations in brain levels of antioxidant enzymes of superoxide dismutase and glutathione,while reduction in tumor necrosis factor-α and malondialdehyde. Our results demonstrate that Kmp is capable of alleviating STZ-induced memory impairment in OVX rats, probably by elevating endogenous hippocampal antioxidants of superoxide dismutase and glutathione, and reducing neuroinflammation. This study suggests that Kmp may be a potential neuroprotective agent against cognitive deficit in AD.

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    High-frequency (50 Hz) electroacupuncture ameliorates cognitive impairment in rats with amyloid beta 1–42-induced Alzheimer’s disease
    Chao-Chao Yu, Ying Wang, Feng Shen, Li-Hong Kong, Ya-Wen Wang, Hua Zhou, Lei Tang
    2018, 13 (10):  1833-1841.  doi: 10.4103/1673-5374.238620
    Abstract ( 96 )   PDF (1742KB) ( 188 )   Save

    Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease. Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture. Rat models of Alzheimer’s disease were established by injecting amyloid beta 1–42 (Aβ1–42) into the bilateral lateral ventricles. Electroacupuncture at 2, 30, and 50 Hz was carried out at Baihui (GV20; 15° obliquely to a depth of 2 mm) and Shenshu (BL23; perpendicularly to 4–6 mm depth), once a day for 20 minutes (each), for 15 days, taking a break every 7 days. The Morris water maze test was conducted to assess the learning and memory. The expression levels of glycogen synthase kinase-3β (GSK-3β), pSer9-GSK-3β, pTyr216-GSK-3β, amyloid precursor protein and Aβ1–40 in the hippocampus were determined by western blot assay. Results demonstrated that electroacupuncture treatment at different frequencies markedly improved learning and memory ability,increased synaptic curvatures, decreased the width of synaptic clefts, thickened postsynaptic densities, and downregulated the expression of GSK-3β, amyloid precursor protein, and Aβ1–40. pSer9-GSK-3β expression markedly decreased, while pTyr216-GSK-3β expression increased. High-frequency (50 Hz) electroacupuncture was more effective than low (2 Hz) or medium-frequency (30 Hz) electroacupuncture. In conclusion, electroacupuncture treatment exerts a protective effect against Aβ1–42-induced learning and memory deficits and synapse-ultrastructure impairment via inhibition of GSK-3β activity. Moreover, high-frequency electroacupuncture was the most effective therapy.

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    Mitogen-activated protein kinase phosphatase 1 protects PC12 cells from amyloid beta-induced neurotoxicity
    Yue Gu, Lian-Jun Ma, Xiao-Xue Bai, Jing Jie, Xiu-Fang Zhang, Dong Chen, Xiao-Ping Li
    2018, 13 (10):  1842-1850.  doi: 10.4103/1673-5374.238621
    Abstract ( 106 )   PDF (854KB) ( 171 )   Save

    The mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation,transformation and death. Mitogen-activated protein kinase phosphatase 1 (MKP1) has an inhibitory effect on the p38MAPK and JNK pathways, but it is unknown whether it plays a role in Aβ-induced oxidative stress and neuronal inflammation. In this study, PC12 cells were infected with MKP1 shRNA, MKP1 lentivirus or control lentivirus for 12 hours, and then treated with 0.1, 1, 10 or 100 μM amyloid beta 42 (Aβ42). The cell survival rate was measured using the cell counting kit-8 assay. MKP1, tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) mRNA expression levels were analyzed using quantitative real time-polymerase chain reaction. MKP1 and phospho-c-Jun N-terminal kinase (JNK) expression levels were assessed using western blot assay. Reactive oxygen species (ROS) levels were detected using 2′,7′-dichlorofluorescein diacetate. Mitochondrial membrane potential was measured using flow cytometry. Superoxide dismutase activity and malondialdehyde levels were evaluated using the colorimetric method. Lactate dehydrogenase activity was measured using a microplate reader. Caspase-3 expression levels were assessed by enzyme-linked immunosorbent assay. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. MKP1 overexpression inhibited Aβ-induced JNK phosphorylation and the increase in ROS levels. It also suppressed the Aβ-induced increase in TNF-α and IL-1β levels as well as apoptosis in PC12 cells. In contrast, MKP1 knockdown by RNA interference aggravated Aβ-induced oxidative stress, inflammation and cell damage in PC12 cells. Furthermore, the JNK-specific inhibitor SP600125 abolished this effect of MKP1 knockdown on Aβ-induced neurotoxicity. Collectively, these results show that MKP1 mitigates Aβ-induced apoptosis, oxidative stress and neuroinflammation by inhibiting the JNK signaling pathway, thereby playing a neuroprotective role.

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    Validity and reliability of the Ocular Motor Nerve Palsy Scale
    Ling-Yun Zhou, Chang Su, Tie-Juan Liu, Xue-Mei Li
    2018, 13 (10):  1851-1856.  doi: 10.4103/1673-5374.238716
    Abstract ( 170 )   PDF (1223KB) ( 233 )   Save

    Objective and accurate assessment of the degree of ocular motor nerve palsy is helpful not only in the evaluation of prognosis, but also for the screening of treatment methods. However, there is currently no comprehensive measure of its severity. In this study, we designed the Ocular Motor Nerve Palsy Scale and investigated its validity and reliability. Six experts were invited to grade and evaluate the scale. The study recruited 106 patients with a definite diagnosis of unilateral isolated ocular motor nerve palsy. Three physicians evaluated the patients using the scale. One of the three physicians evaluated the patients again after 24 hours. The content validity index (CVI) and factor analysis were used to analyze the scale’s construct validity. The intraclass correlation coefficient and Cronbach’s alpha were used to evaluate the inter-rater and test-retest reliability and the internal consistency. The CVI results (I-CVI = 1.0, S-CVI = 0.9, Pc = 0.016, K* = 1) indicated good content validity. Factor analysis extracted two common factors that accounted for 85.2% of the variance. Furthermore, the load value of each component was above 0.8, indicating good construct validity. The Ocular Motor Nerve Palsy Scale was found to be highly reliable, with an inter-rater reliability intraclass correlation coefficient of 0.965 (P < 0.01), a test-retest reliability intraclass correlation coefficient of 0.976 (P < 0.01), and Cronbach’s alpha values of 0.63–0.70. In conclusion, the Ocular Motor Nerve Palsy Scale with good validity and reliability can be used to quantify the severity of ocular motor nerve palsy. This study was registered at Chinese Clinical Trial Registry (registration number: ChiCTR-OOC-17010702).

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