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    15 September 2017, Volume 12 Issue 9 Previous Issue    Next Issue
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    Neuroprotective effects of erythropoietin on neurodegenerative and ischemic brain diseases: the role of erythropoietin receptor
    Carolina Castillo Hernández, Carlos Felipe Burgos, Angela Hidalgo Gajardo, Tiare Silva-Grecchi, Javiera Gavilan,Jorge Roberto Toledo, Jorge Fuentealba
    2017, 12 (9):  1381-1389.  doi: 10.4103/1673-5374.215240
    Abstract ( 158 )   PDF (780KB) ( 542 )   Save

    Erythropoietin (Epo) is a fundamental hormone in the egulation of hematopoiesis, and other secondary roles mediated by the binding of the hormone to its specific receptor (EpoR), which leads to an activation of key signaling pathways that induce an increase in cell differentiation, apoptosis control and neuroprotection.It has been suggested that their function depends on final conformation of glycosylations, related with affinity to the receptor and its half-life. The presence of EpoR has been reported in different tissues including central nervous system, where it has been demonstrated to exert a neuroprotective function against oxidative stress onditions, such as ischemic injury and neurodegenerative diseases. There is also evidence of an increase in EpoR expression in brain cell lysates of Alzheimer’s patients with respect to healthy patients. These results are related with extensive in vitro experimental data of neuroprotection obtained from cell lines, primary cell cultures and hippocampal slices. Additionally, this data is correlated with in vivo experiments (water maze test) in mouse models of Alzheimer’s disease where Epo treatment improved cognitive function. These studies support the idea that receptor activation induces a neuroprotective effect in neurodegenerative disorders including dementias, and especially Alzheimer’s disease. Taken together, available evidence suggests that Epo appears to be a central element for EpoR activation and neuroprotective properties in the central nervous system. In this review, we will describe the mechanisms associated with neuroprotection and its relation with the activation of EpoR in order with identify new targets to develop pharmacological strategies.

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    Autonomic dysreflexia: a cardiovascular disorder following spinal cord injury
    Shaoping Hou
    2017, 12 (9):  1390-1400.  doi: 10.4103/1673-5374.215241
    Abstract ( 249 )   PDF (647KB) ( 423 )   Save

     

    Autonomic dysreflexia (AD) is a serious cardiovascular disorder in patients with spinal cord injury (SCI). The primary underlying cause of AD is loss of supraspinal control over sympathetic preganglionic neurons (SPNs) caudal to the injury, which renders the SPNs hyper-responsive to stimulation. Central maladaptive plasticity, including C-fiber sprouting and propriospinal fiber proliferation exaggerates noxious afferent transmission to the SPNs, causing them to release massive sympathetic discharges that result in severe hypertensive episodes. In parallel, upregulated peripheral vascular sensitivity following SCI exacerbates the hypertensive response by augmenting gastric and pelvic vasoconstriction. Currently, the majority of clinically employed treatments for AD involve anti-hypertensive medications and Botox injections to the bladder. Although these approaches mitigate the severity of AD, they only yield transient effects and target the effector organs, rather than addressing the primary issue of central sympathetic dysregulation. As such, strategies that aim to restore supraspinal reinnervation of SPNs to improve cardiovascular sympathetic regulation are likely more effective for AD. Recent pre-clinical investigations show that cell transplantation therapy is efficacious in reestablishing spinal sympathetic connections and improving hemodynamic per­formance, which holds promise as a potential therapeutic approach.
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    Odorants could elicit repair processes in melanized neuronal and skin cells
    Barbara Pavan, Alessandro Dalpiaz
    2017, 12 (9):  1401-1404.  doi: 10.4103/1673-5374.215246
    Abstract ( 221 )   PDF (548KB) ( 288 )   Save

     

    The expression of ectopic olfactory receptors (ORs) in melanized cells, such as the human brain nigrostri­atal dopaminergic neurons and skin melanocytes, is here pointed out. ORs are recognized to regulate skin melanogenesis, whereas OR expression in the dopaminergic neurons, characterized by accumulation of pigment neuromelanin, is downregulated in Parkinson’s disease. Furthermore, the correlation between the pigmentation process and the dopamine pathway through α-synuclein expression is also highlighted. Purposely, these ORs are suggested as therapeutic target for neurodegenerative diseases related to the pig­mentation disorders. Based on this evidence, a possible way of turning odorants into drugs, acting on three specific olfactory receptors, OR51E2, OR2AT4 and VN1R1, is thus introduced. Various odorous molecules are shown to interact with these ORs and their therapeutic potential against melanogenic and neurodegen­erative dysfunctions, including melanoma and Parkinson’s disease, is suggested. Finally, a direct functional link between olfactory and endocrine systems in human brain through VN1R1 is proposed, helping to counteract female susceptibility to Parkinson’s disease in quiescent life.
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    Post electrical or lightning injury syndrome: a proposal for an American Psychiatric Association’s Diagnostic and Statistical Manual formulation with implications for treatment
    Christopher J. Andrews, Andrew D. Reisner, Mary Ann Cooper
    2017, 12 (9):  1405-1412.  doi: 10.4103/1673-5374.215242
    Abstract ( 127 )   PDF (288KB) ( 365 )   Save

    In the past, victims of electrical and lightning injuries have been assessed in a manner lacking a system­atic formulation, and against ad hoc criteria, particularly in the area of neuropsychological disability. In this manner patients have, for example, only been partially treated, been poorly or incorrectly diagnosed, and have been denied the full benefit of compensation for their injuries. This paper contains a proposal for diagnostic criteria particularly for the neuropsychological aspects of the post injury syndrome. It pays attention to widely published consistent descriptions of the syndrome, and a new cluster analysis of post electrical injury patients. It formulates a proposal which could be incorporated into future editions of the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM). The major neuropsycholog­ical consequences include neurocognitive dysfunction, and memory subgroup dysfunction, with ongoing consequences, and sometimes including progressive or delayed psychiatric, cognitive, and/or neurological symptoms. The proposed diagnostic criteria insist on a demonstrated context for the injury, both specifying the shock circumstance, and also physical consequences. It allows for a certain delay in onset of symptoms. It recognizes exclusory conditions. The outcome is a proposal for a DSM classification for the post electrical or lightning injury syndrome. This proposal is considered important for grounding patient treatment, and for further treatment trials. Options for treatment in electrical or lightning injury are summarised, and future trials are foreshadowed.

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    Tp53 gene mediates distinct dopaminergic neuronal damage in different dopaminergic neurotoxicant models
    Tao Lu, Paul Kim, Yu Luo
    2017, 12 (9):  1413-1417.  doi: 10.4103/1673-5374.215243
    Abstract ( 217 )   PDF (282KB) ( 318 )   Save

    Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson’s disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic (DA) neuronal cell death or neuronal terminal damage in different neurotoxicant models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by phar­macological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure. Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal termi­nal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible that Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive target pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons, assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuro­nal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neuronal damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.

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    Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases
    Laura Foucault-Fruchard, Daniel Antier
    2017, 12 (9):  1418-1421.  doi: 10.4103/1673-5374.215244
    Abstract ( 235 )   PDF (184KB) ( 458 )   Save
    Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases, are all character­ized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.
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    Promises and pitfalls of immune-based strategies for Huntington’s disease
    Gabriela Delevati Colpo, Erin Furr Stimming, Natalia Pessoa Rocha, Antonio Lucio Teixeira
    2017, 12 (9):  1422-1425.  doi: 10.4103/1673-5374.215245
    Abstract ( 217 )   PDF (213KB) ( 294 )   Save

    Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disease characterized by the selec­tive loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD. The objective of this review is to discuss the data obtained so far on the immune-based therapeutic strategies for HD.

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    How the brain can rewire itself after an injury: the lesson from hemispherectomy
    Luca Sebastianelli, Leopold Saltuari, Raffaele Nardone
    2017, 12 (9):  1426-1427.  doi: 10.4103/1673-5374.215247
    Abstract ( 152 )   PDF (147KB) ( 295 )   Save
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    SLP-2: a potential new target for improving mitochondrial func­tion in Parkinson’s disease
    Alessandra Zanon, Andrew A. Hicks, Peter P. Pramstaller, Irene Pichler
    2017, 12 (9):  1435-1436.  doi: 10.4103/1673-5374.215251
    Abstract ( 210 )   PDF (230KB) ( 360 )   Save
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    Glyco-sphingo biology: a novel perspective for potential new treatments in Huntington’s disease
    Alba Di Pardo, Vittorio Maglione
    2017, 12 (9):  1439-1440.  doi: 10.4103/1673-5374.215253
    Abstract ( 130 )   PDF (142KB) ( 264 )   Save
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    DNA damage and neurodegeneration: the unusual suspect
    Daniel Stein, Debra Toiber
    2017, 12 (9):  1441-1442.  doi: 10.4103/1673-5374.215254
    Abstract ( 230 )   PDF (136KB) ( 353 )   Save
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    Constraint-induced movement therapy in treatment of acute and sub-acute stroke: a meta-analysis of 16 randomized controlled trials
    Xi-hua Liu, Juan Huai, Jie Gao, Yang Zhang, Shou-wei Yue
    2017, 12 (9):  1443-1450.  doi: 10.4103/1673-5374.215255
    Abstract ( 166 )   PDF (917KB) ( 707 )   Save

    OBJECTIVE: The aim of this meta-analysis was to evaluate the clinical efficacy of constraint-induced movement therapy in acute and sub-acute stroke.
    DATA SOURCES: The key words were stroke, cerebrovascular accident, constraint-induced therapy, forced use, and randomized controlled trial. The databases, including China National Knowledge Infrastructure,WanFang, Weipu Information Resources System, Chinese Biomedical Literature Database, PubMed, Medline,Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, were searched for studies on randomized controlled trials for treating acute or sub-acute stroke published before March 2016.
    DATA SELECTION: We retrieved relevant randomized controlled trials that compared constraint-induced movement therapy in treatment of acute or sub-acute stroke with traditional rehabilitation therapy (traditional occupational therapy). Patients were older than 18 years, had disease courses less than 6 months, and were evaluated with at least one upper extremity function scale. Study quality was evaluated, and data that met the criteria were extracted. Stata 11.0 software was used for the meta-analysis.
    OUTCOME MEASURES: Fugl-Meyer motor assessment of the arm, the action research-arm test, a motor activity log for amount of use and quality of movement, the Wolf motor function test, and a modified Barthel index.
    RESULTS: A total of 16 prospective randomized controlled trials (379 patients in the constraint-induced movement-therapy group and 359 in the control group) met inclusion criteria. Analysis showed significant mean differences in favor of constraint-induced movement therapy for the Fugl–Meyer motor assessment of the arm (weighted mean difference (WMD) = 10.822; 95% confidence intervals (95% CI): 7.419–14.226),the action research-arm test (WMD = 10.718; 95% CI: 5.704–15.733), the motor activity log for amount of use and quality of movement (WMD = 0.812; 95% CI: 0.331–1.293) and the modified Barthel index (WMD = 10.706; 95% CI: 4.417–16.966).
    CONCLUSION: Constraint-induced movement therapy may be more beneficial than traditional rehabilitation therapy for improving upper limb function after acute or sub-acute stroke.

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    Therapeutic efficacy and safety of various botulinum toxin A doses and concentrations in spastic foot after stroke: a randomized controlled trial
    Jiang Li, Ru Zhang, Bo-li Cui, Yong-xiang Zhang, Guang-tao Bai, Si-shan Gao, Wen-jian Li
    2017, 12 (9):  1451-1457.  doi: 10.4103/1673-5374.215257
    Abstract ( 167 )   PDF (358KB) ( 384 )   Save

    No recommended guidelines currently exist for the therapeutic concentration or dose of botulinum toxin type A (BTXA) injected into the muscle to treat limb spasticity. Therefore, in this randomized controlled trial, we explored the safety and efficacy of two concentrations and two doses of BTXA in the treatment of spastic foot after stroke to optimize this treatment in these patients. Eligible patients (n = 104) were randomized into four groups. The triceps surae and tibialis posterior on the affected side were injected with BTXA at one of two doses (200 U or 400 U) and two concentrations (50 U/mL or 100 U/mL). The following assessments were conducted before as well as 4 days and 1, 2,4, and 12 weeks after treatment: spasticity, assessed using the modified Ashworth scale; basic functional mobility, assessed using a timed up and go test; pace, assessed using a 10-meter timed walking test; and the ability to walk, assessed using Holden’s graded scale and a visual analog scale. The reported results are based on the 89 patients that completed the study. We found significant differences for the two doses and concentrations of BTXA to improve the ability of patients to walk independently, with the high-dose/low-concentration combination providing the best effect. Onset and duration of the ameliorating effects of BTXA were 4–7 days and 12 weeks, respectively. Thus, BTXA effectively treated foot spasms after stroke at an optimal dose of 400 U and concentration of 50 U/mL.

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    Effect of hyperthermia on calbindin-D 28k immunoreactivity in the hippocampal formation following transient global cerebral ischemia in gerbils
    Jae-Chul Lee, Jeong-Hwi Cho, Tae-Kyeong Lee, In Hye Kim, Moo-Ho Won, Geum-Sil Cho, Bich-Na Shin, In Koo Hwang, Joon Ha Park, Ji Hyeon Ahn, Il Jun Kang, Young Joo Lee, Yang Hee Kim
    2017, 12 (9):  1458-1464.  doi: 10.4103/1673-5374.215256
    Abstract ( 173 )   PDF (977KB) ( 534 )   Save

    Calbindin D-28K (CB), a Ca2+-binding protein, maintains Ca2+ homeostasis and protects neurons against various insults. Hyperthermia can exacerbate brain damage produced by ischemic insults. However, little is reported about the role of CB in the brain under hyperthermic condition during ischemic insults. We investigated the effects of transient global cerebral ischemia on CB immunoreactivity as well as neuronal damage in the hippocampal formation under hyperthermic condition using immunohistochemistry for neuronal nuclei (NeuN) and CB, and Fluoro-Jade B histofluorescence staining in gerbils. Hyperthermia (39.5 ± 0.2°C) was induced for 30 minutes before and during transient ischemia. Hyperthermic ischemia resulted in neuronal damage/death in the pyramidal layer of CA1–3 area and in the polymorphic layer of the dentate gyrus at 1, 2, 5 days after ischemia. In addition, hyperthermic ischemia significantly decreaced CB immunoreactivity in damaged or dying neurons at 1, 2, 5 days after ischemia. In brief, hyperthermic condition produced more extensive and severer neuronal damage/death, and reduced CB immunoreactivity in the hippocampus following transient global cerebral ischemia. Present findings indicate that the degree of reduced CB immunoreactivity might be related with various neuronal damage/death overtime and corresponding areas after ischemic insults.

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    Corticoreticular tract lesion in children with developmental delay presenting with gait dysfunction and trunk instability
    Yong Min Kwon, Jessica Rose, Ae Ryoung Kim, Su Min Son
    2017, 12 (9):  1465-1471.  doi: 10.4103/1673-5374.215258
    Abstract ( 163 )   PDF (404KB) ( 744 )   Save

    The corticoreticular tract (CRT) is known to be involved in walking and postural control. Using diffusion tensor tractography (DTT), we investigated the relationship between the CRT and gait dysfunction, including trunk instability, in pediatric patients. Thirty patients with delayed development and 15 age-matched,typically-developed (TD) children were recruited. Fifteen patients with gait dysfunction (bilateral trunk instability) were included in the group A, and the other 15 patients with gait dysfunction (unilateral trunk instability) were included in the group B. The Growth Motor Function Classification System, Functional Ambulation Category scale, and Functional Ambulation Category scale were used for measurement of functional state. Fractional anisotropy, apparent diffusion coefficient, fiber number, and tract integrity of the CRT and corticospinal tract were measured. Diffusion parameters or integrity of corticospinal tract were not significantly different in the three study groups. However, CRT results revealed that both CRTs were disrupted in the group A, whereas CRT disruption in the hemispheres contralateral to clinical manifestations was observed in the group B. Fractional anisotropy values and fiber numbers in both CRTs were decreased in the group A than in the group TD. The extents of decreases of fractional anisotropy values and fiber numbers on the ipsilateral side relative to those on the contralateral side were greater in the group B than in the group TD. Functional evaluation data and clinical manifestations were found to show strong correlations with CRT status, rather than with corticospinal tract status. These findings suggest that CRT status appears to be clinically important for gait function and trunk stability in pediatric patients and DTT can help assess CRT status in pediatric patients with gait dysfunction.

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    Extracellular signal-regulated kinase, substance P and neurokinin-1 are involved in the analgesic mechanism of herb-partitioned moxibustion
    Zhi-yuan Li, Yan-ting Yang, Jue Hong, Dan Zhang, Xiao-fei Huang, Li-jie Wu, Huan-gan Wu, Zheng Shi, Jie Liu, Yi Zhu, Xiao-peng Ma
    2017, 12 (9):  1472-1478.  doi: 10.4103/1673-5374.215259
    Abstract ( 244 )   PDF (695KB) ( 771 )   Save

    Herb-partitioned moxibustion can effectively mitigate visceral pain, a major symptom in inflammatory bowel disease, but the analgesic mechanism is still unclear. Moreover, extracellular signal-regulated kinase, substance P, and neurokinin-1 are involved in formation of central hyperalgesia. Thus, we postulated that the analgesic effect of herb-partitioned moxibustion may be associated with these factors.Accordingly, in this study, we established an inflammatory bowel disease visceral pain model in rat by enema with a mixed solution of 5% trinitrobenzenesulfonic acid and 50% ethanol. Bilateral Tianshu (ST25) and Qihai (CV6) points were selected for herb-partitioned moxibustion.Our results showed that herb-partitioned moxibustion improved visceral pain and down-regulated extracellular signal-regulated kinase, substance P, and neurokinin-1 protein and mRNA expression in dorsal root ganglia. These results indicate that down-regulation of extracellular signal-regulated kinase, substance P, and neurokinin-1 protein and mRNA may be a central mechanism for the analgesic effect of herb-partitioned moxibustion.

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    Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase IV protein levels in Alzheimer’s disease model rats
    Shu Ye, Ting-ting Wang1, Biao Cai, Yan Wang, Jing Li, Ji-xian Zhan, Guo-ming Shen
    2017, 12 (9):  1479-1484.  doi: 10.4103/1673-5374.215260
    Abstract ( 238 )   PDF (1063KB) ( 608 )   Save

    Genistein has a neuroprotective effect in Alzheimer’s disease, but its mechanism of action needs further clarification. Accumulating evidence suggests that excessive phosphorylation of tau protein causes production of neurofibrillary tangles, which is one of the main pathological characteristics of Alzheimer’s disease, and tau protein can be phosphorylated by calcium/calmodulin dependent protein kinase IV (CAMK4). After 7 days of pre-administration of genistein (90 mg/kg), an Alzheimer’s disease rat model was established using an intraperitoneal injection of D-galactose combined with an intracerebral injection of amyloid-β peptide (25–35). The rat was then continuously administered genistein (90 mg/kg) for 42 days. The Morris water maze test, western blotting and hematoxylin-eosin staining results showed that genistein significantly decreased the escape latency and increased the number of times crossing the platform, reduced p-tau,CALM, CAMKK1 and p-CAMK4 protein levels in the hippocampus, and alleviated hippocampal neuron damage. These findings indicate that genistein may play a neuroprotective role in Alzheimer’s disease through regulating CAMK4 to modulate tau hyperphosphorylation.

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    Detecting dopaminergic neuronal degeneration using diffusion tensor imaging in a rotenone-induced rat model of Parkinson’s disease: fractional anisotropyand mean diffusivity values
    Lan-xiang Liu, Dan Du, Tao Zheng, Yuan Fang, Yan-sheng Chen, Hui-ling Yi, Qing-yuan He, Da-wei Gao, Qing-lei Shi
    2017, 12 (9):  1485-1491.  doi: 10.4103/1673-5374.213559
    Abstract ( 354 )   PDF (2161KB) ( 467 )   Save
    Dopamine content in the basal ganglia is strongly associated with the degree of dopaminergic neuron loss in the substantia nigra pars compacta.Symptoms of Parkinson’s disease might not arise until more than 50% of the substantia nigra pars compacta is lost and the dopamine content in the basal ganglia is reduced by more than 80%. Greater diagnostic sensitivity and specificity would allow earlier detection of Parkinson’s disease. Diffusion tensor imaging is a recently developed magnetic resonance imaging technique that measures mean diffusivity and fractional anisotropy, and responds to changes in brain microstructure. When the microscopic barrier (including cell membranes,microtubules and other structures that interfere with the free diffusion of water) is destroyed and extracellular fluid volume accumulates,the mean diffusivity value increases; when the integrity of the microstructure (such as myelin) is destroyed, fractional anisotropy value decreases. However, there is no consensus as to whether these changes can reflect the early pathological alterations in Parkinson’s disease.Here, we established a rat model of Parkinson’s disease by injecting rotenone (or sunflower oil in controls) into the right substantia nigra.Diffusion tensor imaging results revealed that in the stages of disease, at 1, 2, 4, and 6 weeks after rotenone injection, fractional anisotropy value decreased, but mean diffusivity values increased in the right substantia nigra in the experimental group. Fractional anisotropy values were lower at 4 weeks than at 6 weeks in the right substantia nigra of rats from the experimental group. Mean diffusivity values were markedly greater at 1 week than at 6 weeks in the right corpus striatum of rats from the experimental group. These findings suggest that mean diffusivity and fractional anisotropy values in the brain of rat models of Parkinson’s disease 4 weeks after model establishment can reflect early degeneration of dopaminergic neurons. The change in fractional anisotropy values after destruction of myelin integrity is likely to be of greater early diagnostic significance than the change in mean diffusivity values.
     
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    Neuroprotection of N-benzylcinnamide on scopolamine-induced cholinergic dysfunction in human SH-SY5Y neuroblastoma cells
    Nicha Puangmalai, Wipawan Thangnipon, Rungtip Soi-ampornkul, Nirut Suwanna, Patoomratana Tuchinda, Saksit Nobsathian
    2017, 12 (9):  1492-1498.  doi: 10.4103/1673-5374.215262
    Abstract ( 164 )   PDF (1502KB) ( 563 )   Save
    Alzheimer’s disease, a progressive neurodegenerative disease, affects learning and memory resulting from cholinergic dysfunction. Scopolamine has been employed to induce Alzheimer’s disease-like pathology in vivo and in vitro through alteration of cholinergic system. N-benzylcinnamide (PT-3), purified from Piper submultinerve, has been shown to exhibit neuroprotective properties against amyloid-β-induced neuronal toxicity in rat cortical primary cell culture and to improve spatial learning and memory of aged rats through alleviating oxidative stress. We proposed a hypothesis that PT3 has a neuroprotective effect
    against scopolamine-induced cholinergic dysfunction. PT-3 (125–200 nM) pretreatment was performed in human neuroblastoma SH-SY5Y cell line following scopolamine induction. PT-3 (125–200 nM) inhibited scopolamine (2 mM)-induced generation of reactive oxygen species, cellular apoptosis, upregulation of acetylcholinesterase activity, downregulation of choline acetyltransferase level, and activation of p38 and JNK signalling pathways. These findings revealed the underlying mechanisms of scopolamine-induced Alzheimer’s disease-like cellular dysfunctions, which provide evidence for developing drugs for the treatment of this debilitating disease.
     
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    Blocking beta 2-adrenergic receptor inhibits dendrite ramification in a mouse model of Alzheimer’s disease
    Qin Wu, Jin-xia Sun, Xiang-he Song2, Jing Wang2, Cun-quan Xiong, Fei-xiang Teng, Cui-xiang Gao
    2017, 12 (9):  1499-1506.  doi: 10.4103/1673-5374.215261
    Abstract ( 166 )   PDF (498KB) ( 349 )   Save
    Dendrite ramification affects synaptic strength and plays a crucial role in memory. Previous studies revealed a correlation between beta 2-adrenergic receptor dysfunction and Alzheimer’s disease (AD), although the mechanism involved is still poorly understood. The current study investigated the potential effect of the selective β2-adrenergic receptor antagonist, ICI 118551 (ICI), on Aβ deposits and AD-related cognitive impairment. Morris water maze test results demonstrated that the performance of AD-transgenic (TG) mice treated with ICI (AD-TG/ICI) was significantly poorer compared with NaCl-treated AD-TG mice (AD-TG/NaCl), suggesting that β2-adrenergic receptor blockage by ICI might reduce the learning and memory abilities of mice. Golgi staining and immunohistochemical staining revealed that blockage of the β2-adrenergic receptor by ICI treatment decreased the number of dendritic branches, and ICI treatment in AD-TG mice decreased the expression of hippocampal synaptophysin and synapsin 1. Western blot assay results showed that the blockage of β2-adrenergic receptor increased amyloid-β accumulation by downregulating hippocampal α-secretase activity and increasing the phosphorylation of amyloid precursor protein. These findings suggest that blocking the β2-adrenergic receptor inhibits dendrite ramification of hippocampal neurons in a mouse model of AD.
     
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    Methotrexate combined with methylprednisolone for the recovery of motor function and differential gene expression in rats with spinal cord injury
    Jian-tao Liu, Si Zhang, Bing Gu, Hua-nan Li, Shuo-yu Wang, Shui-yin Zhang
    2017, 12 (9):  1507-1518.  doi: 10.4103/1673-5374.215263
    Abstract ( 227 )   PDF (1290KB) ( 501 )   Save
    Methylprednisolone is a commonly used drug for the treatment of spinal cord injury, but high doses of methylprednisolone can increase the incidence of infectious diseases. Methotrexate has anti-inflammatory activity and immunosuppressive effects, and can reduce inflammation after spinal cord injury. To analyze gene expression changes and the molecular mechanism of methotrexate combined with methylprednisolone in the treatment of spinal cord injury, a rat model of spinal cord contusion was prepared using the PinPoint™ precision cortical impactor technique. Rats were injected with methylprednisolone 30 mg/kg 30 minutes after injury, and then subcutaneously injected with 0.3 mg/kg methotrexate 1 day after injury, once a day, for 2 weeks. TreadScan gait analysis found that at 4 and 8 weeks after injury, methotrexate combined with methylprednisolone significantly improved hind limb swing time, stride time, minimum longitudinal deviation, instant speed, footprint area and regularity index. Solexa high-throughput sequencing was used to analyze differential gene expression.Compared with methylprednisolone alone, differential expression of 316 genes was detected in injured spinal cord treated with methotrexate and ethylprednisolone. The 275 up-regulated genes were mainly related to nerve recovery, anti-oxidative, anti-inflammatory and anti-apoptotic functions, while 41 down-regulated genes were mainly related to proinflammatory and pro-apoptotic functions. These results indicate that methotrexate combined with methylprednisolone exhibited better effects on inhibiting the activity of inflammatory cytokines and enhancing antioxidant and anti-apoptotic effects and thereby produced stronger neuroprotective effects than methotrexate alone. The 316 differentially expressed genes play an important role in the above processes.
     
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    Jisuikang, a Chinese herbal formula, increases neurotrophic factor expression and promotes the recovery of neurological function after spinal cord injury
    Yang Guo, Yong Ma, Ya-lan Pan, Su-yang Zheng, Jian-wei Wang, Gui-cheng Huang
    2017, 12 (9):  1519-1528.  doi: 10.4103/1673-5374.215264
    Abstract ( 239 )   PDF (2117KB) ( 584 )   Save
    The Chinese medicine compound, Jisuikang, can promote recovery of neurological function by inhibiting lipid peroxidation, scavenging oxygen free radicals, and effectively improving the local microenvironment after spinal cord injury. However, the mechanism remains unclear. Thus, we established a rat model of acute spinal cord injury using a modified version of Allen’s method. Jisuikang (50, 25, and 12.5 g/kg/d) and prednisolone were administered 30 minutes after anesthesia. Basso, Beattie, and Bresnahan locomotor scale scores and the oblique board test showed improved motor function recovery in the prednisone group and moderate-dose Jisuikang group compared with the other groups at 3–7 days post-injury. The rats in the moderate-dose Jisuikang group recovered best at 14 days post-injury. Hematoxylin-eosin staining and transmission electron microscopy showed that the survival rate of neurons in treatment groups increased after 3–7 days of administration. Further, the structure of neurons and glial cells was more distinct, especially in prednisolone and moderate-dose Jisuikang groups. Western blot assay and immunohistochemistry showed that expression of brain-derived neurotrophic factor (BDNF) in injured segments was maintained at a high level after 7–14 days of treatment. In contrast, expression of nerve growth factor (NGF) was down-regulated at 7 days after spinal cord injury. Real-time fluorescence quantitative polymerase chain reaction showed that expression of BDNF and NGF mRNA was induced in injured segments by prednisolone and Jisuikang. At 3–7 days after injury, the effect of prednisolone was greater, while 14 days after injury, the effect of moderate-dose Jisuikang was greater. These results confirm that Jisuikang can upregulate BDNF and NGF expression for a prolonged period after spinal cord injury and promote repair of acute spinal cord injury, with its effect being similar to prednisolone.
     
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    Scaffoldless tissue-engineered nerve conduit promotes peripheral nerve regeneration and functional recovery after tibial nerve injury in rats
    Aaron M. Adams, Keith W. VanDusen, Tatiana Y. Kostrominova, Jacob P. Mertens, Lisa M. Larkin
    2017, 12 (9):  1529-1537.  doi: 10.4103/1673-5374.215265
    Abstract ( 133 )   PDF (1437KB) ( 537 )   Save
    Damage to peripheral nerve tissue may cause loss of function in both the nerve and the targeted muscles it innervates. This study compared the repair capability of engineered nerve conduit (ENC), engineered fibroblast conduit (EFC), and autograft in a 10-mm tibial nerve gap. ENCs were fabricated utilizing primary fibroblasts and the nerve cells of rats on embryonic day 15 (E15). EFCs were fabricated utilizing primary fibroblasts only. Following a 12-week recovery, nerve repair was assessed by measuring contractile properties in the medial gastrocnemius muscle, distal motor nerve conduction velocity in the lateral gastrocnemius,and histology of muscle and nerve. The autografts, ENCs and EFCs reestablished 96%, 87% and 84% of native distal motor nerve conduction velocity in the lateral gastrocnemius, 100%, 44% and 44% of native specific force of medical gastrocnemius, and 63%, 61% and 67% of native medial gastrocnemius mass, respectively. Histology of the repaired nerve revealed large axons in the autograft, larger but fewer axons in the ENC repair, and many smaller axons in the EFC repair. Muscle histology revealed similar muscle fiber cross-sectional areas among autograft, ENC and EFC repairs. In conclusion, both ENCs and EFCs promoted nerve regeneration in a 10-mm tibial nerve gap repair, suggesting that the E15 rat nerve cells may not be necessary for nerve regeneration, and EFC alone can suffice for peripheral nerve injury repair.
     
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    Phenotypic changes of Schwann cells on the proximal stump of injured peripheral nerve during repair using small gap conduit tube
    Shi-jun Zhang, Wen-liang Wu, Kai-yun Yang, Yun-zhen Chen, Hai-chun Liu
    2017, 12 (9):  1538-1543.  doi: 10.4103/1673-5374.215266
    Abstract ( 238 )   PDF (993KB) ( 584 )   Save
    Dedifferentiation of Schwann cells is an important feature of the response to peripheral nerve injury and specific negative myelination regulators are considered to have a major role in this process. However, most experiments have focused on the distal nerve stump, where the Notch signaling pathway is strongly associated with Schwann cell dedifferentiation and repair of the nerve. We observed the phenotypic changes of Schwann cells and changes of active Notch signaling on the proximal stump during peripheral nerve repair using small gap conduit tubulization. Eighty rats, with right sciatic nerve section of 4 mm, were randomly assigned to conduit bridging group and control group (epineurium suture). Glial fibrillary acidic protein expression, in myelinating Schwann cells on the proximal stump, began to up-regulate at 1 day after injury and was still evident at 5 days. Compared with the control group, Notch1 mRNA was expressed at a higher level in the conduit bridging group during the first week on the proximal stump. Hes1 mRNA levels in the conduit bridging group significantly increased compared with the control group at 3, 5, 7 and 14 days post-surgery. The change of the Notch intracellular domain shared a similar trend as Hes1 mRNA expression. Our results confirmed that phenotypic changes of Schwann cells occurred in the proximal stump. The differences in these changes between the conduit tubulization and epineurium suture groups correlate with changes in Notch signaling.This suggests that active Notch signaling might be a key mechanism during the early stage of neural regeneration in the proximal nerve stump.
     
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    Adipose-derived mesenchymal stem cells accelerate nerve regeneration and functional recovery in a rat model of recurrent laryngeal nerve injury
    Yun Li, Wen Xu, Li-yu Cheng
    2017, 12 (9):  1544-1550.  doi: 10.4103/1673-5374.215267
    Abstract ( 206 )   PDF (1851KB) ( 607 )   Save
    Medialization thyroplasty or injection laryngoplasty for unilateral vocal fold paralysis cannot restore mobility of the vocal fold. Recent studies have shown that transplantation of mesenchymal stem cells is effective in the repair of nerve injuries. This study investigated whether adipose-derived stem cell transplantation could repair recurrent laryngeal nerve injury. Rat models of recurrent laryngeal nerve injury were established by crushing with micro forceps. Adipose-derived mesenchymal stem cells (ADSCs; 8 × 105) or differentiated Schwann-like adipose-derived mesenchymal stem cells (dADSCs; 8 × 105) or extracellular matrix were injected at the site of injury. At 2, 4 and 6 weeks post-surgery, a higher density of myelinated nerve fiber, thicker myelin sheath, improved vocal fold movement, better recovery of nerve conduction capacity and reduced thyroarytenoid muscle atrophy were found in ADSCs and dADSCs groups compared with the extracellular matrix group. The effects were more pronounced in the ADSCs group than in the dADSCs group. These experimental results indicated that ADSCs transplantation could be an early interventional strategy to promote regeneration after recurrent laryngeal nerve injury.
     
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    Structure and function of the contactin-associated protein family in myelinated axons and their relationship with nerve diseases
    Yan Zou, Wei-feng Zhang, Hai-ying Liu, Xia Li, Xing Zhang, Xiao-fang Ma, Yang Sun, Shi-yi Jiang, Quan-hong Ma, De-en Xu
    2017, 12 (9):  1551-1558.  doi: 10.4103/1673-5374.215268
    Abstract ( 273 )   PDF (812KB) ( 774 )   Save

    The contactin-associated protein (Caspr) family participates in nerve excitation and conduction, and neurotransmitter release in myelinated axons. We analyzed the structures and functions of the Caspr family–CNTNAP1 (Caspr1), CNTNAP2 (Caspr2), CNTNAP3 (Caspr3), CNTNAP4 (Caspr4) and CNTNAP5 (Caspr5), Caspr1–5 is not only involved in the formation of myelinated axons, but also participates in maintaining the stability of adjacent connections. Caspr1 participates in the formation, differentiation, and proliferation of neurons and astrocytes, and in motor control and cognitive function. We also analyzed the relationship between the Caspr family and neurodegenerative diseases, multiple sclerosis, and autoimmune encephalitis. However, the effects of Caspr on disease course and prognosis remain poorly understood. The effects of Caspr on disease diagnosis and treatment need further investigation.

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