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15 July 2020, Volume 15 Issue 7 Previous Issue    Next Issue

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Glial cells in intracerebral transplantation for Parkinson’s disease Nikola Tomov 2020, 15 (7):  1173-1178.  doi: 10.4103/1673-5374.270296 Abstract ( 91 )   PDF (337KB) ( 125 )   Save In the last few decades, intracerebral transplantation has grown from a dubious neuroscientific topic to a plausible modality for treatment of neurological disorders. The possibility for cell replacement opens a new field of perspectives in the therapy of neurodegenerative disorders, ischemia, and neurotrauma, with the most lessons learned from intracerebral transplantation in Parkinson’s disease. Multiple animal studies and a few small-scale clinical trials have proven the concept of intracerebral grafting, but still have to provide a uniform and highly efficient approach to the procedure, suitable for clinical application. The success of intracerebral transplantation is highly dependent on the integration of the grafted cells with the host brain. In this process, glial cells are clearly more than passive bystanders. They provide transplanted cells with mechanical support, trophics, mediate synapse formation, and participate in graft vascularization. At the same time, glial cells mediate scarring, graft rejection, and neuroinflammation, which can be detrimental. We can use this information to try to understand the mechanisms behind the glial reaction to intracerebral transplantation. Recognizing and utilizing glial reactivity can move translational research forward and provide an insight not only to post-transplantation events but also to mechanisms of neuronal death and degeneration. Knowledge about glial reactivity to transplanted cells could also be a key for optimization of transplantation protocols, which ultimately should contribute to greater patient benefit. Related Articles | Metrics

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Fast-tracking regenerative medicine for traumatic brain injury Brooke Bonsack , Matt Heyck, Chase Kingsbury, Blaise Cozene, Nadia Sadanandan, Jea-Young Lee, Cesar V. Borlongan 2020, 15 (7):  1179-1190.  doi: 10.4103/1673-5374.270294 Abstract ( 122 )   PDF (484KB) ( 261 )   Save Traumatic brain injury remains a global health crisis that spans all demographics, yet there exist limited treat ment options that may effectively curtail its lingering symptoms. Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death. Sequestering this inflam mation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect. In this review, we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation, edema, and blood-brain barrier disintegra tion through pharmacotherapy and stem cell transplants. Although these studies of stand-alone treatments have yielded some positive results, more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy. Harnessing the facilitatory properties of certain pharmaceu ticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts. The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials. Related Articles | Metrics

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The N-formyl peptide receptors: contemporary roles  in neuronal function and dysfunction Peter J.G. Cussell, Margarita Gomez Escalada, Nathaniel G.N. Milton, Andrew W.J. Paterson 2020, 15 (7):  1191-1198.  Abstract ( 96 )   PDF (697KB) ( 231 )   Save N-formyl peptide receptors (FPRs) were first identified upon phagocytic leukocytes, but more than four de cades of research has unearthed a plethora of non-myeloid roles for this receptor family. FPRs are expressed within neuronal tissues and markedly in the central nervous system, where FPR interactions with endoge nous ligands have been implicated in the pathophysiology of several neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease, as well as neurological cancers such as neuroblastoma. Whilst the homeostatic function of FPRs in the nervous system is currently undefined, a variety of novel physio logical roles for this receptor family in the neuronal context have been posited in both human and animal settings. Rapid developments in recent years have implicated FPRs in the process of neurogenesis and neu ronal differentiation which, upon greater characterisation, could represent a novel pharmacological target for neuronal regeneration therapies that may be used in the treatment of brain/spinal cord injury, stroke and neurodegeneration. This review aims to summarize the recent progress made to determine the physi ological role of FPRs in a neuronal setting, and to put forward a case for FPRs as a novel pharmacological target for conditions of the nervous system, and for their potential to open the door to novel neuronal re generation therapies. Related Articles | Metrics

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Adrenomedullin: an important participant in neurological diseases Feng-Jiao Li, Si-Ru Zheng, Dong-Mei Wang 2020, 15 (7):  1199-1207.  doi: 10.4103/1673-5374.272567 Abstract ( 99 )   PDF (1009KB) ( 259 )   Save Adrenomedullin, a peptide with multiple physiological functions in nervous system injury and disease, has aroused the interest of researchers. This review summarizes the role of adrenomedullin in neuropatho logical disorders, including pathological pain, brain injury and nerve regeneration, and their treatment. As a newly characterized pronociceptive mediator, adrenomedullin has been shown to act as an upstream factor in the transmission of noxious information for various types of pathological pain including acute and chronic inflammatory pain, cancer pain, neuropathic pain induced by spinal nerve injury and diabetic neuropathy. Initiation of glia-neuron signaling networks in the peripheral and central nervous system by adrenomedullin is involved in the formation and maintenance of morphine tolerance. Adrenomedullin has been shown to exert a facilitated or neuroprotective effect against brain injury including hemorrhagic or ischemic stroke and traumatic brain injury. Additionally, adrenomedullin can serve as a regulator to pro mote nerve regeneration in pathological conditions. Therefore, adrenomedullin is an important participant in nervous system diseases. Related Articles | Metrics

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Shifting equilibriums in Alzheimer’s disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis Sophie C. Gray, Kerri J. Kinghorn , Nathaniel S. Woodling 2020, 15 (7):  1208-1219.  doi: 10.4103/1673-5374.272571 Abstract ( 78 )   PDF (2771KB) ( 234 )   Save Alzheimer’s disease is the leading cause of dementia. Its increased prevalence in developed countries, due to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In order to find disease-modifying therapies to confront this challenge, a more complete understanding of the pathogenesis of Alzheimer’s disease is necessary. Recent studies have revealed increasing evidence for the roles played by microglia, the resident innate immune system cells of the brain. Reflecting the well-es tablished roles of microglia in reacting to pathogens and inflammatory stimuli, there is now a growing literature describing both protective and detrimental effects for individual cytokines and chemokines pro duced by microglia in Alzheimer’s disease. A smaller but increasing number of studies have also addressed the divergent roles played by microglial neurotrophic and neurogenic factors, and how their perturbation may play a key role in the pathogenesis of Alzheimer’s disease. Here we review recent findings on the roles played by microglia in neuroinflammation, neuronal survival and neurogenesis in Alzheimer’s disease. In each case, landmark studies have provided evidence for the divergent ways in which microglia can either promote neuronal function and survival, or perturb neuronal function, leading to cell death. In many cases, the secreted molecules of microglia can lead to divergent effects depending on the magnitude and context of microglial activation. This suggests that microglial functions must be maintained in a fine equilibrium, in order to support healthy neuronal function, and that the cellular microenvironment in the Alzheimer’s disease brain disrupts this fine balance, leading to neurodegeneration. Thus, an understanding of microglial homeostasis, both in health and across the trajectory of the disease state, will improve our understanding of the pathogenic mechanisms underlying Alzheimer’s disease, and will hopefully lead to the development of microglial-based therapeutic strategies to restore equilibrium in the Alzheimer’s disease brain. Related Articles | Metrics

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Protective effects of pharmacological therapies in animal models of multiple sclerosis: a review of studies 2014–2019 Bridget Martinez, , Philip V. Peplow, 2020, 15 (7):  1220-1234.  doi: 10.4103/1673-5374.272572 Abstract ( 65 )   PDF (271KB) ( 126 )   Save Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is reversible. Once there is considerable loss of axons, MS patients enter a secondary progressive stage. Disease-modifying drugs currently in use for MS suppress the immune system and reduce relapse rates but are not effective in the progressive stage. Various animal models of MS (mostly mouse and rat) have been established and proved useful in studying the disease process and response to therapy. The experimental autoimmune encephalomyelitis animal studies reviewed here showed that a chronic progressive disease can be induced by immunization with appropriate amounts of myelin oligodendrocyte glycoprotein together with mycobacterium tuberculosis and pertussis toxin in Freund’s adjuvant. The clinical manifestations of autoimmune encephalomyelitis disease were prevented or reduced by treatment with certain pharmacological agents given prior to, at, or after peak disease, and the agents had protective effects as shown by inhibiting demyelination and damage to neurons, axons and oligodendrocytes. In the cuprizone-induced toxicity animal studies, the pharmacological agents tested were able to promote remyelination and increase the number of oligodendrocytes when administered therapeutically or prophylactically. A monoclonal IgM antibody protected axons in the spinal cord and preserved motor function in animals inoculated with Theiler’s murine encephalomyelitis virus. In all these studies the pharmacological agents were administered singly. A combination therapy may be more effective, especially using agents that target neuroinflammation and neurodegeneration, as they may exert synergistic actions. Related Articles | Metrics

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ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders Liam M. Koehn 2020, 15 (7):  1235-1242.  doi: 10.4103/1673-5374.272568 Abstract ( 132 )   PDF (673KB) ( 146 )   Save The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases. The family of ATP-binding cassette (ABC) transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers. These efflux transporters include P-glycoprotein (abcb1), ‘breast cancer resistance protein’ (abcg2) and the various ‘multidrug resistance-associated proteins’ (abccs). Understanding which efflux transporters are present at the blood-spinal cord, blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue. Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age, disease and environmental challenge. This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist. In the present review, the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on: (i) protecting the spinal cord from adverse effects of systemically directed drugs, and (ii) limiting centrally directed drugs from accessing their active sites within the spinal cord. Related Articles | Metrics

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Biomaterials and neural regeneration Yi Liu, Shan-hui Hsu 2020, 15 (7):  1243-1244.  doi: 10.4103/1673-5374.272573 Abstract ( 105 )   PDF (979KB) ( 239 )   Save Related Articles | Metrics

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Targeting the P2X7 receptor in microglial cells to prevent brain inflammation Lin-Hua Jiang , Sébastien Roger 2020, 15 (7):  1245-1246.  doi: 10.4103/1673-5374.272575 Abstract ( 84 )   PDF (209KB) ( 186 )   Save Related Articles | Metrics

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Moderate/severe traumatic brain injury as a trigger of chronic neurodegeneration in humans Sergio Bagnato , Cristina Boccagni 2020, 15 (7):  1247-1248.  doi: 10.4103/1673-5374.272574 Abstract ( 101 )   PDF (287KB) ( 235 )   Save Related Articles | Metrics

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Role of the NLRP3 inflammasome in neurodegenerative diseases and therapeutic implications Yanhui Duan, Nathan Kelley, Yuan He 2020, 15 (7):  1249-1250.  doi: 10.4103/1673-5374.272576 Abstract ( 107 )   PDF (950KB) ( 169 )   Save Related Articles | Metrics

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Insights from human sleep research on neural mechanisms of Alzheimer’s disease Susanna Cordone, Luigi De Gennaro 2020, 15 (7):  1251-1252.  doi: 10.4103/1673-5374.272579 Abstract ( 74 )   PDF (425KB) ( 192 )   Save Related Articles | Metrics

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Diabetic retinopathy: a matter of retinal ganglion cell homeostasis Elisabetta Catalani , Davide Cervia 2020, 15 (7):  1253-1254.  doi: 10.4103/1673-5374.272577 Abstract ( 79 )   PDF (488KB) ( 194 )   Save Related Articles | Metrics

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The new KV3.4 inhibitor BDS-I[1–8] as a potential pharmacological opportunity in Alzheimer’s disease therapy Ilaria Piccialli# , Roselia Ciccone# , Anna Pannaccione 2020, 15 (7):  1255-1256.  doi: 10.4103/1673-5374.272580 Abstract ( 66 )   PDF (735KB) ( 195 )   Save Related Articles | Metrics

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Role of animal models in glaucoma research Atsuko Kimura , Takahiko Noro, Takayuki Harada 2020, 15 (7):  1257-1258.  doi: 10.4103/1673-5374.272578 Abstract ( 83 )   PDF (1177KB) ( 181 )   Save Related Articles | Metrics

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Risk factors for corticosteroid insufficiency during the sub-acute phase of acute traumatic brain injury  Xin Chen, , Yan Chai, Shao-Bo Wang, Jia-Chong Wang, Shu-Yuan Yue, Rong-Cai Jiang, Jian-Ning Zhang, 2020, 15 (7):  1259-1265.  doi: 10.4103/1673-5374.272611 Abstract ( 79 )   PDF (479KB) ( 241 )   Save Hypothalamic-pituitary-adrenal axis dysfunction may lead to the occurrence of critical illness-related corticosteroid insufficiency. Critical illness-related corticosteroid insufficiency can easily occur after traumatic brain injury, but few studies have examined this occurrence. A multicenter, prospective, cohort study was performed to evaluate the function of the hypothalamic-pituitary-adrenal axis and the inci dence of critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury. One hundred and forty patients with acute traumatic brain injury were enrolled from the neurosurgical departments of three tertiary-level hospitals in China, and the critical illness-related corticosteroid insufficiency incidence, critical-illness-related corticosteroid insufficiency-related risk factors, complications, and 28-day mortality among these patients was recorded. Critical illness-related corticosteroid insufficiency was diagnosed in patients with plasma total cortisol levels less than 10 μg/dL (275.9 nM) on post-injury day 4 or when serum cortisol was insufficiently suppressed (less than 50%) during a dexamethasone suppression test on post-injury day 5. The results demonstrated that critical illness-re lated corticosteroid insufficiency occurred during the sub-acute phase of traumatic brain injury in 5.6% of patients with mild injury, 22.5% of patients with moderate injury, and 52.2% of patients with severe injury. Traumatic brain injury-induced critical illness-related cortico steroid insufficiency was strongly correlated to injury severity during the sub-acute stage of traumatic brain injury. Traumatic brain injury patients with critical illness-related corticosteroid insufficiency frequently presented with hemorrhagic cerebral contusions, diffuse axonal injury, brain herniation, and hypotension. Differences in the incidence of hospital-acquired pneumonia, gastrointestinal bleeding, and 28-day mortality were observed between patients with and without critical illness-related corticosteroid insufficiency during the sub-acute phase of traumatic brain injury. Hypotension, brain-injury severity, and the types of traumatic brain injury were independent risk factors for traumatic brain injury-induced critical illness-related corticosteroid insufficiency. These findings indicate that critical illness-related corticosteroid insufficiency is common during the sub-acute phase of traumatic brain injury and is strongly associated with poor progno sis. The dexamethasone suppression test is a practical assay for the evaluation of hypothalamic-pituitary-adrenal axis function and for the diagnosis of critical illness-related corticosteroid insufficiency in patients with traumatic brain injury, especially those with hypotension, hemorrhagic cerebral contusions, diffuse axonal injury, and brain herniation. Sub-acute infection of acute traumatic brain injury may be an important factor associated with the occurrence and development of critical illness-related corticosteroid insufficiency. This study protocol was approved by the Ethics Committee of General Hospital of Tianjin Medical University, China in December 2011 (approval No. 201189). Related Articles | Metrics

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Efficacy of cattle encephalon glycoside and ignotin in patients with acute cerebral infarction: a randomized, double-blind, parallel-group, placebo-controlled study Hui Zhang , Chuan-Ling Li , Feng Wan , Su-Juan Wang , Xiu-E Wei , Yan-Lei Hao , Hui-Lin Leng , Jia-Min Li , Zhong-Rui Yan , Bao-Jun Wang, Ren-Shi Xu, Ting-Min Yu, Li-Chun Zhou, Dong-Sheng Fan 2020, 15 (7):  1266-1273.  Abstract ( 108 )   PDF (834KB) ( 168 )   Save Cattle encephalon glycoside and ignotin (CEGI) injection is a compound preparation formed by a combination of muscle extract from hea lthy rabbits and brain gangliosides from cattle, and it is generally used as a neuroprotectant in the treatment of central and peripheral nerve injuries. However, there is still a need for high-level clinical evidence from large samples to support the use of CEGI. We therefore carried out a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in which we recruited 319 patients with acute cerebral infarction from 16 centers in China from October 2013 to May 2016. The patients were randomized at a 3:1 ratio into CEGI (n = 239; 155 male, 84 female; 61.2 ± 9.2 years old) and placebo (n = 80; 46 male, 34 female; 63.2 ± 8.28 years old) groups. All patients were given standard care once daily for 14 days, including a 200 mg aspirin enteric-coated tablet and 20 mg atorvastatin calcium, both taken orally, and intravenous infusion of 250–500 mL 0.9% sodium chloride containing 40 mg sodium tanshinone IIA sulfonate. Based on conventional treatment, patients in the CEGI and placebo groups were given 12 mL CEGI or 12 mL sterile water, respectively, in an intravenous drip of 250 mL 0.9% sodium chloride (2 mL/min) once daily for 14 days. According to baseline National Institutes of Health Stroke Scale scores, patients in the two groups were divided into mild and moderate subgroups. Based on the modified Rankin Scale results, the rate of patients with good outcomes in the CEGI group was higher than that in the placebo group, and the rate of disability in the CEGI group was lower than that in the placebo group on day 90 after treatment. In the CEGI group, neurological deficits were decreased on days 14 and 90 after treatment, as measured by the National Institutes of Health Stroke Scale and the Barthel Index. Subgroup analysis revealed that CEGI led to more significant improvements in moderate stroke patients. No drug-related adverse events occurred in the CEGI or placebo groups. In conclusion, CEGI may be a safe and effective treatment for acute cerebral infarction patients, especially for moderate stroke patients. This study was approved by the Ethical Committee of Peking University Third Hospital, China (approval No. 2013-068-2) on May 20, 2013, and registered in the Chinese Clinical Trial Registry (registration No. ChiCTR1800017937). Related Articles | Metrics

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MicroRNA-181c provides neuroprotection in an intracerebral hemorrhage model Xi Lu, Hui-Yuan Zhang, Zhi-Yi He 2020, 15 (7):  1274-1282.  doi: 10.4103/1673-5374.272612 Abstract ( 72 )   PDF (1800KB) ( 142 )   Save Apoptosis is an important factor during the early stage of intracerebral hemorrhage. MiR-181c plays a key regulatory role in apoptosis. However, whether miR-181c is involved in apoptosis of prophase cells after intracerebral hemorrhage remains unclear. Therefore, in vitro and in vivo experiments were conducted to test this hypothesis. In vivo experiments: collagenase type VII was injected into the basal ganglia of adult Sprague-Dawley rats to establish an intracerebral hemorrhage model. MiR-181c mimic or inhibitor was injected in situ 4 hours after intracerebral hemorrhage. Neurological functional defects (neurological severity scores) were assessed 1, 7, and 14 days after model establishment. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and western blot assay were conducted 14 days after model establishment. In vitro experiments: PC12 cells were cultured under oxygen-glucose deprivation, and hemins were added to simulate intracerebral hemorrhage in vitro. MiR-181c mimic or inhibitor was added to regulate miR-181c expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, luciferase reporter system, and western blot assay were performed. Experimental results revealed differences in miR-181c expression in brain tissues of both patients and rats with cerebral hemorrhage. In addition, in vitro experiments found that miR-181c overexpression could upregulate the Bcl-2/Bax ratio to inhibit apoptosis, while inhibition of miR-181c expression could reduce the Bcl-2/Bax ratio and aggravate apoptosis of cells. Regulation of apoptosis occurred through the phosphoinositide 3 kinase (PI3K)/Akt pathway by targeting of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Higher miR-181c overexpression correlated with lower neurological severity scores, indicating better recovery of neurological function. In conclusion, miR-181c affects the prognosis of intracerebral hemorrhage by regulating apoptosis, and these effects might be directly mediated and regulated by targeting of the PTEN\PI3K/Akt pathway and Bcl-2/Bax ratio. Furthermore, these results indicated that miR-181c played a neuroprotective role in intracerebral hemorrhage by regulating apoptosis of nerve cells, thus providing a potential target for the prevention and treatment of intracerebral hemorrhage. Testing of human serum was authorized by the Ethics Committee of China Medical University (No. 2012-38-1) on February 20, 2012. The protocol was registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR-COC-17013559). The animal study was approved by the Institutional Animal Care and Use Committee of China Medical University (approval No. 2017008) on March 8, 2017. Related Articles | Metrics

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Target inhibition of caspase-8 alleviates brain damage after subarachnoid hemorrhage Da-Qiang Ke, Zhi-Yang Chen, Zhou-Ling Li, Xia Huang, Hui Liang 2020, 15 (7):  1283-1289.  doi: 10.4103/1673-5374.272613 Abstract ( 72 )   PDF (1590KB) ( 143 )   Save Caspase-8 plays an important role in the mediation of inflammation and the effect of its role in subarachnoid hemorrhage remains elusive. The nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome has been postulated to mediate inflammation during SAH. The aim of the present study was to investigate the effects of caspase-8 inhibition on SAH injury and further elucidate the molecular mechanisms. In this study, a subarachnoid hemorrhage model was established by endovascular perforation process in adult male Sprague-Dawley rats. Z-IETD-FMK (0.5, 1, 2 mg/kg; an inhibitor of caspase-8) was delivered via intravenous (tail vein) injection immediately after subarachnoid hemorrhage. After 12 hours of subarachnoid hemorrhage, western blot assay showed that the expression of cleaved caspase-8 was significantly increased at 12 hours, peaked at 24 hours, and then decreased at 72 hours after subarachnoid hemorrhage. Immunofluorescence staining demonstrated that caspase-8 was expressed in microglia after subarachnoid hemorrhage. Z-IETDFMK significantly improved neurological deficits and reduced brain water content 24 hours after subarachnoid hemorrhage. The Morris water maze and rotarod test confirmed that Z-IETD-FMK significantly improved spatial learning and memory abilities and motor coordination at 21–27 days after subarachnoid hemorrhage. Furthermore, inhibition of caspase-8 activation reduced the expression of pyrin domain-containing 3, caspase-1, and interleukin-1β after subarachnoid hemorrhage. In conclusion, our findings suggest that caspase-8 inhibition alleviates subarachnoid hemorrhage-induced brain injuries by suppressing inflammation. The study was approved by the Institutional Animal Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University, China (approval No. 2016- 193) on February 25, 2016. Related Articles | Metrics

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No DCX-positive neurogenesis in the cerebral cortex of the adult primate Ruo-Xu Liu, , Jie Ma , Bin Wang , Tian Tian , Ning Guo , Shao-Jun Liu, 2020, 15 (7):  1290-1299.  doi: 10.4103/1673-5374.272610 Abstract ( 95 )   PDF (6162KB) ( 282 )   Save Whether endogenous neurogenesis occurs in the adult cortex remains controversial. An increasing number of reports suggest that doublecortin (DCX)-positive neurogenesis persists in the adult primate cortex, attracting enormous attention worldwide. In this study, different DCX antibodies were used together with NeuN antibodies in immunohistochemistry and western blot assays using adjacent cortical sections from adult monkeys. Antibody adsorption, antigen binding, primary antibody omission and antibody-free experiments were used to assess specificity of the signals. We found either strong fluorescent signals, medium-weak intensity signals in some cells, weak signals in a few perikarya or near complete lack of labeling in adjacent cortical sections incubated with the various DCX antibodies. The putative DCX-positive cells in the cortex were also positive for NeuN, a specific marker of mature neurons. However, further experiments showed that most of these signals were either the result of antibody cross reactivity, the non-specificity of secondary antibodies or tissue autofluorescence. No confirmed DCX-positive cells were detected in the adult macaque cortex by immunofluorescence. Our findings show that DCX-positive neurogenesis does not occur in the cerebral cortex of adult primates, and that false-positive signals (artefacts) are caused by antibody cross reactivity and autofluorescence. The experimental protocols were approved by the Institutional Animal Care and Use Committee of the Institute of Neuroscience, Beijing, China (approval No. IACUC-AMMS-2014-501). Related Articles | Metrics

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Endothelial progenitor cells, potential biomarkers for diagnosis and prognosis of ischemic stroke: protocol for an observational case-control study Kamini Rakkar, Othman Othman, Nikola Sprigg, Philip Bath, Ulvi Bayraktutan 2020, 15 (7):  1300-1307.  doi: 10.4103/1673-5374.269028 Abstract ( 158 )   PDF (561KB) ( 200 )   Save Ischemic stroke is a devastating, life altering event which can severely reduce patient quality of life. Despite years of research there have been minimal therapeutic advances. Endothelial progenitor cells (EPCs), stem cells involved in both vasculogenesis and angiogenesis, may be a potential therapeutic target. After a stroke, EPCs migrate to the site of ischemic injury to repair cerebrovascular damage, and their numbers and functional capacity may determine patients’ outcome. This study aims to determine whether the number of circulating EPCs and their functional aspects may be used as biomarkers to identify the type (cortical or lacunar) and/or severity of ischemic stroke. The study will also investigate if there are any differences in these characteristics between healthy volunteers over and under 65 years of age. 100 stroke patients (50 lacunar and 50 cortical strokes) will be recruited in this prospective, observational case-controlled study. Blood samples will be taken from stroke patients at baseline (within 48 hours of stroke) and days 7, 30 and 90. EPCs will be counted with flow cytometry. The plasma levels of pro- and anti-angiogenic factors and inflammatory cytokines will also be determined. Outgrowth endothelial cells will be cultured to be used in tube formation, migration and proliferation functional assays. Primary outcome is disability or dependence on day 90 after stroke, assessed by the modified Rankin Scale. Secondary outcomes are changes in circulating EPC numbers and/or functional capacity between patient and healthy volunteers, between patient subgroups and between elderly and young healthy volunteers. Recruitment started in February 2017, 167 participants have been recruited. Recruitment will end in November 2019. West Midlands - Coventry & Warwickshire Research Ethics Committee approved this study (REC number: 16/WM/0304) on September 8, 2016. Protocol version: 2.0. The Bayraktutan Dunhill Medical Trust EPC Study was registered in ClinicalTrials.gov (NCT02980354) on November 15, 2016. This study will determine whether the number of EPCs can be used as a prognostic or diagnostic marker for ischemic strokes and is a step towards discovering if transplantation of EPCs may aid patient recovery. Related Articles | Metrics

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Fingolimod (FTY720) improves postoperative cognitive dysfunction in mice subjected to D-galactose-induced aging Jie Zhang, , Bin Xiao , Chen-Xu Li , Yi Wang 2020, 15 (7):  1308-1315.  doi: 10.4103/1673-5374.272617 Abstract ( 107 )   PDF (2967KB) ( 202 )   Save Neurocognitive dysfunction is a common postoperative complication, especially in older adult patients. Fingolimod (FTY720) is a sphingosine-1-phosphate receptor modulator that has been found to be neuroprotective in several animal models of central nervous system disease. However, few reports have examined whether FTY720 could mitigate postoperative cognitive dysfunction. In this study, we investigated whether FTY720 could prevent postoperative neurocognitive impairment in mice subjected to D-galactose-induced aging. We induced an accelerated model of aging by administering an intraperitoneal injection of D-galactose. Subsequently, we performed a partial hepatolobectomy under sevoflurane anesthesia. FTY720 (1 mg/kg) was administered intraperitoneally 3 hours before and 24 hours after anesthesia and surgery. Our results indicated that anesthesia and surgery significantly impaired spatial memory in the Y-maze test 6 hours after surgery. We also found that problem solving ability and long-term memory in the puzzle box test on postoperative days 2–4 were significantly improved by FTY720 treatment. Immunohistochemical staining and western blot assay demonstrated that FTY720 significantly inhibited microglial activation in the hippocampal CA1 region of mice 6 hours and 3 days after anesthesia, and down-regulated the expression of synaptic-related proteins postsynaptic density protein 95 and GluR2 in the hippocampus. These results indicate that FTY720 improved postoperative neurocognitive dysfunction in mice subjected to D-galactose-induced aging. This study was approved by the Experimental Animal Ethics Committee of the Third Xiangya Hospital of Central South University of China (approval No. LLSC (LA) 2016- 025) on September 27, 2016. Related Articles | Metrics

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Resatorvid protects against hypoxic-ischemic brain damage in neonatal rats Li-Jun Jiang, Zhen-Xing Xu, Ming-Fu Wu , Gai-Qin Dong, Li-Li Zhang , Jun-Yan Gao , Chen-Xi Feng , Xing Feng 2020, 15 (7):  1316-1325.  doi: 10.4103/1673-5374.272615 Abstract ( 90 )   PDF (7201KB) ( 30 )   Save Secondary brain damage caused by hyperactivation of autophagy and inflammatory responses in neurons plays an important role in hypoxic-ischemic brain damage (HIBD). Although previous studies have implicated Toll-like receptor 4 (TLR4) and nuclear factor kappa-B (NF-κB) in the neuroinflammatory response elicited by brain injury, the role and mechanisms of the TLR4-mediated autophagy signaling pathway in neonatal HIBD are still unclear. We hypothesized that this pathway can regulate brain damage by modulating neuron autophagy and neuroinflammation in neonatal rats with HIBD. Hence, we established a neonatal HIBD rat model using the Rice-Vannucci method, and injected 0.75, 1.5, or 3 mg/kg of the TLR4 inhibitor resatorvid (TAK-242) 30 minutes after hypoxic ischemia. Our results indicate that administering TAK-242 to neonatal rats after HIBD could significantly reduce the infarct volume and the extent of cerebral edema, alleviate neuronal damage and neurobehavioral impairment, and decrease the expression levels of TLR4, phospho-NF-κB p65, Beclin-1, microtubule-associated protein l light chain 3, tumor necrosis factor-α, and interleukin-1β in the hippocampus. Thus, TAK-242 appears to exert a neuroprotective effect after HIBD by inhibiting activation of autophagy and the release of inflammatory cytokines via inhibition of the TLR4/NF-κB signaling pathway. This study was approved by the Laboratory Animal Ethics Committee of Affiliated Hospital of Yangzhou University, China (approval No. 20180114-15) on January 14, 2018. Related Articles | Metrics

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Inflammation and apoptosis accelerate progression to irreversible atrophy in denervated intrinsic muscles of the hand compared with biceps: proteomic analysis of a rat model of obstetric brachial plexus palsy Xiao-Heng Yu, Ji-Xin Wu, Liang Chen, Yu-Dong Gu 2020, 15 (7):  1326-1332.  doi: 10.4103/1673-5374.272619 Abstract ( 97 )   PDF (1331KB) ( 800 )   Save In treating patients with obstetric brachial plexus palsy, we noticed that denervated intrinsic muscles of the hand become irreversibly atrophic at a faster than denervated biceps. In a rat model of obstetric brachial plexus palsy, denervated intrinsic musculature of the forepaw entered the irreversible atrophy far earlier than denervated biceps. In this study, isobaric tags for relative and absolute quantitation were examined in the intrinsic musculature of forepaw and biceps on denervated and normal sides at 3 and 5 weeks to identify dysregulated proteins. Enrichment of pathways mapped by those proteins was analyzed by Kyoto Encyclopedia of Genes and Genomes analysis. At 3 weeks, 119 dysregulated proteins in denervated intrinsic musculature of the forepaw were mapped to nine pathways for muscle regulation, while 67 dysregulated proteins were mapped to three such pathways at 5 weeks. At 3 weeks, 27 upregulated proteins were mapped to five pathways involving inflammation and apoptosis, while two upregulated proteins were mapped to one such pathway at 5 weeks. At 3 and 5 weeks, 53 proteins from pathways involving regrowth and differentiation were downregulated. At 3 weeks, 64 dysregulated proteins in denervated biceps were mapped to five pathways involving muscle regulation, while, five dysregulated proteins were mapped to three such pathways at 5 weeks. One protein mapped to inflammation and apoptotic pathways was upregulated from one pathway at 3 weeks, while three proteins were downregulated from two other pathways at 5 weeks. Four proteins mapped to regrowth and differentiation pathways were upregulated from three pathways at 3 weeks, while two proteins were downregulated in another pathway at 5 weeks. These results implicated inflammation and apoptosis as critical factors aggravating atrophy of denervated intrinsic muscles of the hand during obstetric brachial plexus palsy. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Fudan University, China (approval No. DF-325) in January 2015. Related Articles | Metrics

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Exendin-4 attenuates pain-induced cognitive impairment by alleviating hippocampal neuroinflammation in a rat model of spinal nerve ligation Shan-Shan Cui , Xiao-Bo Feng , Bing-Hong Zhang , Zhong-Yuan Xia , Li-Ying Zhan, 2020, 15 (7):  1333-1339.  doi: 10.4103/1673-5374.272620 Abstract ( 75 )   PDF (2499KB) ( 188 )   Save Glucagon-like peptide-1 receptor has anti-apoptotic, anti-inflammatory, and neuroprotective effects. It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses; however, it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms. We explored the effects of glucagon-like peptide-1 receptor on nociception, cognition, and neuroinflammation in chronic pain. A rat model of chronic pain was established using left L5 spinal nerve ligation. The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation. Electrophysiological examinations showed that, after treatment with exendin-4, paw withdrawal frequency of the left limb was significantly reduced, and pain was relieved. In addition, in the Morris water maze test, escape latency increased and the time to reach the platform decreased following exendin-4 treatment. Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus, as well as an increase in the expression of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6. All of these effects could be reversed by exendin-4 treatment. These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China (approval No. WDRM 20171214) on September 22, 2017. Related Articles | Metrics

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Pattern of triptans use: a retrospective prescription study in Calabria, Italy Damiana Scuteri , Annagrazia Adornetto , Laura Rombolà , Maria Diana Naturale , Adele Emanuela De Francesco , Stefania Esposito , Mariacristina Zito , Luigi Antonio Morrone , Giacinto Bagetta, Paolo Tonin, Maria Tiziana Corasaniti 2020, 15 (7):  1340-1343.  doi: 10.4103/1673-5374.272630 Abstract ( 108 )   PDF (322KB) ( 153 )   Save Triptans are 5-hydroxytryptamine 1B/1D receptor agonists used in moderate to severe migraine attacks as first line when non-specific, symptomatic, nonsteroidal anti-inflammatory drugs are not effective. To gain insight in the treatment of migraine in the regional context, this retrospective (from January to August of the years 2017 and 2018) study aimed at monitoring the use of triptans approved by the regional health authority in Calabria. The data demonstrate that the overall treatment of migraine with triptans in the different provinces of Calabria falls in the average regional prescription/dispensation. Interestingly, Crotone showed a trend to an increased amount of defined daily dose/1000 inhabitants per day. The present analysis might stand for homogeneity of treatment of migraineurs in Calabria and highlights the need for better understanding the apparent differences in the local pattern of almotriptan use to improve the appropriateness. Related Articles | Metrics

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Compression analysis of the gray and white matter of the spinal cord Norihiro Nishida, , Fei Jiang , Junji Ohgi , Akihiro Tanaka , Yasuaki Imajo , Hidenori Suzuki , Masahiro Funaba , Takashi Sakai , Itsuo Sakuramoto , Xian Chen 2020, 15 (7):  1344-1349.  Abstract ( 85 )   PDF (1932KB) ( 147 )   Save The spinal cord is composed of gray matter and white matter. It is well known that the properties of these two tissues differ considerably. Spinal diseases often present with symptoms that are caused by spinal cord compression. Understanding the mechanical properties of gray and white matter would allow us to gain a deep understanding of the injuries caused to the spinal cord and provide information on the pathological changes to these distinct tissues in several disorders. Previous studies have reported on the physical properties of gray and white matter, however, these were focused on longitudinal tension tests. Little is known about the differences between gray and white matter in terms of their response to compression. We therefore performed mechanical compression test of the gray and white matter of spinal cords harvested from cows and analyzed the differences between them in response to compression. We conducted compression testing of gray matter and white matter to detect possible differences in the collapse rate. We found that increased compression (especially more than 50% compression) resulted in more severe injuries to both the gray and white matter. The present results on the mechanical differences between gray and white matter in response to compression will be useful when interpreting findings from medical imaging in patients with spinal conditions. Related Articles | Metrics

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Neurotoxic role of interleukin-17 in neural stem cell differentiation after intracerebral hemorrhage Lu Gao , Ping-Ping Li , Tian-Yu Shao, Xiang Mao, Hao Qi, Bing-Shan Wu, Ming Shan, Lei Ye , Hong-Wei Cheng 2020, 15 (7):  1350-1359.  doi: 10.4103/1673-5374.272614 Abstract ( 101 )   PDF (3724KB) ( 257 )   Save Interleukin 17 (IL-17) and its main producer, T cell receptor γδ cells, have neurotoxic effects in the pathogenesis of intracerebral hemorrhage (ICH), aggravating brain injuries. To investigate the correlation between IL-17 and ICH, we dynamically screened serum IL-17 concentrations using enzyme-linked immunosorbent assay and explored the clinical values of IL-17 in ICH patients. There was a significant negative correlation between serum IL-17 level and neurological recovery status in ICH patients (r = –0.498, P < 0.01). To study the neurotoxic role of IL-17, C57BL/6 mice were used to establish an ICH model by injecting autologous blood into the caudate nucleus. Subsequently, the mice were treated with mouse neural stem cells (NSCs) and/or IL-17 neutralizing antibody for 72 hours. Flow cytometry, brain water content detection, Nissl staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling results indicated that NSC transplantation significantly reduced IL-17 expression in peri-hematoma tissue, but there was no difference in T cell receptor γδ cells. Compared with the ICH group, there were fewer apoptotic bodies and more Nissl bodies in the ICH + NSC group and the ICH + NSC + IL-17 group. To investigate the potential effect of IL-17 on directional differentiation of NSCs, we cultured mouse NSCs (NE-4C) alone or co-cultured them with T cell receptor γδ cells, which were isolated from mouse peripheral blood mononuclear cells, for 7 days. The results of western blot assays revealed that IL-17 secreted by T cell receptor γδ cells reduced the differentiation of NSCs into astrocytes and neurons, while IL-17 neutralization relieved the inhibition of directional differentiation into astrocytes rather than neurons. In conclusion, serum IL-17 levels were elevated in the early stage of ICH and were negatively correlated with outcome in ICH patients. Animal experiments and cytological investigations therefore demonstrated that IL-17 probably has neurotoxic roles in ICH because of its inhibitory effects on the directional differentiation of NSCs. The application of IL-17 neutralizing antibody may promote the directional differentiation of NSCs into astrocytes. This study was approved by the Clinical Research Ethics Committee of Anhui Medical University of China (For human study: Approval No. 20170135) in December 2016. All animal handling and experimentation were reviewed and approved by the Institutional Animal Care and Use Committee of Anhui Medical University (approval No. 20180248) in December 2017. Related Articles | Metrics

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Temporal changes in the spinal cord transcriptome after peripheral nerve injury Jian Weng, Dong-Dong Li, Bao-Guo Jiang, Xiao-Feng Yin 2020, 15 (7):  1360-1367.  doi: 10.4103/1673-5374.272618 Abstract ( 112 )   PDF (2298KB) ( 162 )   Save Peripheral nerve injury may trigger changes in mRNA levels in the spinal cord. Finding key mRNAs is important for improving repair after nerve injury. This study aimed to investigate changes in mRNAs in the spinal cord following sciatic nerve injury by transcriptomic analysis. The left sciatic nerve denervation model was established in C57BL/6 mice. The left L4–6 spinal cord segment was obtained at 0, 1, 2, 4 and 8 weeks after severing the sciatic nerve. mRNA expression profiles were generated by RNA sequencing. The sequencing results of spinal cord mRNA at 1, 2, 4, and 8 weeks after severing the sciatic nerve were compared with those at 0 weeks by bioinformatic analysis. We identified 1915 differentially expressed mRNAs in the spinal cord, of which 4, 1909, and 2 were differentially expressed at 1, 4, and 8 weeks after sciatic nerve injury, respectively. Sequencing results indicated that the number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury. These mRNAs were associated with the cellular response to lipid, ATP metabolism, energy coupled proton transmembrane transport, nuclear transcription factor complex, vacuolar proton-transporting V-type ATPase complex, inner mitochondrial membrane protein complex, tau protein binding, NADH dehydrogenase activity and hydrogen ion transmembrane transporter activity. Of these mRNAs, Sgk1, Neurturin and Gpnmb took part in cell growth and development. Pathway analysis showed that these mRNAs were mainly involved in aldosterone-regulated sodium reabsorption, oxidative phosphorylation and collecting duct acid secretion. Functional assessment indicated that these mRNAs were associated with inflammation and cell morphology development. Our findings show that the number and type of spinal cord mRNAs involved in changes at different time points after peripheral nerve injury were different. The number of differentially expressed mRNAs in the spinal cord was highest at 4 weeks after sciatic nerve injury. These results provide reference data for finding new targets for the treatment of peripheral nerve injury, and for further gene therapy studies of peripheral nerve injury and repair. The study procedures were approved by the Ethics Committee of the Peking University People’s Hospital (approval No. 2017PHC004) on March 5, 2017. Related Articles | Metrics

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Recovery of injured corticoreticulospinal tract following cranioplasty in an ischemic stroke patient: a diffusion tensor tractography study Sung Ho Jang , Han Do Lee 2020, 15 (7):  1368-1368.  doi: 10.4103/1673-5374.272625 Abstract ( 71 )   PDF (476KB) ( 162 )   Save Related Articles | Metrics