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15 November 2019, Volume 14 Issue 11 Previous Issue    Next Issue

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Normal tension glaucoma: from the brain to the eye or the inverse? Hui-Jun Zhang, Xue-Song Mi,Kwok-Fai So 2019, 14 (11):  1845-1850.  doi: 10.4103/1673-5374.259601 Abstract ( 125 )   PDF (437KB) ( 122 )   Save Glaucoma is a chronic, progressive optic neuropathy characterized by the loss of peripheral vision first and then central vision. Clinically, normal tension glaucoma is considered a special subtype of glaucoma, in which the patient’s intraocular pressure is within the normal range, but the patient experiences typical glaucomatous changes. However, increasing evidence has challenged the traditional pathophysiological view of normal tension glaucoma, which is based only on intraocular pressure, and breakthroughs in central nervous system imaging may now greatly increase our knowledge about the mechanisms underlying normal tension glaucoma. In this article, we review the latest progress in understanding the pathogenesis of normal tension glaucoma and in developing imaging techniques to detect it, to strengthen the appreciation for the connection between normal tension glaucoma and the brain. Related Articles | Metrics

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Mesenchymal stromal cell therapy for damaged retinal ganglion cells, is gold all that glitters? Fernando Lucas-Ruiz,Caridad Galindo-Romero,David García-Bernal,María Norte-Muñoz,Kristy T. Rodríguez-Ramírez,Manuel Salinas-Navarro,Jose E. Millán-Rivero,Manuel Vidal-Sanz,Marta Agudo-Barriuso 2019, 14 (11):  1851-1857.  doi: 10.4103/1673-5374.259601 Abstract ( 145 )   PDF (1134KB) ( 106 )   Save Mesenchymal stromal cells are an excellent source of stem cells because they are isolated from adult tissues or perinatal derivatives, avoiding the ethical concerns that encumber embryonic stem cells. In preclinical models, it has been shown that mesenchymal stromal cells have neuroprotective and immunomodulatory properties, both of which are ideal for central nervous system treatment and repair. Here we will review the current literature on mesenchymal stromal cells, focusing on bone marrow mesenchymal stromal cells, adipose-derived mesenchymal stromal cells and mesenchymal stromal cells from the umbilical cord stroma, i.e., Wharton’s jelly mesenchymal stromal cells. Finally, we will discuss the use of these cells to alleviate retinal ganglion cell degeneration following axonal trauma. Related Articles | Metrics

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MicroRNAs as biomarkers of diabetic retinopathy and disease progression Bridget Martinez,Philip V. Peplow 2019, 14 (11):  1858-1869.  doi: 10.4103/1673-5374.259602 Abstract ( 94 )   PDF (604KB) ( 129 )   Save Diabetes mellitus, together with its complications, has been increasing in prevalence worldwide. Its complications include cardiovascular disease (e.g., myocardial infarction, stroke), neuropathy, nephropathy, and eye complications (e.g., glaucoma, cataracts, retinopathy, and macular edema). In patients with either type 1 or type 2 diabetes mellitus, diabetic retinopathy is the leading cause of visual impairment or blindness. It is characterized by progressive changes in the retinal microvasculature. The progression from nonproliferative diabetic retinopathy to a more advanced stage of moderate to severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy occurs very quickly after diagnosis of mild nonproliferative diabetic retinopathy. The etiology of diabetic retinopathy is unclear, and present treatments have limited effectiveness. Currently diabetic retinopathy can only be diagnosed by a trained specialist, which reduces the population that can be examined. A screening biomarker of diabetic retinopathy with high sensitivity and specificity would aid considerably in identifying those individuals in need of clinical assessment and treatment. The majority of the studies reviewed identified specific microRNAs in blood serum/plasma able to distinguish diabetic patients with retinopathy from those without retinopathy and for the progresion of the disease from nonproliferative diabetic retinopathy to proliferative diabetic retinopathy. In addition, certain microRNAs in vitreous humor were dysregulated in proliferative diabetic retinopathy compared to controls. A very high percentage of patients with diabetic retinopathy develop Alzheimer’s disease. Thus, identifying diabetic retinopathy by measurement of suitable biomarkers would also enable better screening and treatment of those individuals at risk of Alzheimer’s disease. Related Articles | Metrics

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Diabetic neuropathy research: from mouse models to targets for treatment Vuong M. Pham,Shinji Matsumura,Tayo Katano,Nobuo Funatsu,Seiji Ito 2019, 14 (11):  1870-1879.  doi: 10.4103/1673-5374.259603 Abstract ( 99 )   PDF (970KB) ( 140 )   Save Diabetic neuropathy is one of the most serious complications of diabetes, and its increase shows no sign of stopping. Furthermore, current clinical treatments do not yet approach the best effectiveness. Thus, the development of better strategies for treating diabetic neuropathy is an urgent matter. In this review, we first discuss the advantages and disadvantages of some major mouse models of diabetic neuropathy and then address the targets for mechanism-based treatment that have been studied. We also introduce our studies on each part. Using stem cells as a source of neurotrophic factors to target extrinsic factors of diabetic neuropathy, we found that they present a promising treatment. Related Articles | Metrics

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Potential therapeutic roles of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease Bhaskar C. Das,Somsankar Dasgupta,Swapan K. Ray 2019, 14 (11):  1880-1892.  doi: 10.4103/1673-5374.259604 Abstract ( 142 )   PDF (1871KB) ( 173 )   Save All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid (RA) signaling is extremely important in the central nervous system. Impairment of RA signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired RA signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease (AD), which is pathologically characterized by extra-neuronal accumulation of amyloid plaques (aggregated amyloid-beta) and intra-neurofibrillary tangles (hyperphosphorylated tau protein) in the temporal lobe of the brain. AD is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in AD patients. Deficiency or deprivation of RA in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in AD. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of AD in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in AD. Related Articles | Metrics

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Sigma-2 receptor as a potential therapeutic target for treating central nervous system disorders Kazuki Terada, Keisuke Migita, Yukari Matsushima, Chiaki Kamei 2019, 14 (11):  1893-1894.  doi: 10.4103/1673-5374.259609 Abstract ( 138 )   PDF (567KB) ( 86 )   Save The sigma receptor (Sig-R) was first reported by Martin et al. and was initially classified into the opioid receptor family. However, Sig-R was subsequently found to differ from the opioid receptor in various studies including ligand binding assays and autoradiography analysis. Sig-R is widely distributed in tissues such as central nervous, digestive, immune, and endocrine tissues. There are two types of Sig-R: sigma-1 (Sig-1R) and sigma-2 receptors (Sig-2R). Recent studies reported that each subtype has distinct cellular and physiological functions. Since Hanner et al. successfully cloned the Sig-1R gene, the functions of Sig-1R have been widely evaluated in the fields of cell biology, molecular biology, cancer, immunology, and behavioral neuroscience. Particularly, it has been suggested that Sig-1R activates neurons in the central nervous system (CNS) and contributes to physiological functions such as memory and cranial nerve protection. In contrast, Sig-2R has not been cloned. Sig-2R is thought to be involved in cellular processes related to neuropathy, as pharmacological studies suggested that Sig-2R is widely distributed in the CNS. Recently, Alon et al. identified the gene encoding Sig-2R. This perspective focuses on whether Sig-2R is useful as a therapeutic target for CNS disorders such as Alzheimer’s disease, Parkinson’s disease, and depression, based on the structure of Sig-2R and its role in nerve growth. Related Articles | Metrics

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Therapeutic implications of advanced age at time of spinal cord injury Andrew N.Stewart,John C. Gensel, Bei Zhang 2019, 14 (11):  1895-1896.  doi: 10.4103/1673-5374.259606 Abstract ( 103 )   PDF (340KB) ( 112 )   Save A recent demographic shift towards increased age at time of spinal cord injury (SCI), as well as decreased functional recovery following SCI in older populations, create the need to investigate how age effects SCI pathology and repair. While decreased neuroplasticity or physical strength with age may contribute to functional deficits, work from our lab and others have identified exacerbated acute inflammatory events as contributors to age-dependent secondary injury. Specifically, our recent paper identified that increased production of reactive oxygen species (ROS) from macrophage nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) with age exacerbates secondary injury after SCI. Collectively, we identified ROS as instrumental in worsening functional outcomes following aged SCI and demonstrated that the therapeutic efficacy of ROS based treatments is age-dependent. This short review focuses on the role of age on worsening functional outcomes following SCI and provides a mechanistic overview into how age exaggerates secondary injury. Related Articles | Metrics

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Inducing α-synuclein compaction: a new strategy for inhibiting α-synuclein aggregation? Francisca Pinheiro, Salvador Ventura 2019, 14 (11):  1897-1898.  doi: 10.4103/1673-5374.259608 Abstract ( 104 )   PDF (418KB) ( 89 )   Save Proteins might misfold during translation and folding or even once they are in their native states, due to stochastic fluctuations, destabilizing mutations or cellular stress. Aberrant protein species are usually detected and either refolded or cleared by the protein quality control machinery . When misfolded protein conformers cannot be degraded, they tend to self-assemble to form aggregates, a characteristic of many neurodegenerative diseases. Related Articles | Metrics

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Tubulin glutamylation: a skeleton key for neurodegenerative diseases Siem van der Laan, Geronimo Dubra, Krzysztof Rogowski 2019, 14 (11):  1899-1900.  doi: 10.4103/1673-5374.259611 Abstract ( 136 )   PDF (501KB) ( 139 )   Save Microtubules (MTs) are cytoskeletal elements formed by a non-covalent association of α- and β-tubulin heterodimers. They provide structure and shape to all eukaryotic cells and are implicated in a variety of fundamental cellular processes including cell motility, cell division, mechanotransduction as well as long-distance intracellular cargo transport. In neurons, they constitute the molecular frame that maintains the lengthy axonal projections. In view of the relative size of some axons in the human body, which can reach up to 1 m, the active transport of e.g., vesicles over the MT arrays to the synaptic cleft, is of particular importance. Considering the numerous roles of MTs, it is not surprising that already 30 years ago, impairment of the MT-based system was proposed as a unifying hypothesis for the variable clinical presentations in Alzheimer’s disease. In this context, a key question is how the MT network accommodates all these different functions, often within the same cell? Current view is that every MT-dependent process is executed through the recruitment of a specific set of MT-associated proteins (MAPs) and molecular motors. Thus, it is of fundamental importance to understand how recruitment of these MAPs and motors is regulated. Since many of the MAPs and motors bind to the C-terminal tails of α- and β-tubulin, which are known to protrude from the MT surface, one important mechanism by which MTs may regulate the association of the effector proteins is through posttranslational modifications (PTMs). Related Articles | Metrics

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Protective potential of glucagon like peptide 2 (GLP-2) against the neurodegeneration Antonella Amato, Flavia Mulè 2019, 14 (11):  1901-1902.  doi: 10.4103/1673-5374.259612 Abstract ( 87 )   PDF (675KB) ( 93 )   Save Neurodegeneration consists in loss of neuron specific types, pattern and distribution, leading to progressive dysfunctions of the central nervous system. Neurodegenerative diseases include diverse pathological conditions, among which Alzheimer’s and Parkinson’s diseases are the most prevalent ones. Alzheimer’s disease is known as a growing dementia, characterized by progressive language, memory, and cognitive loss, while Parkinson’s disease is primarily characterized as a motor disorder. Senile plaques, caused by amyloid β peptide, hyperphosphorylated taubased neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of Alzheimer’s disease. Amyloid β oligomer formation is associated with development of reactive oxygen and nitrogen species, inflammation, calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions related with learning and memory. Parkinson’s disease is produced by dopaminergic neuron deterioration in the extrapyramidal tract of the midbrain. Accumulation of α-synuclein proteins (Lewy bodies) in the central, autonomic, and peripheral nervous system is the hallmark of the Parkinson’s disease. The Levy bodies break the neuronal membrane leading to neuronal death through oxidative stress, excitotoxicity, energy failure and neuroinflammation. Related Articles | Metrics

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Antibody-based immunotherapies for Parkinsonian syndromes Lars Tönges,Maria Angela Samis Zella 2019, 14 (11):  1903-1904.  doi: 10.4103/1673-5374.259613 Abstract ( 89 )   PDF (284KB) ( 153 )   Save What is the rationale for immunotherapies in Parkinsonian syndromes (PS)? PS are neurodegenerative diseases which are clinically characterized by a hypokinetic phenotype in combination with additional motor and non-motor symptoms. One major pathological hallmark of all PS consists of a non-physiological detrimental accumulation of protein aggregates which appear intracellularly in neurons and glial cells but also in the extracellular space. Depending on the pathogenic protein, PS can be divided into synucleinopathies, characterized by aggregation of the protein alpha-Synuclein (aSyn), and tauopathies, characterized by aggregation of the protein Tau. Clinical syndromes of synucleinopathies include Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies, and tauopathies include progressive supranuclear palsy (PSP) and corticobasal degeneration. Related Articles | Metrics

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New perspectives in iron chelation therapy for the treatment of Parkinson’s disease Marco T. Nuñez,Pedro Chana-Cuevas 2019, 14 (11):  1905-1906.  doi: 10.4103/1673-5374.259614 Abstract ( 140 )   PDF (403KB) ( 104 )   Save Neurodegenerative diseases with an iron accumulation component: A wide variety of neurological diseases are characterized by the accumulation of iron in different areas of the central nervous system, include Parkinson’s disease, Huntington disease, Alzheimer’s disease, Friedreich’s ataxia, amyotrophic lateral sclerosis, pantothenate kinase-associated neurodegeneration and other neuropathologies associated with brain iron accumulation Related Articles | Metrics

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The role of muscle LIM protein in the nervous system Daniel Terheyden-Keighley, Dietmar Fischer 2019, 14 (11):  1907-1908.  doi: 10.4103/1673-5374.259607 Abstract ( 96 )   PDF (111KB) ( 100 )   Save Unlike the peripheral nervous system (PNS), the central nervous system (CNS) has a low intrinsic regenerative capacity and has mechanisms that actively suppress axon regrowth, for example, glial scarring and myelin inhibition. Even in the PNS, which has the principle ability to regenerate injured axons, functional recovery remains limited, particularly in cases where the nerve target has become unreceptive to re-innervation over time due to an insufficient axonal growth rate . Progress towards robust neuroregenerative therapies depends upon an understanding of the relevant signaling and cytoskeletal proteins that drive and control axon extension. Muscle LIM  protein (MLP), also known as cysteine and glycine-rich protein 3, was recently discovered to be one such protein that is expressed in regenerating rat neurons and whose overexpression can promote the axon regeneration of adult central, and peripheral neurons of different species. Related Articles | Metrics

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Micromechanical adaptation as a treatment for spinal cord injury Veronica Estrada, Hans Werner Müller 2019, 14 (11):  1909-1911.  doi: 10.4103/1673-5374.259605 Abstract ( 100 )   PDF (1068KB) ( 102 )   Save Spinal cord injury: Thus far injury of the spinal cord is incurable and, in the majority of cases, a devastating and life-changing event. The worldwide incidence rate of spinal cord injury (SCI) ranges from 250,000 to 900,000 new cases per year. SCI outcome includes the damage of axons, demyelination of axons, loss of signal transduction, and consequential long-lasting motor and sensory deficits. Additionally, the non-use of muscles can lead to atrophy and joint contractures, thereby further reducing the possibility of recovery. Depending on the spinal level and the severity of the injury, the extent of the damage can vary and spontaneous recovery is possible to varying degrees. There is an enormous number and also a great variety of both experimental approaches and clinical trials for spinal cord trauma. Although the general pathomechanisms of primary and secondary traumatic injury events are known, the complicated multifactorial and multiphasic SCI outcomes have led to only little progress in the development of successful therapeutic treatments to achieve substantial degrees of axonal regeneration and consequently locomotor functional recovery – despite almost 40 years of extensive SCI research. Related Articles | Metrics

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G protein-coupled receptor 37 (GPR37) emerges as an important modulator of adenosinergic transmission in the striatum Xavier Morató, Rodrigo A. Cunha, Francisco Ciruela 2019, 14 (11):  1912-1914.  doi: 10.4103/1673-5374.259610 Abstract ( 93 )   PDF (1470KB) ( 111 )   Save G protein-coupled receptor 37 (GPR37), also known as parkin associated endothelin-like (Pael) receptor, is an orphan G protein-coupled receptor, which suffers a defective parking ubiquitination in autosomal recessive Parkinson’s disease promoting its endoplasmic reticulum aggregation and stress, neurotoxicity and neuronal death. Interestingly, we have demonstrated previously that GPR37 heteromerizes with adenosine A 2A receptor (A 2A R) in the striatum. In addition, we also reported some functional consequences of this direct interaction, whereby GPR37 deletion enhanced striatal A 2A R cell surface expression with a concomitant increase in A 2A R agonist-mediated cAMP accumulation; accordingly, an enhancement of A 2A R agonist-induced catalepsy and antagonist-induced locomotor activity was observed upon GPR37 deletion. Overall, it has been hypothesized that GPR37 might hold a chaperone-like activity controlling A 2A R cell surface targeting and function. However, the precise physiological function of GPR37 still is unidentified. The current findings now provide additional evidence for the role of GPR37 as a repressor of A 2A R function. Thus, while chronic A 2A R antagonist treatment (i.e., SCH58261, 1 mg/kg per day, intraperitoneal administration, 10 days) of mice lacking GPR37 did not affect the striatum-dependent cued learning, it enhanced locomotor sensitization. Moreover, chronic A 2A R blockade boosted striatal long-term depression (LTD) in corticostriatal synapses of GPR37 -/- but not of wild type mice; this observation correlated well with the adenosinergic neurochemical modifications present in GPR37 -/- mice, namely an increased density of A 2A R and decreased levels of adenosine. Overall, GPR37 emerged as key contestant controlling A 2A R function particularly upon chronic A 2A R blockade, thus delineating A 2A R-dependent long-term plastic changes in corticostriatal synapses. Related Articles | Metrics

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Mesenchymal stem cells, implications for pain therapy Elena Trallori, Carla Ghelardini, Lorenzo Di Cesare Mannelli 2019, 14 (11):  1915-1916.  doi: 10.4103/1673-5374.259615 Abstract ( 96 )   PDF (452KB) ( 102 )   Save History and biology of mesenchymal stem cell (MSC): MSCs were firstly described around 1970s by Friedenstein and his collaborators as a subpopulation of colony forming, clonogenic, plastic adherent stromal bone marrow derived cells, with the capacity to regenerate other tissues . Caplan proposed that these mesenchymal cells were “stem” because of their ability to differentiate to any lineage of mesodermal cells. The richest sources of MSCs are bone marrow and adipose tissue, but they can also be isolated from synovial fluid, periosteum, fetal organs, placenta, umbilical cord blood and amniotic fluid. Related Articles | Metrics

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Neurogenesis in the hippocampus of adult humans: controversy “fixed” at last Silene M.A. Lima,Walace Gomes-Leal 2019, 14 (11):  1917-1918.  doi: 10.4103/1673-5374.259616 Abstract ( 130 )   PDF (509KB) ( 104 )   Save The presence of adult neurogenesis in the mammalian brain has been a theme of intense controversy for a long time since the original report by Altman and Das. The scientific community, for about 30 years, has difficulties to accept that progenitor cells give rise to new neurons in some specific regions of the mammalian adult brain, the neurogenic niches. Related Articles | Metrics

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MK-801 attenuates lesion expansion following acute brain injury in rats: a meta-analysis Nan-Xing Yi,Long-Yun Zhou,Xiao-Yun Wang, Yong-Jia Song,Hai-Hui Han,Tian-Song Zhang,Yong-Jun Wang,Qi Shi,Hao Xu,Qian-Qian Liang,Ting Zhang 2019, 14 (11):  1919-1931.  doi: 10.4103/1673-5374.259619 Abstract ( 101 )   PDF (6967KB) ( 38 )   Save OBJECTIVE: To evaluate the efficacy and safety of MK-801 and its effect on lesion volume in rat models of acute brain injury. DATA SOURCES: Key terms were “stroke”, “brain diseases”, “brain injuries”, “brain hemorrhage, traumatic”, “acute brain injury”, “dizocilpine maleate”, “dizocilpine”, “MK-801”, “MK801”, “rat”, “rats”, “rattus” and “murine”. PubMed, Cochrane library, EMBASE, the China National Knowledge Infrastructure, WanFang database, the VIP Journal Integration Platform (VJIP) and SinoMed databases were searched from their inception dates to March 2018. DATA SELECTION: Studies were selected if they reported the effects of MK-801 in  xperimental acute brain injury. Two investigators independently conducted literature screening, data extraction, and methodological quality assessments. OUTCOME MEASURES: The primary outcomes included lesion volume and brain edema. The secondary outcomes included behavioral assessments with the Bederson neurological grading system and the water maze test 24 hours after brain injury. RESULTS:  A total of 52 studies with 2530 samples were included in the systematic review. Seventeen of these studies had a high methodological quality. Overall, the lesion volume (34 studies, n = 966, MD = −58.31, 95% CI: −66.55 to −50.07; P < 0.00001) and degree of cerebral edema (5 studies, n = 75, MD = −1.21, 95% CI: −1.50 to −0.91; P < 0.00001) were significantly decreased in the MK-801 group compared with the control group. MK-801 improved spatial cognition assessed with the water maze test (2 studies, n = 60, MD = −10.88, 95% CI: −20.75 to −1.00; P = 0.03) and neurological function 24 hours after brain injury (11 studies, n = 335, MD = −1.04, 95% CI: −1.47 to −0.60; P < 0.00001). Subgroup analysis suggested an association of reduction in lesion volume with various injury models (34 studies, n = 966, MD = −58.31, 95% CI: −66.55 to −50.07; P = 0.004). Further network analysis showed that 0–1 mg/kg MK-801 may be the optimal dose for treatment in the middle cerebral artery occlusion animal model. CONCLUSION: MK-801 effectively reduces brain lesion volume and the degree of cerebral edema in rat models of experimental acute brain injury, providing a good neuroprotective effect. Additionally, MK-801 has a good safety profile, and its mechanism of action is well known. Thus, MK-801 may be suitable for future clinical trials and applications. Related Articles | Metrics

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Contralateral C7 transfer combined with acellular nerve allografts seeded with differentiated adipose stem cells for repairing upper brachial plexus injury in rats Jian-Tao Yang,Jin-Tao Fang,Liang Li, Gang Chen, Ben-Gang Qin, Li-Qiang Gu 2019, 14 (11):  1932-1940.  doi: 10.4103/1673-5374.259626 Abstract ( 108 )   PDF (5269KB) ( 103 )   Save Nerve grafting has always been necessary when the contralateral C7 nerve root is transferred to treat brachial plexus injury. Acellular nerve allograft is a promising alternative for the treatment of nerve defects, and results were improved by grafts laden with differentiated adipose stem cells. However, use of these tissue-engineered nerve grafts has not been reported for the treatment of brachial plexus injury. The aim of the present study was to evaluate the outcome of acellular nerve allografts seeded with differentiated adipose stem cells to improve nerve regeneration in a rat model in which the contralateral C7 nerve was transferred to repair an upper brachial plexus injury. Differentiated adipose stem cells were obtained from Sprague-Dawley rats and transdifferentiated into a Schwann cell-like phenotype. Acellular nerve allografts were prepared from 15-mm bilateral sections of rat sciatic nerves. Rats were randomly divided into three groups: acellular nerve allograft, acellular nerve allograft + differentiated adipose stem cells, and autograft. The upper brachial plexus injury model was established by traction applied away from the intervertebral foramen with micro-hemostat forceps. Acellular nerve allografts with or without seeded cells were used to bridge the gap between the contralateral C7 nerve root and C5–6 nerve. Histological staining, electrophysiology, and neurological function tests were used to evaluate the effect of nerve repair 16 weeks after surgery. Results showed that the onset of discernible functional recovery occurred earlier in the autograft group first, followed by the acellular nerve allograft + differentiated adipose stem cells group, and then the acellular nerve allograft group; moreover, there was a significant difference between autograft and acellular nerve allograft groups. Compared with the acellular nerve allograft group, compound muscle action potential, motor conduction velocity, positivity for neurofilament and S100, diameter of regenerating axons, myelin sheath thickness, and density of myelinated fibers were remarkably increased in autograft and acellular nerve allograft + differentiated adipose stem cells groups. These findings confirm that acellular nerve allografts seeded with differentiated adipose stem cells effectively promoted nerve repair after brachial plexus injuries, and the effect was better than that of acellular nerve repair alone. This study was approved by the Animal Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University of China (approval No. 2016-150) in June 2016. Related Articles | Metrics

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Hyodeoxycholic acid protects the neurovascular unit against oxygen-glucose deprivation and reoxygenation-induced injury in vitro Chang-Xiang Li,Xue-Qian Wang,Fa-Feng Cheng, Xin Yan, Juan Luo, Qing-Guo Wang 2019, 14 (11):  1941-1949.  doi: 10.4103/1673-5374.259617 Abstract ( 136 )   PDF (7325KB) ( 39 )   Save Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid (HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin and jas-minoidin, HDCA prevents hypoxia-reoxygenation-induced brain injury by suppressing endoplasmic reticulum stress-mediated apoptotic signaling. However, the effects of HDCA in ischemic stroke injury have not yet been studied. Neurovascular unit (NVU) dysfunction occurs in ischemic stroke. Therefore, in this study, we investigated the effects of HDCA on the NVU under ischemic conditions in vitro. We co-cultured primary brain microvascular endothelial cells, neurons and astrocytes using a transwell chamber co-culture system. The NVU was pre-treated with 10.16 or 2.54 μg/mL HDCA for 24 hours before exposure to oxygen-glucose deprivation for 1 hour. The cell counting kit-8 assay was used to detect cell activity. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to assess apoptosis. Enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor-α, and neurotrophic factors, including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Oxidative stress-related factors, such as superoxide dismutase, nitric oxide, malondialdehyde and γ-glutamyltransferase, were measured using kits. Pretreatment with HDCA significantly decreased blood-brain barrier permeability and neuronal apoptosis, significantly increased transendothelial electrical resistance and γ-glutamyltransferase activity, attenuated oxidative stress damage and the release of inflammatory cytokines, and increased brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression. Our findings suggest that HDCA maintains NVU morphological integrity and function by modulating inflammation, oxidation stress, apoptosis, and the expression of neurotrophic factors. Therefore, HDCA may have therapeutic potential in the clinical management of ischemic stroke. This study was approved by the Ethics Committee of Experimental Animals of Beijing University of Chinese Medicine (approval No. BUCM-3-2016040201-2003) in April 2016. Related Articles | Metrics

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The next-generation sphingosine-1 receptor modulator BAF312 (siponimod) improves cortical network functionality in focal autoimmune encephalomyelitis Petra Hundehege,Manuela Cerina,Susann Eichler, Christian Thomas,Alexander M. Herrmann,Kerstin Göbel,Thomas Müntefering,Juncal Fernandez-Orth,Stefanie Bock,Venu Narayanan,Thomas Budde,Erwin-Josef Speckmann,Heinz Wiendl,Anna Schubart,Tobias Ruck,Sven G. Meuth 2019, 14 (11):  1950-1960.  doi: 10.4103/1673-5374.259622 Abstract ( 123 )   PDF (2894KB) ( 142 )   Save Autoimmune diseases of the central nervous system (CNS) like multiple sclerosis (MS) are characterized by inflammation and demyelinated lesions in white and grey matter regions. While inflammation is present at all stages of MS, it is more pronounced in the relapsing forms of the disease, whereas progressive MS (PMS) shows significant neuroaxonal damage and grey and white matter atrophy. Hence, disease-modifying treatments beneficial in patients with relapsing MS have limited success in PMS. BAF312 (siponimod) is a novel sphingosine-1-phosphate receptor modulator shown to delay progression in PMS. Besides reducing inflammation by sequestering lymphocytes in lymphoid tissues, BAF312 crosses the blood-brain barrier and binds its receptors on neurons, astrocytes and oligodendrocytes. To evaluate potential direct neuroprotective effects, BAF312 was systemically or locally administered in the CNS of experimental autoimmune encephalomyelitis mice with distinct grey- and white-matter lesions (focal experimental autoimmune encephalomyelitis using an osmotic mini-pump). Ex-vivo flow cytometry revealed that systemic but not local BAF312 administration lowered immune cell infiltration in animals with both grey and white matter lesions. Ex-vivo voltage-sensitive dye imaging of acute brain slices revealed an altered spatio-temporal pattern of activation in the lesioned cortex compared to controls in response to electrical stimulation of incoming white-matter fiber tracts. Here, BAF312 administration showed partial restore of cortical neuronal circuit function. The data suggest that BAF312 exerts a neuroprotective effect after crossing the blood-brain barrier independently of peripheral effects on immune cells. Experiments were carried out in accordance with German and EU animal protection law and approved by local authorities (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen; 87-51.04.2010.A331) on December 28, 2010. Related Articles | Metrics

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Matrine promotes neural circuit remodeling to regulate motor function in a mouse model of chronic spinal cord injury Norio Tanabe, Tomoharu Kuboyama, Chihiro Tohda 2019, 14 (11):  1961-1967.  doi: 10.4103/1673-5374.259625 Abstract ( 124 )   PDF (2856KB) ( 107 )   Save In chronic phase of spinal cord injury, functional recovery is more untreatable compared with early intervention in acute phase of spinal cord injury. In the last decade, several combination therapies successfully improved motor dysfunction in chronic spinal cord injury. However, their effectiveness is not sufficient. We previously found a new effective compound for spinal cord injury, matrine, which induced axonal growth and functional recovery in acute spinal cord injury mice via direct activation of extracellular heat shock protein 90. Although our previous study clarified that matrine was an activator of extracellular heat shock protein 90, the potential of matrine for spinal cord injury in chronic phase has not been sufficiently evaluated. Thus, this study aimed to investigate whether matrine ameliorates chronic spinal cord injury in mice. Once daily intragastric administration of matrine (100 μmol/kg per day) to spinal cord injury mice were starte at 28 days after injury, and continued for 154 days. Continuous matrine treatment improved hindlimb motor function in chronic spinal cord injury mice. In injured spinal cords of the matrine-treated mice, the density of neurofilament-H-positive axons was increased. Moreover, matrine treatment increased the density of bassoon-positive presynapses in contact with choline acetyltransferase-positive motor neurons in the lumbar spinal cord. These findings suggest that matrine promotes remodeling and reconnection of neural circuits to regulate hindlimb movement. All protocols were approved by the Committee for Animal Care and Use of the Sugitani Campus of the University of Toyama (approval No. A2013INM-1 and A2016INM-3) on May 7, 2013 and May 17, 2016, respectively. Related Articles | Metrics

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Paired associative stimulation improves synaptic plasticity and functional outcomes after cerebral ischemia Yan Hu,Tie-Cheng Guo,Xiang-Yu Zhang,Jun Tian,Yin-Shan Lu 2019, 14 (11):  1968-1976.  doi: 10.4103/1673-5374.259618 Abstract ( 127 )   PDF (2529KB) ( 126 )   Save Paired associative stimulation is a relatively new non-invasive brain stimulation technique that combines transcranial magnetic stimulation and peripheral nerve stimulation. The effects of paired associative stimulation on the excitability of the cerebral cortex can vary according to the time interval between the transcranial magnetic stimulation and peripheral nerve stimulation. We established a model of cerebral ischemia in rats via transient middle cerebral artery occlusion. We administered paired associative stimulation with a frequency of 0.05 Hz 90 times over 4 weeks. We then evaluated spatial learning and memory using the Morris water maze. Changes in the cerebral ultra-structure and synaptic plasticity were assessed via transmission electron microscopy and a 64-channel multi-electrode array. We measured mRNA and protein expression levels of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 in the hippocampus using a real-time polymerase chain reaction and western blot assay. Paired associative stimulation treatment significantly improved learning and memory in rats subjected to cerebral ischemia. The ultra-structures of synapses in the CA1 area of the hippocampus in rats subjected to cerebral ischemia were restored by paired associative stimulation. Long-term potentiation at synapses in the CA3 and CA1 regions of the hippocampus was enhanced as well. The protein and mRNA expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1 increased after paired associative stimulation treatment. These data indicate that paired associative stimulation can protect cognition after cerebral ischemia. The observed effect may be mediated by increases in the mRNA and protein expression of brain-derived neurotrophic factor and N-methyl-D-aspartate receptor 1, and by enhanced synaptic plasticity in the CA1 area of the hippocampus. The animal experiments were approved by the Animal Ethics Committee of Tongji Medical College, Huazhong University of Science & Technology, China (approval No. TJ-A20151102) on July 11, 2015. Related Articles | Metrics

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Silencing Huwe1 reduces apoptosis of cortical neurons exposed to oxygen-glucose deprivation and reperfusion Guo-Qian He,Wen-Ming Xu,Hui-Juan Liao,Chuan Jiang,Chang-Qing Li,Wei Zhang 2019, 14 (11):  1977-1985.  doi: 10.4103/1673-5374.259620 Abstract ( 99 )   PDF (2810KB) ( 124 )   Save HECT, UBA and WWE domain-containing 1 (Huwe1), an E3 ubiquitin ligase involved in the ubiquitin-proteasome system, is widely expressed in brain tissue. Huwe1 is involved in the turnover of numerous substrates, including p53, Mcl-1, Cdc6 and N-myc, thereby playing a critical role in apoptosis and neurogenesis. However, the role of Huwe1 in brain ischemia and reperfusion injury remains unclear. Therefore, in this study, we investigated the role of Huwe1 in an in vitro model of ischemia and reperfusion injury. At 3 days in vitro, primary cortical neurons were transduced with a control or shRNA-Huwe1 lentiviral vector to silence expression of Huwe1. At 7 days in vitro, the cells were exposed to oxygen-glucose deprivation for 3 hours and reperfusion for 24 hours. To examine the role of the c-Jun N-terminal kinase (JNK)/p38 pathway, cortical neurons were pretreated with a JNK inhibitor (SP600125) or a p38MAPK inhibitor (SB203508) for 30 minutes at 7 days in vitro, followed by ischemia and reperfusion. Neuronal apoptosis was assessed by TUNEL assay. Protein expression levels of JNK and p38MAPK and of apoptosis-related proteins (p53, Gadd45a, cleaved caspase-3, Bax and Bcl-2) were measured by western blot assay. Immunofluorescence labeling for cleaved caspase-3 was performed. We observed a significant increase in neuronal apoptosis and Huwe1 expression after ischemia and reperfusion. Treatment with the shRNA-Huwe1 lentiviral vector markedly decreased Huwe1 levels, and significantly decreased the number of TUNEL-positive cells after ischemia and reperfusion. The silencing vector also downregulated the pro-apoptotic proteins Bax and cleaved caspase-3, and upregulated the anti-apoptotic proteins Gadd45a and Bcl-2. Silencing Huwe1 also significantly reduced p-JNK levels and increased p-p38 levels. Our findings show that downregulating Huwe1 affects the JNK and p38MAPK signaling pathways as well as the expression of apoptosis-related genes to provide neuroprotection during ischemia and reperfusion. All animal experiments and procedures were approved by the Animal Ethics Committee of Sichuan University, China in January 2018 (approval No. 2018013). Related Articles | Metrics

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Association between PPARG genetic polymorphisms and ischemic stroke risk in a northern Chinese Han population: a case-control study Yan-Zhe Wang, He-Yu Zhang, Fang Liu, Lei Li, Shu-Min Deng, Zhi-Yi He 2019, 14 (11):  1986-1993.  doi: 10.4103/1673-5374.259621 Abstract ( 121 )   PDF (1201KB) ( 131 )   Save Two common polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARG) gene, rs1801282 and rs3856806, may be important candidate gene loci affecting the susceptibility to ischemic stroke. This case-control study sought to identify the relationship between these two single-nucleotide polymorphisms and ischemic stroke risk in a northern Chinese Han population. A total of 910 ischemic stroke participants were recruited from the First Hospital of China Medical University, Shenyang, China as a case group, of whom 895 completed the study. The 883 healthy controls were recruited from the Health Check Center of the First Hospital of China Medical University, Shenyang, China. All participants or family members provided informed consent. The study protocol was approved by the Ethics Committee of the First Hospital of China Medical University, China on February 20, 2012 (approval No. 2012-38-1). The protocol was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559). Plasma genomic DNA was extracted from all participants and analyzed for rs1801282 and rs3856806 single nucleotide polymorphisms using a SNaPshot Multiplex sequencing assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression to estimate the association between ischemic stroke and a particular genotype. Results demonstrated that the G allele frequency of the PPARG gene rs1801282 locus was significantly higher in the case group than in the control group (P < 0.001). Individuals carrying the G allele had a 1.844 fold increased risk of ischemic stroke (OR = 1.844, 95% CI: 1.286–2.645, P < 0.001). Individuals carrying the rs3856806 T allele had a 1.366 fold increased risk of ischemic stroke (OR = 1.366, 95% CI: 1.077–1.733, P = 0.010). The distribution frequencies of the PPARG gene haplotypes rs1801282-rs3856806 in the control and case groups were determined. The frequency of distribution in the G-T haplotype case group was significantly higher than that in the control group. The risk of ischemic stroke increased to 2.953 times in individuals carrying the G-T haplotype (OR = 2.953, 95% CI: 2.082–4.190, P < 0.001). The rs1801282 G allele and rs3856806 T allele had a multiplicative interaction (OR = 3.404, 95% CI: 1.631–7.102, P < 0.001) and additive interaction (RERI = 41.705, 95% CI: 14.586–68.824, AP = 0.860; 95% CI: 0.779–0.940; S = 8.170, 95% CI: 3.772–17.697) on ischemic stroke risk, showing a synergistic effect. Of all ischemic stroke cases, 86% were attributed to the interaction of the G allele of rs1801282 and the T allele of rs3856806. The effect of the PPARG rs1801282 G allele on ischemic stroke risk was enhanced in the presence of the rs3856806 T allele (OR = 8.001 vs. 1.844). The effect of the rs3856806 T allele on ischemic stroke risk was also enhanced in the presence of the rs1801282 G allele (OR = 2.546 vs. 1.366). Our results confirmed that the G allele of the PPARG gene rs1801282 locus and the T allele of the rs3856806 locus may be independent risk factors for ischemic stroke in the Han population of northern China, with a synergistic effect between the two alleles. Related Articles | Metrics

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Atsttrin reduces lipopolysaccharide-induced neuroinflammation by inhibiting the nuclear factor kappa B signaling pathway Lian Liu,Yuan Qu,Yi Liu,Hua Zhao,He-Cheng Ma,Ahmed Fayyaz Noor,Chang-Jiao Ji,Lin Nie,Meng Si,Lei Cheng 2019, 14 (11):  1994-2002.  doi: 10.4103/1673-5374.259623 Abstract ( 98 )   PDF (4526KB) ( 149 )   Save Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). Atsttrin (2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor α and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor α in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy. The study was approved by the Animal Ethics Committee of Qilu Hospital of Shandong University, China (approval No. KYLL-2015(KS)-088) on February 10, 2015. Related Articles | Metrics

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MicroRNA expression in the hippocampal CA1 region under deep hypothermic circulatory arrest Xiao-Hua Wang,Dong-Xu Yao,Xiu-Shu Luan,Yu Wang,Hai-Xia Liu,Bei Liu,Yang Liu,Lei Zhao,Xun-Ming Ji,Tian-Long Wang 2019, 14 (11):  2003-2010.  doi: 10.4103/1673-5374.253174 Abstract ( 96 )   PDF (2112KB) ( 97 )   Save Using deep hypothermic circulatory arrest, thoracic aorta diseases and complex heart diseases can be subjected to corrective procedures. However, mechanisms underlying brain protection during deep hypothermic circulatory arrest are unclear. After piglet models underwent 60 minutes of deep hypothermic circulatory arrest at 14°C, expression of microRNAs (miRNAs) was analyzed in the hippocampus by microarray. Subsequently, TargetScan 6.2, RNA22 v2.0, miRWalk 2.0, and miRanda were used to predict potential targets, and gene ontology enrichment analysis was carried out to identify functional pathways involved. Quantitative reverse transcription-polymerase chain reaction was conducted to verify miRNA changes. Deep hypothermic circulatory arrest altered the expression of 35 miRNAs. Twenty-two miRNAs were significantly downregulated and thirteen miRNAs were significantly upregulated in the hippocampus after deep hypothermic circulatory arrest. Six out of eight targets among the differentially expressed miRNAs were enriched for neuronal projection (cyclin dependent kinase, CDK16 and SLC1A2), central nervous system development (FOXO3, TYRO3, and SLC1A2), ion transmembrane transporter activity (ATP2B2 and SLC1A2), and interleukin-6 receptor binding (IL6R) – these are the key functional pathways involved in cerebral protection during deep hypothermic circulatory arrest. Quantitative reverse transcription-polymerase chain reaction confirmed the results of microarray analysis. Our experimental results illustrate a new role for transcriptional regulation in deep hypothermic circulatory arrest, and provide significant insight for the development of miRNAs to treat brain injuries. All procedures were approved by the Animal Care Committee of Xuanwu Hospital, Capital Medical University, China on March 1, 2017 (approval No. XW-INI-AD2017-0112). Related Articles | Metrics

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Pain inhibition through transplantation of fetal neuronal progenitors into the injured spinal cord in rats Chary M. Batista,Eric D. Mariano,Camila S. Dale,Alexandre F. Cristante,Luiz R. Britto,Jose P. Otoch,Manoel J. Teixeira,Matthias Morgalla,Guilherme Lepski 2019, 14 (11):  2011-2019.  doi: 10.4103/1673-5374.259624 Abstract ( 104 )   PDF (3943KB) ( 105 )   Save Neuropathic pain after spinal cord injury (SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy; nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells (fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium (sham) or fNSCs extracted from telencephalic vesicles (TV group) or the ventral medulla (VM group) of E/14 embryos. Sensory (von Frey filaments and hot plate) and motor (the Basso, Beattie, Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ~70% of TV and VM cells differentiated into NeuN+ neurons, with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of São Paulo (protocol number 033/14) on March 4, 2016. Related Articles | Metrics

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Etomidate affects the anti-oxidant pathway to protect retinal ganglion cells after optic nerve transection Xuan Zhao,Fang Kuang,Yi-Yan You,Ming-Mei Wu,Si-Wei You 2019, 14 (11):  2020-2024.  doi: 10.4103/1673-5374.259627 Abstract ( 112 )   PDF (1593KB) ( 126 )   Save Our previous studies revealed that etomidate, a non-barbiturate intravenous anesthetic agent, has protective effects on retinal ganglion cells within 7 days after optic nerve transection. Whether this process is related to anti-oxidative stress is not clear. To reveal its mechanism, we established the optic nerve transection injury model by transecting 1 mm behind the left eyeball of adult male Sprague-Dawley rats. The rats received an intraperitoneal injection of etomidate (4 mg/kg) once per day for 7 days. The results showed that etomidate significantly enhanced the number of retinal ganglion cells retrogradely labeled with Fluorogold at 7 days after optic nerve transection. Etomidate also significantly reduced the levels of nitric oxide and malonaldehyde in the retina and increased the level of glutathione at 12 hours after optic nerve transection. Thus, etomidate can protect retinal ganglion cells after optic nerve transection in adult rats by activating an anti-oxidative stress response. The study was approved by the Animal Ethics Committee at Air Force Medical University, China (approval No. 20180305) on March 5, 2018. Related Articles | Metrics