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15 January 2020, Volume 15 Issue 1 Previous Issue    Next Issue

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Classic axon guidance molecules control correct nerve bridge tissue formation and precise axon regeneration Xin-Peng Dun, David B. Parkinson 2020, 15 (1):  6-9.  doi: 10.4103/1673-5374.264441 Abstract ( 111 )   PDF (664KB) ( 121 )   Save The peripheral nervous system has an astonishing ability to regenerate following a compression or crush injury; however, the potential for full repair following a transection injury is much less. Currently, the major clinical challenge for peripheral nerve repair come from long gaps between the proximal and distal nerve stumps, which prevent regenerating axons reaching the distal nerve. Precise axon targeting during nervous system development is controlled by families of axon guidance molecules including Netrins, Slits, Ephrins and Semaphorins. Several recent studies have indicated key roles of Netrin1, Slit3 and EphrinB2 signalling in controlling the formation of new nerve bridge tissue and precise axon regeneration after peripheral nerve transection injury. Inside the nerve bridge, nerve fibroblasts express EphrinB2 while migrating Schwann cells express the receptor EphB2. EphrinB2/EphB2 signalling between nerve fibroblasts and migrating Schwann cells is required for Sox2 upregulation in Schwann cells and the formation of Schwann cell cords within the nerve bridge to allow directional axon growth to the distal nerve stump. Macrophages in the outermost layer of the nerve bridge express Slit3 while migrating Schwann cells and regenerating axons express the receptor Robo1; within Schwann cells, Robo1 expression is also Sox2-dependent. Slit3/Robo1 signalling is required to keep migrating Schwann cells and regenerating axons inside the nerve bridge. In addition to the Slit3/Robo1 signalling system, migrating Schwann cells also express Netrin1 and regenerating axons express the DCC receptor. It appears that migrating Schwann cells could also use Netrin1 as a guidance cue to direct regenerating axons across the peripheral nerve gap. Engineered neural tissues have been suggested as promising alternatives for the repair of large peripheral nerve gaps. Therefore, understanding the function of classic axon guidance molecules in nerve bridge formation and their roles in axon regeneration could be highly beneficial in developing engineered neural tissue for more effective peripheral nerve repair. Related Articles | Metrics

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Axon regeneration induced by environmental enrichment- epigenetic mechanisms 2020, 15 (1):  10-15.  doi: 10.4103/1673-5374.264440 Abstract ( 64 )   PDF (744KB) ( 790 )   Save Environmental enrichment is known to be beneficial for cognitive improvement. In many animal models of neurological disorders and brain injury, EE has also demonstrated neuroprotective benefits in neurodegenerative diseases and in improving recovery after stroke or traumatic brain injury. The exact underlying mechanism for these phenomena has been unclear. Recent findings have now indicated that neuronal activity elicited by environmental enrichment induces Ca2+ influx in dorsal root ganglion neurons results in lasting enhancement of CREB-binding protein-mediated histone acetylation. This, in turn, increases the expression of pro-regeneration genes and promotes axonal regeneration. This mechanism associated with neuronal activity elicited by environmental enrichment-mediated pathway is one of several epigenetic mechanisms which modulate axon regeneration upon injury that has recently come to light. The other prominent mechanisms, albeit not yet directly associated with environmental enrichment, include DNA methylation/demethylation and N6-methyladenosine modification of transcripts. In this brief review, I highlight recent work that has shed light on the epigenetic basis of environmental enrichment-based axon regeneration, and discuss the mechanism and pathways involved. I further speculate on the implications of the findings, in conjunction with the other epigenetic mechanisms, that could be harness to promote axon regeneration upon injury. Related Articles | Metrics

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Angiogenesis and neuronal remodeling after ischemic stroke Masahiro Hatakeyama, Itaru Ninomiya, Masato Kanazawa 2020, 15 (1):  16-19.  doi: 10.4103/1673-5374.264442 Abstract ( 294 )   PDF (298KB) ( 260 )   Save Increased microvessel density in the peri-infarct region has been reported and has been correlated with longer survival times in ischemic stroke patients and has improved outcomes in ischemic animal models. This raises the possibility that enhancement of angiogenesis is one of the strategies to facilitate functional recovery after ischemic stroke. Blood vessels and neuronal cells communicate with each other using various mediators and contribute to the pathophysiology of cerebral ischemia as a unit. In this mini-review, we discuss how angiogenesis might couple with axonal outgrowth/neurogenesis and work for functional recovery after cerebral ischemia. Angiogenesis occurs within 4 to 7 days after cerebral ischemia in the border of the ischemic core and periphery. Post-ischemic angiogenesis may contribute to neuronal remodeling in at least two ways and is thought to contribute to functional recovery. First, new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by vascular endothelial growth factor and laminin/β1-integrin signaling. Second, blood vessels are thought to enhance neurogenesis in three stages: 1) Blood vessels enhance proliferation of neural stem/progenitor cells by expression of several extracellular signals, 2) microvessels support the migration of neural stem/progenitor cells toward the peri-infarct region by supplying oxygen, nutrients, and soluble factors as well as serving as a scaffold for migration, and 3) oxygenation induced by angiogenesis in the ischemic core is thought to facilitate the differentiation of migrated neural stem/progenitor cells into mature neurons. Thus, the regions of angiogenesis and surrounding tissue may be coupled, representing novel treatment targets. Related Articles | Metrics

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The δ-opioid Receptor as a Potential Therapeutic Target for Ischemic Stroke   Kalpana Subedi, Hongmin Wang 2020, 15 (1):  20-24.  doi: 10.4103/1673-5374.264443 Abstract ( 105 )   PDF (425KB) ( 172 )   Save Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels. Despite having advancement in the use of thrombolytic and clot removal medicine, significant numbers of stroke patients are still left out without option for treatment. In this review, we summarize recent research work on the activation of δ-opioid receptor as a strategy for treating ischemic stroke-caused neuronal injury. Moreover, as activation of δ-opioid receptor by a non-peptidic δ-opioid receptor agonist also modulates the expression, maturation and processing of amyloid precursor protein and β-secretase activity, the potential role of these effects on ischemic stroke caused dementia or Alzheimer’s disease are also discussed. Related Articles | Metrics

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Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging Hiroshi Nakanishi 2020, 15 (1):  25-29.  doi: 10.4103/1673-5374.264444 Abstract ( 100 )   PDF (508KB) ( 205 )   Save Interleukin-1β is a potent proinflammatory cytokine that plays a key role in the pathogenesis of the brain aging and diverse range of neurological diseases including Alzheimer’s disease, Parkinson’s disease, stroke and persistent pain. Activated microglia are the main cellular source of interleukin-1β in the brain. Cathepsin B is associated with the production and secretion of interleukin-1β through pyrin domain-containing protein 3 inflammasome-independent processing of procaspase-3 in the phagolysosomes. The leakage of cathepsin B from the endosomal-lysosomal system during aging is associated with the proteolytic degradation of mitochondrial transcription factor A, which can stabilize mitochondrial DNA. Therefore, microglial cathepsin B could function as a major driver for inflammatory brain diseases and brain aging. Orally active and blood-brain barrier-permeable specific inhibitors for cathepsin B can be potentially effective new pharmaceutical interventions against inflammatory brain diseases and brain aging. Related Articles | Metrics

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Highlights of ASS234: a novel and promising therapeutic agent for Alzheimer’s disease therapy Alejandro Romero, José Marco-Contelles, Eva Ramos 2020, 15 (1):  30-35.  doi: 10.4103/1673-5374.262679 Abstract ( 125 )   PDF (336KB) ( 186 )   Save There is no effective treatment to face Alzheimer’s disease complexity. Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression. In this context, N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl)methyl)-N-methylprop- 2-yn-1-amine (ASS234) has been tested achieving promising results. ASS234 has demonstrated to cross the blood-brain barrier in vivo, and a good in silico safety profile being less toxic than donepezil. Besides, ASS234 reversibly inhibits human acetyl- and butyryl-cholinesterase, and irreversibly inhibits human monoamine oxidase A and B. Moreover, this multitarget molecule has antioxidant and neuroprotective properties, and inhibits Αβ1–42 and Αβ1–40 self-aggregation. Inquiring about the mechanism of action, several signaling pathways related to Alzheimer’s disease had been explored showing that ASS234 induces the wingless-type MMTV integration site (Wnt) family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes. Finally, in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus, ameliorating scopolamine- induced learning deficits. Here we gather the information regarding ASS234 evaluated so far, showing its ability to face different targets, necessary to counteract a neurodegenerative disease as complex as the Alzheimer’s disease. Related Articles | Metrics

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Stem cell therapy for Parkinson’s disease: safety and modeling Theo Stoddard-Bennett, Renee Reijo Pera 2020, 15 (1):  36-40.  doi: 10.4103/1673-5374.264446 Abstract ( 130 )   PDF (354KB) ( 252 )   Save For decades, clinicians have developed medications and therapies to alleviate the symptoms of Parkinson’s disease, but no treatment currently can slow or even stop the progression of this localized neurodegeneration. Fortunately, sparked by the genetic revolution, stem cell reprogramming research and the advancing capabilities of personalization in medicine enable forward-thinking to unprecedented patient-specific modeling and cell therapies for Parkinson’s disease using induced pluripotent stem cells (iPSCs). In addition to modeling Parkinson’s disease more accurately than chemically-induced animal models, patient-specific stem cell lines can be created, elucidating the effects of genetic susceptibility and sub-populations’ differing responses to in vitro treatments. Sourcing cell therapy with iPSC lines provides ethical advantages because these stem cell lines do not require the sacrifice of human zygotes and genetically-specific drug trails can be tested in vitro without lasting damage to patients. In hopes of finally slowing the progression of Parkinson’s disease or re-establishing function, iPSC lines can ultimately be corrected with gene therapy and used as cell sources for neural transplantation for Parkinson’s disease. With relatively localized neural degeneration, similar to spinal column injury, Parkinson’s disease presents a better candidacy for cell therapy when compared to other diffuse degeneration found in Alzheimer’s or Huntington’s Disease. Neurosurgical implantation of pluripotent cells poses the risk of an innate immune response and tumorigenesis. Precautions, therefore, must be taken to ensure cell line quality before transplantation. While cell quality can be quantified using a number of assays, a yielding a high percentage of therapeutically relevant dopaminergic neurons, minimal de novo genetic mutations, and standard chromosomal structure is of the utmost importance. Current techniques focus on iPSCs because they can be matched with donors using human leukocyte antigens, thereby reducing the severity and risk of immune rejection. In August of 2018, researchers in Kyoto, Japan embarked on the first human clinical trial using iPSC cell therapy transplantation for patients with moderate Parkinson’s disease. Transplantation of many cell sources has already proven to reduce Parkinson’s disease symptoms in mouse and primate models. Here we discuss the history and implications for cell therapy for Parkinson’s disease, as well as the necessary safety standards needed for using iPSC transplantation to slow or halt the progression of Parkinson’s disease. Related Articles | Metrics

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Selective serotonin reuptake inhibitors and Alzheimer’s disease Bernadette Mdawar, Elias Ghossoub, Rita Khoury 2020, 15 (1):  41-46.  doi: 10.4103/1673-5374.264445 Abstract ( 94 )   PDF (867KB) ( 216 )   Save Given the failure to develop disease-modifying therapies for Alzheimer’s disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention. Related Articles | Metrics

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tRNA cleavage: a new insight Sherif Rashad, Kuniyasu Niizuma, Teiji Tominaga 2020, 15 (1):  47-52.  doi: 10.4103/1673-5374.264447 Abstract ( 157 )   PDF (378KB) ( 242 )   Save Over the past decades, tRNA was found to be a rich hub of RNA modifications such as 1-methyladenosine and 5-methycytosine modifications and others, holding more than half of all modifications occurring in RNA molecules. Moreover, tRNA was discovered to be a source of various small noncoding RNA species, such as the stress induced angiogenin cleaved tRNA halves (tiRNA) or the miRNA like tRNA derived fragments. tRNA cleavage under stress was fist discovered in bacteria and later was found to be conserved across different species, including mammals. Under cellular stress conditions, tRNA undergoes conformational changes and angiogenin cleaves it into 3′ and 5′ halves. 5′tiRNA halves were shown to repress protein translations. tRNA cleavage is thought of to be a cytoprotective mechanism by which cells evade apoptosis, however some data hints to the opposite; that tiRNA are cytotoxic or at least related to apoptosis initiation. tRNA cleavage also was shown to be affected by tRNA modifications via different enzymes in the cytosol and mitochondria. In this review, we will highlight the biology of tRNA cleavage, show the evidence of it being cytoprotective or a marker of cell death and shed a light on its role in disease models and human diseases as well as possible future directions in this field of RNA research. Related Articles | Metrics

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Modulation of lysophosphatidic acid (LPA) receptor activity: the key to successful neural regeneration? Isabel Gross, Anja U. Bräuer 2020, 15 (1):  53-54.  doi: 10.4103/1673-5374.264452 Abstract ( 102 )   PDF (559KB) ( 168 )   Save The central nervous system (CNS) is characterized by a remarkably elaborate cellular architecture comprising large numbers of glial and neuronal cells with enormous functional diversity, organized into highly complex and specific networks. During development, the various neural cell types must first be correctly specified, then assume their appropriate positions through carefully choreographed cellular migration, and finally establish and refine their functional connections, often over long distances. The end result of all these processes is an extraordinarily intricate anatomical structure, able to receive, integrate, and store information and orchestrate appropriate responses. Related Articles | Metrics

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Blood extracellular vesicles (EVs) of central nervous system origin: a window into the brain Cristina Agliardi, Mario Clerici 2020, 15 (1):  55-56.  doi: 10.4103/1673-5374.264454 Abstract ( 80 )   PDF (669KB) ( 198 )   Save Extracellular vesicles (EVs) are heterogeneous nano-sized vesicles of endocytic origin shed into blood and other body fluids such as urine, saliva, seminal fluid, ascites, amniotic liquid, synovial fluid, breast milk and cerebrospinal fluid (CSF) by quite all cell types. EVs actively contribute to intercellular communication as they carry bioactive molecules that are selectively incorporated by the originating cell and are delivered to recipient cells over long and short distances (Simons and Raposo, 2009). EVs can be divided into three main groups according to their size and cellular origin: 1) exosomes (40–120 nm), that have an endocytic origin and are formed by inward budding of the limiting membrane of multivescicular bodies, which fuse with the plasma membrane and release exosomes into the extracellular space; 2) microvesicles (50–1000 nm), budding directly off the plasma membrane; 3) apoptotic bodies (> 1000 nm), which are released during apoptosis. Besides originating via distinct processes, different subtypes of EVs carry different proteins within their membrane and luminal compartments that reflect the phenotype of the tissue of origin. Related Articles | Metrics

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The plasticity of plasticity: lesson from remote microglia induced by focal central nervous system injury Maria Teresa Viscomi 2020, 15 (1):  57-58.  doi: 10.4103/1673-5374.264448 Abstract ( 103 )   PDF (172KB) ( 261 )   Save The last decades have represented an important season in the re-conceptualization of brain plasticity, especially in extending the concept at events occurring beyond the developmental stage and in demonstrating the profound impact of these changes on so-called spontaneous recovery after central nervous system (CNS) injuries. The study of the cellular, molecular, functional and structural mechanisms involved in brain plasticity has clearly emphasized the multitude of players engaged in this phenomenon, leading to the conceptualization that non-neuronal cells and non-neuronal mechanisms intervene in these changes and orchestrate some of the responses observed (Werner and Stevens, 2015). Among the different non-neuronal cells and non-neuronal substrates of injury-induced plasticity is becoming increasingly recognized that microglia drive a series of intrinsic CNS responses after damage (Sandvig et al., 2018; Bisicchia et al., 2019). Interestingly, the modulatory influence of microglia on brain after injury constitutes a subset of the broader brain plasticity phenomena, defined “plasticity of plasticity” (Banati, 2002). The term well describes the great capacity of microglia in modifying their morphology and their transcriptional identity in response to environment alteration/injury. The responses of microglia, like the other CNS cells, are not linear, compartmentalized, or binary, but are multifaceted, finely tuned by the extrinsic and intrinsic factors such as the nature of the stimulus, the extracellular environment and the molecular repertoire that is involved in the response and the prior state of the cells Related Articles | Metrics

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Study of alpha-synuclein fibrillation: state of the art and expectations Francesca Longhena, Gaia Faustini, Arianna Bellucci 2020, 15 (1):  59-60.  doi: 10.4103/1673-5374.264453 Abstract ( 209 )   PDF (193KB) ( 215 )   Save Since the discovery of the presence of fibrillary forms of α-synuclein (α-syn) in Lewy bodies (LB) and Lewy neurites in the brain of patients affected by Parkinson’s disease (PD) and dementia with LB, great effort has been dedicated to study the features of α-syn fibrillation. In parallel, the pathological relevance of the different toxic forms of α-syn has been also matter of investigation. In the last twenty years, scientists have been able to single out that α-syn fibrillation initiates pathological mechanisms that by contributing to or triggering neurodegeneration/neuroinflammation, may lead to PD pathogenesis. This notwithstanding, we still ignore the reasons why α-syn shifts from its natively unfolded conformation to toxic oligomeric and fibrillary forms. The chameleonic nature of monomeric α-syn, and the extremely polymorphic characteristics of aggregated strains, renders it difficult to picture the real nature of α-syn fibrils, their exact composition and formation dynamics. Recently, sophisticated biophysical methods and microscopy techniques have been exploited to study α-syn fibrillation. Here, we provide an overview of the most relevant advancement in our understanding of α-syn fibrils formation and conformation. Nonetheless, numerous techniques and patient- derived experimental models still need to be optimized to actively disclose causes and characteristics of α-syn fibrillation in disease-specific cellular milieux. Related Articles | Metrics

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In vivo bioluminescence imaging to elucidate stem cell graft differentiation Stefanie Vogel, Mathias Hoehn, Markus Aswendt 2020, 15 (1):  61-62.  doi: 10.4103/1673-5374.264449 Abstract ( 86 )   PDF (266KB) ( 149 )   Save Neurological disorders including neurodegeneration (e.g., Alzheimer’s disease and Parkinson’s disease) and acute injuries (e.g., stroke and traumatic brain injury) are the leading cause group of disability-adjusted life years and the second leading cause group of deaths. Different to other tissues, the adult brain retains only a very limited repair potential. Adult neurogenesis, the lifelong generation of new neurons, declines with age and in degenerative diseases, such as Alzheimer’s disease. Nevertheless, independently of age, the proliferation and migration of endogenous stem cells is stimulated after brain injuries and might be related to recovery processes (Adamczak et al., 2017). The limited number of endogenous stem cells during adulthood is one of the major limitations for an efficient regeneration of the injury affected brain regions. Therefore, the transplantation of neural stem or progenitor cells (NSCs/NPCs) is extensively studied in mouse models and applied in first clinical trials with the aim to replace dysfunctional or lost neural cells and thus to restore brain function. Long-term survival and differentiation of engrafted NSCs/NPCs, synaptic integration, and projections to distant brain regions, as well as behavioral improvements are promising observations in numerous pre-clinical studies (Grade and Gotz, 2017). Transplanted stem cells initiate a complex series of potentially pro-regenerative processes with an individual time profile as it was shown by in vivo molecular imaging Related Articles | Metrics

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Periostin in cerebrovascular disease Fumihiro Kawakita, Hidenori Suzuki 2020, 15 (1):  63-64.  doi: 10.4103/1673-5374.264456 Abstract ( 103 )   PDF (234KB) ( 161 )   Save Cerebrovascular diseases, which include ischemic and hemorrhagic strokes, remain serious conditions with high mortality and disability worldwide (He et al., 2018). Ischemic stroke accounts for around 80% of all strokes (He et al., 2018). Hemorrhagic stroke consisting of intracerebral hemorrhage and subarachnoid hemorrhage (SAH) occurs less frequently but may cause poorer outcomes than ischemic stroke (Ji et al., 2017; Luo et al., 2018). It is also well known that aneurysmal SAH may have delayed cerebral ischemia (DCI): thus aneurysmal SAH has both characteristics of hemorrhagic and ischemic strokes (Kanamaru et al., 2019). In spite of enormous efforts to improve outcomes, no conclusive treatment exists thus far, once stroke is completed. Related Articles | Metrics

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Pannexin 1-based channels activity as a novel regulator of multiple sclerosis progression Fernando C. Ortiz, Carlos Puebla 2020, 15 (1):  65-66.  doi: 10.4103/1673-5374.264450 Abstract ( 80 )   PDF (166KB) ( 249 )   Save MS is a neurodegenerative disease affecting around 2.5 million people worldwide, representing the second cause of disabilities in the young adult population. MS is a demyelinating pathology which originates in the autoimmune attack of T and B lymphocytes against myelin. This lack of myelin leads, in turn, to axonal degeneration, neuronal death and the consequent neurological disabilities (Franklin and Ffrench-Constant, 2017). A main hallmark of MS is a preserved local neuroinflammatory environment. It is now acknowledged that this persistent inflammatory scenario is a central and common condition in almost all neurodegenerative pathologies (as in Parkinson’s and Alzheimer’s diseases, among others) controlling and modulating the regulatory responses of the system to the triggering insult. In the case of MS, this original insult corresponds to the loss of myelin (Chitnis and Weiner, 2017; Franklin and Ffrench-Constant, 2017). Of particular interest for the understanding of MS progression, is how and when surrounded pro- and anti-inflammatory cytokines and chemokines modulate cross-glial communication in demyelinated lesions. After a demyelinated insult there is an -unfortunately deficient or incomplete- spontaneous myelin repair process (i.e., remyelination), characterized by the highly interdependent function of microglia, astrocytes and oligodendroglia, the latest corresponding to cells responsible for the formation of myelin in the central nervous system (CNS) (Chitnis and Weiner, 2017; Franklin and Ffrench-Constant, 2017). For instance, it is known that signaling molecules released by microglia induce the activation of astrocytes and promote differentiation of oligodendrocytes in demyelinated areas (Franklin and Ffrench-Constant, 2017). Similarly, astrocyte activity and secretion can promote oligodendrocyte maturation (Franklin and Ffrench-Constant, 2017). In the complex cellular interaction observed in demyelinated lesions, connexin (Cx)-based channels and hemichannels has been pointed out as a major components underlying glial communication (Vejar et al., 2018). However, less attention has been paid to the putative role of pannexin (Panx)- based channels, a functional equivalent of Cxs, usually involved in inflammatory processes, particularly in the CNS. Here we discuss evidence supporting a role of pannexin-based channels on the progression of MS that, we believe, deserves further investigation. Related Articles | Metrics

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Combining fatty acid amide hydrolase (FAAH) inhibition with peroxisome proliferator-activated receptor (PPAR) activation: a new potential multi-target therapeutic strategy for the treatment of Alzheimer’s disease Leonardo Brunetti, Antonio Laghezza, Fulvio Loiodice, Paolo Tortorella, Luca Piemontese 2020, 15 (1):  67-68.  doi: 10.4103/1673-5374.264458 Abstract ( 144 )   PDF (193KB) ( 271 )   Save Alzheimer’s disease (AD) is a widespread pathology described for the first time by Aloïs Alzheimer in 1907. It can be classified as a neurodegenerative disease consisting in a progressive loss of memory and cognitive functions, whose prevalence is estimated to grow due to the increasing life expectancies all over the world. To date, the only treatments available for this disease are symptomatic and no actual effective cure is available. The main effect of the drugs commonly used in therapeutic protocols is to temporarily delay the onset of the disease and to slightly improve the patients’ cognitive capabilities Related Articles | Metrics

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Excitatory synapse impairment and mitochondrial dysfunction in Huntington’s disease: heat shock factor 1 (HSF1) converging mechanisms Nicole Zarate, Rocio Gomez-Pastor 2020, 15 (1):  69-70.  doi: 10.4103/1673-5374.264459 Abstract ( 121 )   PDF (363KB) ( 198 )   Save Heat shock factor 1 (HSF1) is abnormally degraded in Huntington’s disease (HD): HD is a neurodegenerative disorder characterized by severe cognitive and motor impairments. HD is caused by a CAG repeat expansion within exon 1 of the huntingtin (HTT) gene (The Huntington’s Disease Collaborative Research Group, 1993). These expansions lead to the production of an aberrant mutant huntingtin protein (mHTT) that is prone to misfolding and aggregation. Expression and aggregation of mHTT is present in virtually all cell types in the body but preferentially affects medium spiny neurons of the striatum, a brain region that controls movement and some forms of cognition. Accumulation of mHTT leads to, but not only, transcriptional dysregulation, DNA damage, mitochondrial dysfunction and excitatory synaptic failure ultimately causing neuronal death. However, the molecular mechanisms by which mHTT exerts these defects are still unclear. Related Articles | Metrics

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The multifaceted potential of the lipid transmitter oleoylethanolamide to treat alcohol-induced neuroinflammation and alcohol use disorders#br# Laura Orio 2020, 15 (1):  71-72.  doi: 10.4103/1673-5374.264457 Abstract ( 92 )   PDF (131KB) ( 262 )   Save Is there a need for new pharmacotherapies to treat alcohol use disorders (AUDs)? AUD is a highly prevalent condition in the world population that causes medical, psychological, personal, social and economic problems. The most severe dimension of AUDs is alcohol dependence, a condition in which individuals lose control over alcohol intake despite the negative consequences. Although some medications have been approved for this purpose, existing pharmacotherapies are not effective for all people due to the heterogeneity of AUDs. Current approved medications include: Disulfiram (Antabuse®), which induces an aversion to drink by increasing alcohol metabolism-derived acetaldehyde; Naltrexone (ReVia®, Vivitrol®), a competitive opioid antagonist for μ-receptors that decreases heavy drinking and prevents relapse; Acamprosate (Campral®), an indirect partial agonist at N-methyl-D-aspartic acid glutamate receptors and antagonist at metabotropic glutamate receptors that is used to prevent relapse in detoxified alcoholics. Strong efforts to develop new medication are ongoing, with multiple pharmacological targets being explored. Whereas initial medical development for AUDs focused on the binge/intoxicating state of addiction, current challenges involve finding new targets for the craving and withdrawal/ negative emotional states of addictive behaviour. Thus, extensive research is currently looking for new drugs that correct the dysfunction of the reward and stress systems by improving the motivational signs of withdrawal, which are a hallmark of alcohol dependence. Some new targets, such as γ-aminobutyric acid or glucocorticoid receptors, have shown their efficacy not only in preclinical models but also in human laboratory models (Gabapentin and Mifeprestone, respectively) (Koob and Mason, 2016). Related Articles | Metrics

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Nicotine-induced dopamine plasticity: a gateway to neurotransmitter replacement? I-Chi Lai, Davide Dulcis 2020, 15 (1):  73-74.  doi: 10.4103/1673-5374.264451 Abstract ( 139 )   PDF (282KB) ( 132 )   Save Nicotine, the principal neuroactive component of tobacco, acts on the reward systems of smokers, inducing addiction. Experimental evidence indicates that nicotine-induced addiction alters the activity of dopaminergic neurons within reward-processing brain centers. The effect of developmental nicotine exposure on neuroplasticity of identified reward neurocircuitry in the adult is finally emerging and begins to be understood at the molecular, cellular, and behavioral level Related Articles | Metrics

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Mesenchymal stem cells secretome: current trends and future challenges Fábio G. Teixeira, António J. Salgado 2020, 15 (1):  75-77.  doi: 10.4103/1673-5374.264455 Abstract ( 122 )   PDF (327KB) ( 191 )   Save Mesenchymal stem cells (MSCs) secretome: a good candidate for medical biotechnology? Medical biotechnology is currently defined as the application of biotechnological tools for producing multiple technologies and products to health care, becoming an important bridge between different fields, namely neuroscience, regenerative medicine, pharmacology and bio-engineering (Pham, 2018). The use and manipulation of stem cells can potentially represent a medical biotechnology breakthrough that brings regenerative medicine to a new era. Actually, over the last decade, the use of stem cells has remarkably been proposed as a regenerative tool, and within it, MSCs have emerged as a promising therapeutic option. As a consequence, they currently represent an effective tool in the treatment of several diseases due to their tissue protective and reparative mechanisms (Phelps et al., 2018). Indeed, MSCs are the most frequently stem cell population used in clinical trials (as of the end of 2018, a total of 861 trials were registered according to the US National Institute of Health – https://clinicaltrials.gov), presenting key advantages such as (1) be isolated from a patient and used for autologous transplantation; (2) not divide uncontrollably and form teratomas; and (3) have the capability to differentiate into multiple lineages (Kusuma et al., 2017). The initial therapeutic rationale of the use of MSCs in regenerative medicine as mostly attributed to their capability of homing to injury sites and differentiates into different cell types, leading to tissue repair. Although promising, this theory was revisited at the beginning of the 20th century when, for the first time, Gnecchi and colleagues revealed that MSCs mediated its therapeutical effects by the secretion and release of trophic molecules, nowadays known as secretome (Gnecchi et al., 2005). Indeed, cell tracking analysis has revealed that when transplanted, MSCs (and stem cells in general) do not commonly become a part of the injured site, whereby accumulating pieces of evidence indicate that the secretome is considered the primary attribute of MSC-mediated repair and regeneration (Teixeira et al., 2013). Related Articles | Metrics

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Characterization of astrocytes and microglial cells in the hippocampal CA1 region after transient focal cerebral ischemia in rats treated with Ilexonin A Ai-Ling Xu, Guan-Yi Zheng, Hui-Ying Ye, Xiao-Dong Chen, Qiong Jiang 2020, 15 (1):  78-85.  doi: 10.4103/1673-5374.264465 Abstract ( 128 )   PDF (1003KB) ( 225 )   Save Ilexonin A is a compound isolated from the root of Ilex pubescens, a traditional Chinese medicine. Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the peri-infarct area after ischemia. However, the effects of ilexonin A on astrocytes and microglia in the infarct-free region of the hippocampal CA1 region remain unclear. Focal cerebral ischemia models were established by 2-hour occlusion of the middle cerebral artery in rats. Ilexonin A (20, 40 or 80 mg/kg) was administered immediately after ischemia/reperfusion. The astrocyte marker glial fibrillary acidic protein, microglia marker Iba-1, neural stem cell marker nestin and inflammation markers were detected by immunohistochemistry and western blot assay. Expression levels of tumor necrosis factor-α and interleukin 1β were determined by enzyme linked immunosorbent assay in the hippocampal CA1 tissue. Astrocytes were activated immediately in progressively increasing numbers from 1, 3, to 7 days post-ischemia/reperfusion. The number of activated astrocytes further increased in the hippocampal CA1 region after treatment with ilexonin A. Microglial cells remained quiescent after ischemia/ reperfusion, but became activated after treatment with ilexonin A. Ilexonin A enhanced nestin expression and reduced the expression of tumor necrosis factor-α and interleukin 1β in the hippocampus post-ischemia/reperfusion. The results of the present study suggest that ilexonin A has a neuroprotective effect in the hippocampus after ischemia/reperfusion, probably through regulating astrocytes and microglia activation, promoting neuronal stem cell proliferation and reducing the levels of pro-inflammatory factors. This study was approved by the Animal Ethics Committee of the Fujian Medical University Union Hospital, China. Related Articles | Metrics

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Single-nucleotide polymorphism screening and RNA sequencing of key messenger RNAs associated with neonatal hypoxic-ischemia brain damage Liu-Lin Xiong, Lu-Lu Xue, Mohammed Al-Hawwas, Jin Huang, Rui-Ze Niu, Ya-Xin Tan, Yang Xu, Ying-Ying Su, Jia Liu, Ting-Hua Wang 2020, 15 (1):  86-95.  doi: 10.4103/1673-5374.264469 Abstract ( 158 )   PDF (1773KB) ( 339 )   Save A single-nucleotide polymorphism (SNP) is an alteration in one nucleotide in a certain position within a genome. SNPs are associated with disease susceptibility. However, the influences of SNPs on the pathogenesis of neonatal hypoxic-ischemic brain damage remain elusive. Seven- day-old rats were used to establish a hypoxic ischemic encephalopathy model. SNPs and expression profiles of mRNAs were analyzed in hypoxic ischemic encephalopathy model rats using RNA sequencing. Genes exhibiting SNPs associated with hypoxic ischemic encephalopathy were identified and studied by gene ontology and pathway analysis to identify their possible involvement in the disease mechanism. We identified 89 up-regulated genes containing SNPs that were mainly located on chromosome 1 and 2. Gene ontology analysis indicated that the up-regulated genes containing SNPs are mainly involved in angiogenesis, wound healing and glutamatergic synapse and biological processing of calcium-activated chloride channels. Signaling pathway analysis indicated that the differentially expressed genes play a role in glutamatergic synapses, long-term depression and oxytocin signaling. Moreover, intersection analysis of high throughput screening following PubMed retrieval and RNA sequencing for SNPs showed that CSRNP1, DUSP5 and LRRC25 were most relevant to hypoxic ischemic encephalopathy. Significant up-regulation of genes was confirmed by quantitative real-time polymerase chain reaction analysis of oxygen-glucose-deprived human fetal cortical neurons. Our results indicate that CSRNP1, DUSP5 and LRRC25, containing SNPs, may be involved in the pathogenesis of hypoxic ischemic encephalopathy. These findings indicate a novel direction for further hypoxic ischemic encephalopathy research. This animal study was approved on February 5, 2017 by the Animal Care and Use Committee of Kunming Medical University, Yunnan Province, China (approval No. kmmu2019038). Cerebral tissue collection from a human fetus was approved on September 30, 2015 by the Ethics Committee of Kunming Medical University, China (approval No. 2015-9). Related Articles | Metrics

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Sevoflurane plays a reduced role in cognitive impairment compared with isoflurane: limited effect on fear memory retention Ying Du, Xiang-Dan Gong, Xin Fang, Fang Xing, Tian-Jiao Xia, Xiao-Ping Gu 2020, 15 (1):  96-102.  doi: 10.4103/1673-5374.264468 Abstract ( 261 )   PDF (704KB) ( 122 )   Save Isoflurane and sevoflurane are both inhalation anesthetics, but in clinical application, sevoflurane has been considered to be less suitable for long-term anesthesia because of its catabolic compounds and potential nephrotoxicity. Nevertheless, recent studies have shown that these two inhalation anesthetics are similar in hepatorenal toxicity, cost, and long-term anesthetic effect. Moreover, sevoflurane possibly has less cognitive impact on young mice. In this study, C57BL/6 mice aged 8–10 weeks were exposed to 1.2% isoflurane or 2.4% sevoflurane for 6 hours. Cognitive function and memory were examined in young mice using the novel object recognition, contextual fear conditioning, and cued-fear extinction tests. Western blot assay was performed to detect expression levels of D1 dopamine receptor, catechol-O-methyltransferase, phospho-glycogen synthase kinase-3β, and total glycogen synthase kinase-3β in the hippocampus. Our results show that impaired performance was not detected in mice exposed to sevoflurane during the novel object recognition test. Contextual memory impairment in the fear conditioning test was shorter in the sevoflurane group than the isoflurane group. Long-term sevoflurane exposure did not affect memory consolidation, while isoflurane led to memory consolidation and reduced retention. Downregulation of hippocampal D1 dopamine receptors and phosphorylated glycogen synthase kinase-3β/total glycogen synthase kinase-3β and upregulation of catechol-O-methyltransferase may be associated with differing memory performance after exposure to isoflurane or sevoflurane. These results confirm that sevoflurane has less effect on cognitive impairment than isoflurane, which may be related to expression of D1 dopamine receptors and catechol-O-methyltransferase and phosphorylation of glycogen synthase kinase-3β in the hippocampus. This study was approved by the Institutional Animal Care and Use Committee, Nanjing University, China on November 20, 2017 (approval No. 20171102). Related Articles | Metrics

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Bioinformatic identification of key candidate genes and pathways in axon regeneration after spinal cord injury in zebrafish Jia-He Li, Zhong-Ju Shi, Yan Li, Bin Pan, Shi-Yang Yuan, Lin-Lin Shi, Yan Hao, Fu-Jiang Cao, Shi-Qing Feng 2020, 15 (1):  103-111.  doi: 10.4103/1673-5374.264460 Abstract ( 260 )   PDF (1994KB) ( 240 )   Save Zebrafish and human genomes are highly homologous; however, despite this genomic similarity, adult zebrafish can achieve neuronal proliferation, regeneration and functional restoration within 6–8 weeks after spinal cord injury, whereas humans cannot. To analyze differentially expressed zebrafish genes between axon-regenerated neurons and axon-non-regenerated neurons after spinal cord injury, and to explore the key genes and pathways of axonal regeneration after spinal cord injury, microarray GSE56842 was analyzed using the online tool, GEO2R, in the Gene Expression Omnibus database. Gene ontology and protein-protein interaction networks were used to analyze the identified differentially expressed genes. Finally, we screened for genes and pathways that may play a role in spinal cord injury repair in zebrafish and mammals. A total of 636 differentially expressed genes were obtained, including 255 up-regulated and 381 down-regulated differentially expressed genes in axon-regenerated neurons. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment results were also obtained. A protein-protein interaction network contained 480 node genes and 1976 node connections. We also obtained the 10 hub genes with the highest correlation and the two modules with the highest score. The results showed that spectrin may promote axonal regeneration after spinal cord injury in zebrafish. Transforming growth factor beta signaling may inhibit repair after spinal cord injury in zebrafish. Focal adhesion or tight junctions may play an important role in the migration and proliferation of some cells, such as Schwann cells or neural progenitor cells, after spinal cord injury in zebrafish. Bioinformatic analysis identified key candidate genes and pathways in axonal regeneration after spinal cord injury in zebrafish, providing targets for treatment of spinal cord injury in mammals. Related Articles | Metrics

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Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson’s disease Jiao-Tian Xu, Yuan Qian, Wei Wang, Xiao-Xiang Chen, Yang Li, Yu Li, Zhi-Yong Yang, Xiao-Bin Song, Di Lu, Xing-Li Deng 2020, 15 (1):  112-119.  doi: 10.4103/1673-5374.264470 Abstract ( 154 )   PDF (2246KB) ( 196 )   Save Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson’s disease, but its specific mechanism of action is still unclear. Stromal cell-derived factor-1 and its receptor, chemokine receptor 4 (CXCR4), are important regulators of cell migration. We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson’s disease. A Parkinson’s disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway, and then treated with 5 μL of neural stem cell suspension (1.5 × 104/L) in the right substantia nigra. Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation. Parkinson-like behavior in rats was detected using apomorphine-induced rotation. Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase, CXCR4, and stromal cell-derived factor-1 in the brain. Using quantitative real-time polymerase chain reaction, the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured. In addition, western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4. Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation, increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra, and enhanced the immunoreactivity of tyrosine hydroxylase, CXCR4, and stromal cell-derived factor-1 in the brain. Injection of AMD3100 inhibited the aforementioned effects. These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson’s disease. This study was approved by the Animal Care and Use Committee of Kunming Medical University, China (approval No. SYXKK2015-0002) on April 1, 2014. Related Articles | Metrics

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Adipose-derived stem cells modified by BDNF gene rescue erectile dysfunction after cavernous nerve injury Mei Yang, Jiang-Yang Sun, Cheng-Cheng Ying, Yong Wang, Yong-Lian Guo 2020, 15 (1):  120-127.  doi: 10.4103/1673-5374.264464 Abstract ( 224 )   PDF (727KB) ( 206 )   Save Cavernous nerve injury is the main cause of erectile dysfunction following radical prostatectomy. The recovery of erectile function following radical prostatectomy remains challenging. Our previous studies found that injecting adipose-derived stem cells (ADSCs) into the cavernosa could repair the damaged cavernous nerves, but the erectile function of the treated rats could not be restored to a normal level. We evaluated the efficacy of ADSCs infected with a lentiviral vector encoding rat brain-derived neurotrophic factor (lenti-rBDNF) in a rat model of cavernous nerve injury. The rats were equally and randomly divided into four groups. In the control group, bilateral cavernous nerves were isolated but not injured. In the bilateral cavernous nerve injury group, bilateral cavernous nerves were isolated and injured with a hemostat clamp for 2 minutes. In the ADSCGFP and ADSCrBDNF groups, after injury with a hemostat clamp for 2 minutes, rats were injected with ADSCs infected with lenti-GFP (1 × 106 in 20 μL) and lenti-rBDNF (1 × 106 in 20 μL), respectively. Erectile function was assessed 4 weeks after injury by measuring intracavernosal pressures. Then, penile tissues were collected for histological detection and western blot assay. Results demonstrated that compared with the bilateral cavernous nerve injury group, erectile function was significantly recovered in the ADSCGFP and ADSCrBDNF groups, and to a greater degree in the ADSCrBDNF group. Neuronal nitric oxide synthase content in the dorsal nerves and the ratio of smooth muscle/collagen were significantly higher in the ADSCrBDNF and ADSCGFP groups than in the bilateral cavernous nerve injury group. Neuronal nitric oxide synthase expression was obviously higher in the ADSCrBDNF group than in the ADSCGFP group. These findings confirm that intracavernous injection with ADSCs infected with lenti-rBDNF can effectively improve erectile dysfunction caused by cavernous nerve injury. This study was approved by the Medical Animal Care and Welfare Committee of Wuhan University, China (approval No. 2017-1638) on June 20, 2017. Related Articles | Metrics

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GLYX-13 pretreatment ameliorates long-term isoflurane exposure-induced cognitive impairment in mice Huan Liu, Xiang-Dan Gong, Xin Zhao, Yue Qian, Xiao-Ping Gu, Tian-Jiao Xia 2020, 15 (1):  128-135.  doi: 10.4103/1673-5374.264466 Abstract ( 102 )   PDF (1436KB) ( 195 )   Save Accumulating evidence indicates that inhalation anesthetics induce or increase the risk of cognitive impairment. GLYX-13 (rapastinel) acts on the glycine site of N-methyl-D-aspartate receptors (NMDARs) and has been shown to enhance hippocampus-dependent learning and memory function. However, the mechanisms by which GLYX-13 affects learning and memory function are still unclear. In this study, we investigated these mechanisms in a mouse model of long-term anesthesia exposure. Mice were intravenously administered 1 mg/kg GLYX-13 at 2 hours before isoflurane exposure (1.5% for 6 hours). Cognitive function was assessed using the contextual fear conditioning test and the novel object recognition test. The mRNA expression and phosphorylated protein levels of NMDAR pathway components, N-methyl-D-aspartate receptor subunit 2B(NR2B)-Ca2+/calmodulin dependent protein kinase II (CaMKII)-cyclic adenosine monophosphate response element binding protein (CREB), in the hippocampus were evaluated by quantitative RT-PCR and western blot assay. Pretreatment with GLYX-13 ameliorated isoflurane exposure-induced cognitive impairment and restored NR2B, CaMKII and CREB mRNA and phosphorylated protein levels. Intracerebroventricular injection of KN93, a selective CaMKII inhibitor, significantly diminished the effect of GLYX-13 on cognitive function and NR2B, CaMKII and CREB levels in the hippocampus. Taken together, our findings suggest that GLYX-13 pretreatment alleviates isoflurane-induced cognitive dysfunction by protecting against perturbation of the NR2B/CaMKII/CREB signaling pathway in the hippocampus. Therefore, GLYX-13 may have therapeutic potential for the treatment of anesthesia-induced cognitive dysfunction. This study was approved by the Experimental Animal Ethics Committee of Drum Tower Hospital affiliated to the Medical College of Nanjing University, China (approval No. 20171102) on November 20, 2017. Related Articles | Metrics

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Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice Andrew R. Clark, Chia George Hsu, M A Hassan Talukder, Mark Noble, John C. Elfar 2020, 15 (1):  136-144.  doi: 10.4103/1673-5374.264471 Abstract ( 118 )   PDF (2167KB) ( 480 )   Save Oral 4-aminopyridine (4-AP) is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination, improvement of nerve conductivity, and acceleration of functional recovery. We hypothesized that, instead of oral or injection administration, transdermal 4-AP (TD-4-AP) could also improve functional recovery after traumatic peripheral nerve injury. Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability, pharmacokinetics, functional, electrophysiological, and nerve morphological properties. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose. While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function, chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls. These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration. The animal experiments were approved by the University Committee on Animal Research (UCAR) at the University of Rochester (UCAR-2009-019) on March 31, 2017. Related Articles | Metrics

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Effect of the combination of high-frequency repetitive magnetic stimulation and neurotropin on injured sciatic nerve regeneration in rats Jie Chen, Xian-Ju Zhou, Rong-Bin Sun 2020, 15 (1):  145-151.  doi: 10.4103/1673-5374.264461 Abstract ( 121 )   PDF (2024KB) ( 184 )   Save Repetitive magnetic stimulation is effective for treating posttraumatic neuropathies following spinal or axonal injury. Neurotropin is a potential treatment for nerve injuries like demyelinating diseases. This study sought to observe the effects of high-frequency repetitive magnetic stimulation, neurotropin and their combined use in the treatment of peripheral nerve injury in 32 adult male Sprague-Dawley rats. To create a sciatic nerve injury model, a 10 mm-nerve segment of the left sciatic nerve was cut and rotated through 180° and each end restored continuously with interrupted sutures. The rats were randomly divided into four groups. The control group received only a reversed autograft in the left sciatic nerve with no treatment. In the high-frequency repetitive magnetic stimulation group, peripheral high-frequency repetitive magnetic stimulation treatment (20 Hz, 20 min/d) was delivered for 10 consecutive days after auto-grafting. In the neurotropin group, neurotropin therapy (0.96 NU/kg per day) was administrated for 10 consecutive days after surgery. In the combined group, the combination of peripheral high-frequency repetitive magnetic stimulation (20 Hz, 20 min/d) and neurotropin (0.96 NU/kg per day) was given for 10 consecutive days after the operation. The Basso-Beattie-Bresnahan locomotor rating scale was used to assess the behavioral recovery of the injured nerve. The sciatic functional index was used to evaluate the recovery of motor functions. Toluidine blue staining was performed to determine the number of myelinated fibers in the distal and proximal grafts. Immunohistochemistry staining was used to detect the length of axons marked by neurofilament 200. Our results reveal that the Basso-Beattie-Bresnahan locomotor rating scale scores, sciatic functional index, the number of myelinated fibers in distal and proximal grafts were higher and axon lengths were longer in the high-frequency repetitive magnetic stimulation, neurotropin and combined groups compared with the control group. These measures were not significantly different among the high-frequency repetitive magnetic stimulation, neurotropin and combined groups. Therefore, our results suggest that peripheral high-frequency repetitive magnetic stimulation or neurotropin can promote the repair of injured sciatic nerves, but their combined use seems to offer no significant advantage. This study was approved by the Animal Ethics Committee of the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, China on December 23, 2014 (approval No. 2014keyan002-01). Related Articles | Metrics

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Skeletal muscle-derived cells repair peripheral nerve defects in mice Zi-Xiang Chen, Hai-Bin Lu, Xiao-Lei Jin, Wei-Feng Feng, Xiao-Nan Yang, Zuo-Liang Qi 2020, 15 (1):  152-161.  doi: 10.4103/1673-5374.264462 Abstract ( 113 )   PDF (4595KB) ( 176 )   Save Skeletal muscle-derived cells have strong secretory function, while skeletal muscle-derived stem cells, which are included in muscle-derived cells, can differentiate into Schwann cell-like cells and other cell types. However, the effect of muscle-derived cells on peripheral nerve defects has not been reported. In this study, 5-mm-long nerve defects were created in the right sciatic nerves of mice to construct a peripheral nerve defect model. Adult female C57BL/6 mice were randomly divided into four groups. For the muscle-derived cell group, muscle-derived cells were injected into the catheter after the cut nerve ends were bridged with a polyurethane catheter. For external oblique muscle-fabricated nerve conduit and polyurethane groups, an external oblique muscle-fabricated nerve conduit or polyurethane catheter was used to bridge the cut nerve ends, respectively. For the sham group, the sciatic nerves on the right side were separated but not excised. At 8 and 12 weeks post-surgery, distributions of axons and myelin sheaths were observed, and the nerve diameter was calculated using immunofluorescence staining. The number, diameter, and thickness of myelinated nerve fibers were detected by toluidine blue staining and transmission electron microscopy. Muscle fiber area ratios were calculated by Masson’s trichrome staining of gastrocnemius muscle sections. Sciatic functional index was recorded using walking footprint analysis at 4, 8, and 12 weeks after operation. The results showed that, at 8 and 12 weeks after surgery, myelin sheaths and axons of regenerating nerves were evenly distributed in the muscle-derived cell group. The number, diameter, and myelin sheath thickness of myelinated nerve fibers, as well as gastrocnemius muscle wet weight and muscle area ratio, were significantly higher in the muscle-derived cell group compared with the polyurethane group. At 4, 8, and 12 weeks post-surgery, sciatic functional index was notably increased in the muscle-derived cell group compared with the polyurethane group. These criteria of the muscle-derived cell group were not significantly different from the external oblique muscle-fabricated nerve conduit group. Collectively, these data suggest that muscle-derived cells effectively accelerated peripheral nerve regeneration. This study was approved by the Animal Ethics Committee of Plastic Surgery Hospital, Chinese Academy of Medical Sciences (approval No. 040) on September 28, 2016. Related Articles | Metrics

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Beta-nerve growth factor gene therapy alleviates pyridoxine-induced neuropathic damage by increasing doublecortin and tyrosine kinase A in the dorsal root ganglion Hyun-Kee Cho, Woosuk Kim, Kwon-Young Lee, Jin-Ok Ahn, Jung Hoon Choi, In Koo Hwang, Jin-Young Chung 2020, 15 (1):  162-168.  doi: 10.4103/1673-5374.264472 Abstract ( 87 )   PDF (1386KB) ( 201 )   Save Beta-nerve growth factor (β-NGF) is known to be a major leading cause of neuronal plasticity. To identify the possible action mechanisms of β-NGF gene therapy for sciatic nerve recovery, experimental dogs were randomly divided into control, pyridoxine, and pyridoxine + β-NGF groups. We observed chronological changes of morphology in the dorsal root ganglia in response to pyridoxine toxicity based on cresyl violet staining. The number of large neurons positive for cresyl violet was dramatically decreased after pyridoxine intoxication for 7 days in the dorsal root ganglia and the neuron number was gradually increased after pyridoxine withdrawal. In addition, we also investigated the effects of β-NGF gene therapy on neuronal plasticity in pyridoxine-induced neuropathic dogs. To accomplish this, tyrosine kinase receptor A (TrkA), βIII-tubulin and doublecortin (DCX) immunohistochemical staining was performed at 3 days after the last pyridoxine treatment. TrkA-immunoreactive neurons were dramatically decreased in the pyridoxine group compared to the control group, but strong TrkA immunoreactivity was observed in the small-sized dorsal root ganglia in this group. TrkA immunoreactivity in the dorsal root ganglia was similar between β- NGF and control groups. The numbers of βIII-tubulin- and DCX-immunoreactive cells decreased significantly in the pyridoxine group compared to the control group. However, the reduction of βIII-tubulin- and DCX-immunoreactive cells in the dorsal root ganglia in the β-NGF group was significantly ameliorated than that in the pyridoxine group. These results indicate that β-NGF gene therapy is a powerful treatment of pyridoxine-induced neuropathic damage by increasing the TrkA and DCX levels in the dorsal root ganglia. The experimental protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Seoul National University, South Korea (approval No. SNU-060623-1, SNU-091009-1) on June 23, 2006 and October 9, 2009, respectively. Related Articles | Metrics

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Claudin-15 overexpression inhibits proliferation and promotes apoptosis of Schwann cells in vitro Jian-Nan Li, Zhan Zhang, Guang-Zhi Wu, Deng-Bing Yao, Shu-Sen Cui 2020, 15 (1):  169-177.  doi: 10.4103/1673-5374.264463 Abstract ( 118 )   PDF (1568KB) ( 223 )   Save Our previous experiments have discovered that Claudin-15 was up-regulated in Schwann cells of the distal nerve stumps of rat models of sciatic nerve injury. However, how Claudin-15 affects Schwann cell function is still unknown. This study aimed to identify the effects of Claudin-15 on proliferation and apoptosis of Schwann cells cultured in vitro and explore the underlying mechanisms. Primary Schwann cells were obtained from rats. Claudin-15 in Schwann cells was knocked down using siRNA (siRNA-1 group) compared with the negative control siRNA transfection group (negative control group). Claudin-15 in Schwann cells was overexpressed using pGV230-Claudin-15 plasmid (pGV230-Claudin-15 group). The pGV230 transfection group (pGV230 group) acted as the control of the pGV230-Claudin-15 group. Cell proliferation was analyzed with EdU assay. Cell apoptosis was analyzed with flow cytometric analysis. Cell migration was analyzed with Transwell inserts. The mRNA and protein expressions were analyzed with quantitative polymerase chain reaction assay and western blot assay. The results showed that compared with the negative control group, cell proliferation rate was up-regulated; p-AKT/AKT ratio, apoptotic rate, p-c-Jun/c-Jun ratio, mRNA expression of protein kinase C alpha, Bcl-2 and Bax were down-regulated; and mRNA expression of neurotrophins basic fibroblast growth factor and neurotrophin-3 were increased in the siRNA-1 group. No significant difference was found in cell migration between the negative control and siRNA-1 groups. Compared with the pGV230 group, the cell proliferation rate was down-regulated; apoptotic rate, p-c-Jun/c-Jun ratio and c-Fos protein expression increased; mRNA expression of protein kinase C alpha and Bax decreased; and mRNA expressions of neurotrophins basic fibroblast growth factor and neurotrophin-3 were up-regulated in the pGV230-Claudin-15 group. The above results demonstrated that overexpression of Claudin-15 inhibited Schwann cell proliferation and promoted Schwann cell apoptosis in vitro. Silencing of Claudin-15 had the reverse effect and provided neuroprotective effect. This study was approved by the Experimental Animal Ethics Committee of Jilin University of China (approval No. 2016-nsfc001) on March 5, 2016. Related Articles | Metrics

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20S proteasome and glyoxalase 1 activities decrease in erythrocytes derived from Alzheimer’s disease patients Hui Lv, Gui-Yuan Wei, Can-Shou Guo, Yu-Feng Deng, Yong-Ming Jiang, Ce Gao, Chong-Dong Jian 2020, 15 (1):  178-183.  doi: 10.4103/1673-5374.264473 Abstract ( 84 )   PDF (252KB) ( 238 )   Save As a result of accumulating methylglyoxal and advanced glycation end products in the brains of patients with Alzheimer’s disease, it is considered a protein precipitation disease. The ubiquitin proteasome system is one of the most important mechanisms for cells to degrade proteins, and thus is very important for maintaining normal physiological function of the nervous system. This study recruited 48 individuals with Alzheimer’s disease (20 males and 28 females aged 75 ± 6 years) and 50 healthy volunteers (21 males and 29 females aged 72 ± 7 years) from the Affiliated Hospital of Youjiang Medical University for Nationalities (Baise, China) between 2014 and 2017. Plasma levels of malondialdehyde and H2O2 were measured by colorimetry, while glyoxalase 1 activity was detected by spectrophotometry. In addition, 20S proteasome activity in erythrocytes was measured with a fluorescent substrate method. Ubiquitin and glyoxalase 1 protein expression in erythrocyte membranes was detected by western blot assay. The results demonstrated that compared with the control group, patients with Alzheimer’s disease exhibited increased plasma malondialdehyde and H2O2 levels, and decreased glyoxalase 1 activity; however, expression level of glyoxalase 1 protein remained unchanged. Moreover, activity of the 20S proteasome was decreased and expression of ubiquitin protein was increased in erythrocytes. These findings indicate that proteasomal and glyoxalase activities may be involved in the occurrence of Alzheimer’s disease, and erythrocytes may be a suitable tissue for Alzheimer’s disease studies. This study was approved by the Ethics Committee of Youjiang Medical University for Nationalities (approval No. YJ12017013) on May 3, 2017. Related Articles | Metrics