Therapeutic targets for neurological diseases最新文献

{"title":"Prevention of failed back surgery syndrome with applications of different pharmacological agents: A Review article","authors":"Y. Mekaj, A. Mekaj","doi":"10.14800/TTND.507","DOIUrl":"https://doi.org/10.14800/TTND.507","url":null,"abstract":"Failed back surgery syndrome (FBSS) is a severe, long lasting and very common complication of lumbosacral spine surgery. FBSS can result from a variety of factors, such as an incorrect level of surgery, inadequate surgical decompression, recurrent disc herniation and epidural nerve fibrosis. The primary objective of this study was to present the recent data from animal and clinical studies regarding a variety of biological, pharmacological, and different synthetic materials used to prevent scar formation after spine surgery. There are a substantial number of substances that are topically used on the dura mater to prevent epidural fibrosis; however, we have primarily selected the substances that are used most often, such as hyaluronic acid (HA) and its derivatives, mitomycin C (MMC), 5-fluorouracil (5-FU), tacrolimus, melatonin (MLT), and nonsteroidal anti-inflammatory drugs (NSAIDs). Other biological and synthetic materials are also presented, which are used locally in the dura mater but act as mechanical barriers, such as Adcon-L, amniotic membrane (AM), carboxymethylcellulose and polyethylene oxide (CMC/PEO), polytetrafluoroethylene (PTFE), chitosan, collagen dural matrix, polyethylene glycol hydrogel, and fibrin sealant-based medicated adhesion barrier. As indicated in this review paper, the results regarding the use of these substances and barriers in animal models and humans are different; their effects have not always been successful, and they may have even caused adverse effects. However, it is necessary to identify adequate chemical, biological, and synthetic substances that are more successful in the prevention of epidural fibrosis, which is considered one of the main causes of FBSS.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mirror paradigm and mirror therapy: does the \"virtual hand\" have a beneficial impact on motor behavior?","authors":"M. Guerraz","doi":"10.14800/TTND.518","DOIUrl":"https://doi.org/10.14800/TTND.518","url":null,"abstract":"The mirror paradigm can be used to investigate the role of visual afferents in motor control as well as in position perception and kinesthesia. The paradigm has also been evaluated as tool (i.e. mirror therapy) for restoring brain functions in general and promoting recovery from hemiparesis in particular. However, recent reviews have cast doubt on the mirror paradigm's beneficial impact on motor behavior. In this Research Highlight, we briefly review recently published results (including our own work) on the impact of the mirror paradigm and mirror therapy on motor functions in stroke patients and in healthy participants with or without simulated motor dysfunctions. Overall, our assessment failed to evidence clear or systematic mirror facilitation of motor behavior (i.e. bimanual coupling) in either voluntary or involuntary upper limb activity in healthy participants. Our findings thus \"mirror\" those of recent reviews questioning the benefit of mirror therapy over mental imagery or bimanual coupling in recovery from motor dysfunction following stroke.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting heme oxygenase after intracerebral hemorrhage.","authors":"Jing Chen-Roetling,&nbsp;Xiangping Lu,&nbsp;Raymond F Regan","doi":"10.14800/ttnd.474","DOIUrl":"https://doi.org/10.14800/ttnd.474","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is the primary event in approximately 10% of strokes, and has higher rates of morbidity and mortality than ischemic stroke. Experimental evidence suggests that the toxicity of hemoglobin and its degradation products contributes to secondary injury that may be amenable to therapeutic intervention. Hemin, the oxidized form of heme, accumulates in intracranial hematomas to cytotoxic levels. The rate limiting step of its breakdown is catalyzed by the heme oxygenase (HO) enzymes, which consist of inducible HO-1 and constitutively-expressed HO-2. The effect of these enzymes on perihematomal injury and neurological outcome has been investigated in ICH models using both genetic and pharmacological approaches to alter their expression, with variable results reported. These findings are summarized and reconciled in this review; therapeutic strategies that may optimize HO expression and activity after ICH are described.</p>","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310000/pdf/nihms657423.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33020899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropsin is associated with MAP2c dependent dendritic morphology in aging brain","authors":"Arpita Konar, M. Thakur","doi":"10.14800/TTND.503","DOIUrl":"https://doi.org/10.14800/TTND.503","url":null,"abstract":"Brain aging associated impairment in synaptic plasticity and memory increases vulnerability for neurodegenerative pathologies. However, lacunae in understanding the molecular mechanisms underlying such impairment have hindered the development of recovery strategies. In this context, the emerging evidences for modifying the synaptic morphology by activity dependent plasticity proteases are noteworthy. Neuropsin (NP) is one such serine protease implicated in synaptic plasticity and memory acquisition, though it has never been explored in aging brain. Recently, we reported regional variation of NP expression in aging mouse brain. It was predominant in forebrain regions exhibiting age dependent decline in cerebral cortex, sharp increase in adult olfactory bulb and hippocampus and thereafter reduction in old age. The expression pattern of NP was strongly correlated with cleavage of its substrate, L1CAM and downstream dendritic marker MAP2c level in different brain regions during aging. In the present research highlight, we provide a brief overview of our laboratory findings related to brain aging with particular focus on NP expression and its implication in MAP2c dependent dendritic morphological changes. Such novel findings suggest NP as a potential therapeutic target for age associated decline in memory and related disorders.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Functions of 14-3-3 Proteins in Neurogenesis and Neuronal Differentiation In Vivo","authors":"T. Wachi, K. Toyo-oka","doi":"10.14800/TTND.500","DOIUrl":"https://doi.org/10.14800/TTND.500","url":null,"abstract":"During brain development, there are many essential steps for the proper formation of a functional brain, including neurogenesis and neuronal migration. Neuronal progenitor cells (NPCs) proliferate and symmetrically divide to expand their pools in the developing cerebral cortex. NPCs also asymmetrically divide to produce one neuronal progenitor cell and one neuron. These newly-born post-mitotic neurons radially migrate and reach the final destination in the cortical plate (CP) to finally form the six layers of the cortex. We previously found that the protein 14-3-3epsilon is important for neuronal migration and a responsible gene for the development of Miller-Dieker syndrome (MDS). Although fortunately we found the neuronal migration defects in 14-3-3epsilon knockout mice, there may be functional redundancies because there are seven isoforms in the family of 14-3-3 proteins, with high homology among them. Therefore, we produced the 14-3-3epsilon and 14-3-3zeta double knockout mice (14-3-3 dKO mice) and found that the dKO mice showed spontaneous epilepsy. We also found novel in vivo functions of the 14-3-3epsilon and 14-3-3zeta proteins in neurogenesis of radial glial cells (RGCs) as well as intermediate progenitor cells (IPCs) and in neuronal differentiation. In addition to the pathological defects seen in the dKO mice, we identified the molecular mechanisms involved in the neuronal differentiation defects and showed that the binding of 14-3-3 proteins to d-catenin proteins regulated actin dynamics. Thus, 14-3-3 proteins are important for the key steps of brain development, including neurogenesis, neuronal migration and neuronal differentiation as well as their involvement and involved in various brain morphological disorders, such as epilepsy.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIV Tat 101-mediated loss of pericytes at the blood-brain barrier involves PDGF-BB.","authors":"Fang Niu,&nbsp;Honghong Yao,&nbsp;Ke Liao,&nbsp;Shilpa Buch","doi":"10.14800/ttnd.471","DOIUrl":"https://doi.org/10.14800/ttnd.471","url":null,"abstract":"<p><p>HIV-1-associated neurocognitive disorders (HAND) affect almost 30-50% of infected individuals, even in the presence of successful control of virus replication by combined antiretroviral therapy (cART).HIV Tat protein, a nuclear trans-activator of viral gene transcription, that is secreted by infected cells and can be taken up by the neighboring cells, is present in various tissues despite the presence of cART, and has been shown to break down the integrity of the blood-brain barrier (BBB). This, in turn, leads to disruption of the neovascular unit, affecting functioning of the brain microvascular endothelial cells as well as astrocytes. Pericytes, yet another important constituent of the BBB, play a critical role in the maintenance of the integrity of the BBB. Loss of pericytes resulting in disruption of BBB has been observed in several pathologies including HAND. Furthermore, while PDGF-BB is essential for pericyte generation, paradoxically, high concentrations of PDGF-BB lead to loss of pericytes in tumor vessels. In this research highlight, we provide a brief review of our recently published finding, which have demonstrated a novel role of PDGF-BB in HIV-Tat mediated migration of pericytes, leading ultimately to loss of pericyte coverage from the endothelium, with a subsequent breach of the BBB. These findings underpin yet another mechanism by which BBB integrity is disrupted in HAND.</p>","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.14800/ttnd.471","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33342411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The roles of redox enzymes in Parkinson's disease: Focus on glutaredoxin.","authors":"William M Johnson,&nbsp;Amy L Wilson-Delfosse,&nbsp;Shu G Chen,&nbsp;John J Mieyal","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Parkinson's disease (PD) results from the loss of dopaminergic neurons in the <i>substantia nigra</i> portion of the midbrain, and represents the second most common neurodegenerative disease in the world. Although the etiology of PD is currently unclear, oxidative stress and redox dysfunction are generally understood to play key roles in PD pathogenesis and progression. Aging and environmental factors predispose cells to adverse effects of redox changes. In addition to these factors, genetic mutations linked to PD have been observed to disrupt the redox balance. Mutations in leucine-rich repeat kinase 2 (<i>LRRK2</i>) are associated with autosomal dominant PD, and several of these mutations have also been shown to increase the levels of reactive oxygen species in cells. Anti-oxidant proteins are necessary to restore the redox balance and maintain cell viability. Over the past decade studies have started to demonstrate the critical importance for redox proteins mediating neuronal protection in models of PD. This commentary briefly describes some of the factors hypothesized to contribute to PD, specifically regarding the redox changes that occur in PD. Dysregulation of redox proteins in PD is highlighted by some of the work detailing the roles of peroxiredoxin-3 and thioredoxin-1 in models of PD. In an attempt to generate novel therapies for PD, several potent inhibitors of LRRK2 have been developed. The use of these compounds, both as tools to understand the biology of LRRK2 and as potential therapeutic strategies is also discussed. This mini-review then provides a historical prospective on the discovery and characterization of glutaredoxin (Grx1), and briefly describes current understanding of the role of Grx1 in PD. The review concludes by highlighting our recent publication describing the novel role for Grx1 in mediating dopaminergic neuronal protection both <i>in vitro</i> and <i>in vivo</i>.</p>","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474481/pdf/nihms689460.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33407245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPAergic mechanisms linked to cerebral ischemia","authors":"M. Mele, R. Alo’, E. Avolio, M. Zizza, G. Fazzari, M. Canonaco","doi":"10.14800/TTND.478","DOIUrl":"https://doi.org/10.14800/TTND.478","url":null,"abstract":"Brain ischemia is a major cause of death and the most common element of disability in the adult population worldwide. This phenomenon occurs when blood flow is reduced or interrupted in the various brain districts leading to oxygen and glucose deprivation (OGD), which by triggering a complex series of biochemical plus molecular mechanisms such as an exacerbated production of misfolded and oxidized proteins together with the breakdown of cellular integrity are responsible for neuronal cell death. Despite the mechanisms that underlie the triggering of ischemic insults are still unclear, numerous studies are pointing to excitotoxic glutamatergic neuronal signaling processes as key mediators of these events. Indeed, cultured neurons deriving from global cerebral ischemia appear to respond to OGD with a rapid internalization of α ‑ amino ‑ 3 ‑ hydroxy ‑ 5 ‑ methyl ‑ 4 ‑ isoxazolepropionic acid receptors (AMPAR) thereby suggesting them as critical components of OGD-induced cell death. It strongly seems that OGD-dependent neuronal ischemia occurs via GluR2-sites in which a switching from GluR2-containing Ca 2+ -impermeable receptors to GluR2-lacking Ca 2+ -permeable subtypes constitutes an important step. Interestingly attention regarding excitotoxicity-related ischemic events, aside being largely directed to the o veractivation of AMPARs, appear to be also tightly linked to the translocation of the pro-apoptotic protein Bax to the mitochondria accounting for the activation of the caspase factors. Although the brain is able to repair part of the neuronal damages and to restore the morpho-functional organization, cerebral ischemia more than ever continues to attract much attention especially due to its elevated mortality feature. In this review we analyzed the role played by GluR2 AMPAR subunit in the pathological processes that lead to neurodegenerative diseases with particular attention being paid to the assembly of the major synaptic AMPARs together with cellular events that feasibly account for ischemic brain damages. In this context, knowledge of the different molecular mechanisms operating under these conditions may surely provide helpful indications regarding the identification of new therapeutic targets for treating cerebral ischemia.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"181 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy","authors":"Y. Ohno, Kentaro Tokudome, Naofumi Kunisawa, H. Iha, M. Kinboshi, Takahiro Mukai, T. Serikawa, S. Shimizu","doi":"10.14800/TTND.476","DOIUrl":"https://doi.org/10.14800/TTND.476","url":null,"abstract":"The inwardly rectifying potassium (Kir) channel subunit Kir4.1 is specifically expressed in brain astrocytes and Kir4.1-containing channels (Kir4.1 channels) mediate astroglial spatial potassium (K + ) buffering. Recent advances in Kir4.1 research revealed that Kir4.1 channels can serve as a novel therapeutic target for epilepsy. Specifically, reduced expression or dysfunction of Kir4.1 channels seems to be involved in generation of generalized tonic-clonic seizures (GTCS) in animal models of epilepsy and patients with temporal lobe epilepsy. In addition, recent clinical studies showed that loss-of-function mutations of human gene ( KCNJ10 ) encoding Kir4.1 elicit “EAST” or “SeSAME” syndrome which manifests as GTCS and ataxia. Although the precise mechanisms remain to be clarified, it is suggested that dysfunction of Kir4.1 channels disrupts spatial K + buffering by astrocytes, elevates extracellular levels of K + and/or glutamate and causes abnormal excitation of neurons in the limbic regions and neocortex. All these findings suggest that agents that activate or up-regulate astroglial Kir4.1 channels would be effective for epilepsy. In addition, docking simulation analysis using the Kir4.1 homology model provides important information for designing new Kir4.1 ligands. Discovery of such agents that activate or up-regulate Kir4.1 channels would be a novel approach for the treatment of epilepsy.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium and redox homeostasis in Alzheimer's disease: a focus on the endoplasmic reticulum","authors":"A. C. Fonseca, S. Cardoso, C. Pereira","doi":"10.14800/TTND.428","DOIUrl":"https://doi.org/10.14800/TTND.428","url":null,"abstract":"Alzheimer's disease is the most frequent cause of dementia and, similarly to what is observed in other neurodegenerative disorders, neuronal dysfunction and loss is associated with alterations of proteostasis, impaired calcium homeostasis and increased accumulation of reactive oxygen species, which involve several organelles and signalling pathways. The endoplasmic reticulum is a vital organelle that plays a central role in calcium and redox homeostasis. In addition, the accumulation of abnormal proteins in the lumen of the endoplasmic reticulum induces a stress response that, depending on the stress level, activates adaptive pro-survival or deleterious pro-apoptotic pathways. Therefore, the understanding of the molecular mechanisms that regulate the balance between anti- and pro-apoptotic pathways under endoplasmic reticulum stress conditions is essential to discover novel targets for therapy in Alzheimer's disease. This review focused the role of endoplasmic reticulum stress in the deregulation of calcium and redox homeostasis during the progression of Alzheimer's disease.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}