Therapeutic targets for neurological diseases最新文献_第3页

Glutamatergic system modulators as agents in prevention and management of chemotherapy-induced polyneuropathy 谷氨酸系统调节剂在预防和治疗化疗诱导的多发性神经病中的作用

Therapeutic targets for neurological diseases Pub Date : 2015-03-16 DOI: 10.14800/TTND.672

L. Mannelli, D. Cerretani, C. Ghelardini, E. Bianchi

{"title":"Glutamatergic system modulators as agents in prevention and management of chemotherapy-induced polyneuropathy","authors":"L. Mannelli, D. Cerretani, C. Ghelardini, E. Bianchi","doi":"10.14800/TTND.672","DOIUrl":"https://doi.org/10.14800/TTND.672","url":null,"abstract":"Polyneuropathy is a common and important chemotherapy-induced adverse effect which often leads to dose modifications and impact on patients’ quality of life. Limited treatment options for prevention and management of this neuropathology stimulate further research on the topic. Recent attention has been focused on downregulation of glial glutamate transporter expression observed in spinal region of rodents treated with cancer chemotherapy drugs. Consequent extrasynaptic glutamate overflow could be considered a key element in neuropathic pathogenesis resulting in excessive activation of glutamate receptors and neuronal hyper-excitability, finally contributing to develop neuropathic condition. Recently, the onset of neuropathy in bortezomib treated rats could be prevented by preemptive administration of drugs promoting glial glutamate transporter expression and antagonism at mGlur5, a metabotropic receptor which reinforces glutamatergic transmission in presence of high extracellular glutamate concentrations. These findings point to glial-glutamate system dysregulation as a main mechanism in the pathogenesis of anticancer chemotherapy induced neuropathy.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2015-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658914","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}

引用次数: 0

Role of IGF-1 signaling in the pathology of diabetic retinopathy IGF-1信号在糖尿病视网膜病变病理中的作用

Therapeutic targets for neurological diseases Pub Date : 2015-03-11 DOI: 10.14800/TTND.639

Haitao Wang, Jiangping Xu, Jiashu Chen, P. Little, Wenhua Zheng

{"title":"Role of IGF-1 signaling in the pathology of diabetic retinopathy","authors":"Haitao Wang, Jiangping Xu, Jiashu Chen, P. Little, Wenhua Zheng","doi":"10.14800/TTND.639","DOIUrl":"https://doi.org/10.14800/TTND.639","url":null,"abstract":"Diabetic retinopathy (DR) is a common eye disease caused by diabetic mellitus and can lead to blindness of eye. Currently, researches on the mechanisms and clinical interventions of DR are at an early stage. Under the condition of DR, insulin is usually used for the control of blood glucose. Similar to insulin, Insulin-like growth factor-1 (IGF-1), a protein which has been reported to lower the level of blood glucose, may also promote cell survival and proliferation in various tissues. However, effects of IGF-1 on DR are complex and controversial. The effect of IGF-1 on the normalization of blood glucose is beneficial for the patients, especially those with severe insulin resistance. However, IGF-1 mediates a strong mitogenic signaling and long term application of IGF-1 may aggravate retinal deterioration through promoting the proliferation of retinal endothelial cells. IGF-1 enhances the expression of vascular endothelial growth factor and erythropoietin. The binding of IGF-I to IGF-IR also promotes the activation of multiple signaling pathways, including phosphatidylinositol 3-kinase/protein kinase B pathway, mitogen activated protein kinase pathway and nuclear factor-κB signaling pathway. All of these have been shown to be associated with the pathology of DR. In this review, we discuss the signaling pathway of IGF-1, evidence for a functional relationship between the IGF-I and DR, as well as a possible role of IGF-1 signaling pathway in the process of DR.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658841","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}

引用次数: 4

The in-vitro sciatic nerve model: new Insights into neuropathy 体外坐骨神经模型:对神经病变的新见解

Therapeutic targets for neurological diseases Pub Date : 2015-03-11 DOI: 10.14800/TTND.662

Melanie Wegener, M. Stecker

{"title":"The in-vitro sciatic nerve model: new Insights into neuropathy","authors":"Melanie Wegener, M. Stecker","doi":"10.14800/TTND.662","DOIUrl":"https://doi.org/10.14800/TTND.662","url":null,"abstract":"Polyneuropathy is a prevalent condition that can severely impair a person’s quality of life. In-vitro experiments were conducted in order to study external factors associated with polyneuropathy in isolation from systemic effects in live models. Sciatic nerves were isolated from Sprague-Dawley rats and placed in perfusion chambers that contained artificial cerebral spinal fluid. The nerves were stimulated, the averaged nerve action potential (NAP) waveforms were digitized, and the NAP amplitude, velocity, duration, and amplitude of the paired pulse response were analyzed. The effects of anoxia, hypothermia, and external metabolic substrates on the NAP were analyzed. Results showed a complex interaction between the three categories and their effects on the NAP parameters. Cyclic episodes of anoxia had different effects on NAP amplitude and velocity, and also resulted in ischemic preconditioning of the nerve, which is perhaps due to the build-up of glycogen during the re-oxygenated (recovery) phases. Hypothermia appeared to best preserve nerve function when present during the anoxic phases and absent during the recovery phases, perhaps allowing for glycogenolysis during the recovery phases. The metabolic function of the nerve during intermittent anoxia was then analyzed, and it was determined that hyperglycemia improved ischemic preconditioning while decreasing NAP amplitude overtime, suggesting that there are other contributing processes such as the production of free radicals and advanced glycation end-products. Lactate uniquely supported the nerve in high and low concentrations during both continuous oxygenation and intermittent anoxia. The existence of a lactate shuttle between Schwann cells and peripheral nerves may explain these results. The findings from these in-vitro experiments may be important in future hypothesis testing in search for effective treatment of polyneuropathy.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658899","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}

引用次数: 0

Differential effects of chronic predictable and unpredictable stress on neurobehavioral and biochemical responses in rats 慢性可预测和不可预测应激对大鼠神经行为和生化反应的不同影响

Therapeutic targets for neurological diseases Pub Date : 2015-02-14 DOI: 10.14800/TTND.603

Tarun Thakur, R. Anand, A. Ray, K. Gulati

{"title":"Differential effects of chronic predictable and unpredictable stress on neurobehavioral and biochemical responses in rats","authors":"Tarun Thakur, R. Anand, A. Ray, K. Gulati","doi":"10.14800/TTND.603","DOIUrl":"https://doi.org/10.14800/TTND.603","url":null,"abstract":"The present study was designed to investigate the effects of exposure to chronic predictable and unpredictable stress on neurobehavioral and biochemical responses in rats. Male Wistar rats (200-250g) were exposed to either chronic predictable stress (CPS) i.e. immobilization for 1 hour/day for 14 days or chronic unpredictable stress (CUS) i.e. daily a different, random, novel stressor sequence (immobilization stress for 1h, footshock, cold stress, overnight food and water deprivation and social isolation) for 14 days. Behavioral responses were assessed by the elevated plus maze (EPM) test and biochemical parameters, viz. malondialdehyde (MDA, a marker of oxidative stress) and stable NO metabolites (NOx, marker of nitrosative stress), were measured in brain homogenates of the rats. Exposure to chronic CPS resulted in adaptation to neurobehavioral suppression in the EPM (as observed after acute Restraint stress), which was not seen after CUS. These behavioral changes after CPS and CUS were closely paralleled by alterations in the levels of brain MDA and NOx. These results suggest that CPS and CUS results in differential modulation of the neurobehavioral profile and oxidative/nitrosative stress markers in the brain.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658516","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}

引用次数: 8

LRRK2 a pivotal player in mitochondrial dynamics and lysosomal clustering: highlights to sporadic Parkinson's disease LRRK2是线粒体动力学和溶酶体聚类的关键参与者:散发性帕金森病的亮点

Therapeutic targets for neurological diseases Pub Date : 2015-02-14 DOI: 10.14800/TTND.629

S. Cardoso, A. R. Esteves

{"title":"LRRK2 a pivotal player in mitochondrial dynamics and lysosomal clustering: highlights to sporadic Parkinson's disease","authors":"S. Cardoso, A. R. Esteves","doi":"10.14800/TTND.629","DOIUrl":"https://doi.org/10.14800/TTND.629","url":null,"abstract":"Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder affecting more than 1% of the population over 65 years of age. Dominant mutations in the leucine-rich repeat kinase 2 (lrrk2) gene are found associated with both familial and sporadic cases and represent the most frequent genetic lesions associated with PD. Remarkably, lrrk2 mutations cause PD with age-related penetrance and clinical features similar to late-onset sporadic PD (sPD). LRRK2 is a complex and large protein constituted by multiple domains executing several functions, including GTP hydrolysis, kinase activity and protein binding. Although the cellular function of LRRK2 is largely unknown there is increasing evidence that LRRK2 posits a role in autophagic regulation, microtubule (MT) dynamics, and mitochondrial function. In our recent report, we tackled LRRK2 physiological role taking advantage of a potent and selective inhibitor (LRRK2-IN-1) of LRRK2 kinase activity. We evaluated LRRK2-IN-1 effects on several mechanisms known to be impaired in PD, such as MT network and trafficking, mitochondrial dynamics and function and the autophagic-lysosomal pathway. Importantly, we found that LRRK2 is necessary to maintain the levels of acetylated tubulin, which is a post-translational modification essential for MTs structure and function and with a prevalent role for axonal intracellular trafficking. In addition, we also provided evidence that LRRK2 kinase activity regulates mitochondrial dynamics through phosphorylation of mitochondrial dynamin-like protein (Drp1) increasing mitochondrial fission. Adding up, LRRK2 kinase activity is essential for regulation of lysosomal clustering and distribution through Rab7. Therefore, our recent findings reveal novel insights into the function of LRRK2 in a normal or diseased context.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658793","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}

引用次数: 0

NT-113, A Novel, High CNS Penetrance pan-ERBB Inhibitor for Glioma Therapy NT-113，一种用于神经胶质瘤治疗的新型高中枢外显率泛erbb抑制剂

Therapeutic targets for neurological diseases Pub Date : 2015-02-14 DOI: 10.14800/TTND.585

Tsun‐Wen Yao, T. Nicolaides, J. Sarkaria, C. James

引用次数: 2

Brain cytochrome p450 enzymes: a possible therapeutic targets for neurological diseases 脑细胞色素p450酶:神经系统疾病的可能治疗靶点

Therapeutic targets for neurological diseases Pub Date : 2015-02-14 DOI: 10.14800/TTND.598

S. Gambaro, R. Moretti, C. Tiribelli, S. Gazzin

{"title":"Brain cytochrome p450 enzymes: a possible therapeutic targets for neurological diseases","authors":"S. Gambaro, R. Moretti, C. Tiribelli, S. Gazzin","doi":"10.14800/TTND.598","DOIUrl":"https://doi.org/10.14800/TTND.598","url":null,"abstract":"Neurological diseases (ND) afflict hundreds of millions of people worldwide and constitute 12% of total deaths of the population all around the world. According to a global study conducted by the World Health Organization, 8 out of 10 disorders in the 3 rd highest disability classes are neurologic problems. Commonly they have disabling consequences, compromising severely the quality of the life of affected subjects. Often therapeutic strategies are limited in efficacy. Limitations lie with the enormous fragility of the so complex structure and functions accomplished by the central nervous system, together with the presence of the barrier between the tissue and the blood limiting the penetration of drugs. For these reason new strategies to protect the brain are essential. One way might be the enhancement of local biomolecular mechanisms (metabolizing enzymes, transporters, etc.). However, increasing evidence underline that our knowledge of the brain is still partial, and information cannot simply be derived from other well-known organs such as the liver. This is the case for the brain cytochrome P450 enzymes, showing differential cellular localization, brain regional expression and modulation.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2015-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658504","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}

引用次数: 4

Minocycline as a potential treatment in the early stages of schizophrenia: a translational approach 二甲胺四环素作为精神分裂症早期阶段的潜在治疗方法:一种转化方法

Therapeutic targets for neurological diseases Pub Date : 2015-02-14 DOI: 10.14800/TTND.580

C. Chaves, A. Zuardi, J. Hallak

{"title":"Minocycline as a potential treatment in the early stages of schizophrenia: a translational approach","authors":"C. Chaves, A. Zuardi, J. Hallak","doi":"10.14800/TTND.580","DOIUrl":"https://doi.org/10.14800/TTND.580","url":null,"abstract":"Despite the wide variety of currently available antipsychotics, their efficacy is limited only to the improvement in positive symptoms. In addition, longitudinal cohort studies of patients with first episode psychosis show worsening in different psychopathological domains and progressive loss of brain gray matter volumes. Beyond changes in neurotransmitter systems, most notably in the dopaminergic and glutamatergic systems, there is growing evidence of an immune and inflammatory component in the pathophysiology of schizophrenia, indicating an increase of cytokines (e.g., interleukin 1β, interleukin 6 and TNF-α) and microglial activation in patients with this disorder. Growing evidence indicates that minocycline may enhance the antipsychotic treatment and may prevent some brain changes observed in the early stages of schizophrenia. Minocycline is a tetracycline with broad anti-inflammatory activity and with evidence of neuroprotective action. However, the precise effects of minocycline in the CNS are still elusive. In the other hand, several points can be addressed, providing rational hypotheses for understanding how minocycline can improve symptoms and modulate brain structure and function in schizophrenia. In this article, relevant data about minocycline action are reviewed, linking bench to bedside. The potent inhibition of brain microglia activation and the broad anti-inflammatory effects of minocycline, in addition to indirect modulation of dopaminergic and glutamatergic systems, may mediate the effects of minocycline in schizophrenia. Further longitudinal studies with larger samples and measurement of inflammatory markers are needed to evaluate the potential of minocycline as adjunctive treatment in schizophrenia.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658402","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}

引用次数: 5

Antioxidants as a preventive therapeutic option for age related neurodegenerative diseases 抗氧化剂作为与年龄相关的神经退行性疾病的预防性治疗选择

Therapeutic targets for neurological diseases Pub Date : 2015-02-14 DOI: 10.14800/TTND.592

Sarika Singh

{"title":"Antioxidants as a preventive therapeutic option for age related neurodegenerative diseases","authors":"Sarika Singh","doi":"10.14800/TTND.592","DOIUrl":"https://doi.org/10.14800/TTND.592","url":null,"abstract":"Advances in our understanding for neurodegenerative mechanisms have increased significantly in last few decades. But still no novel disease modifying therapy has been developed which could prevent the disease progression and drawn our attention towards the development of new alternative therapy. The major obstacle for the development of disease therapy is incomplete knowledge about neurodegenerative mechanisms. Due to the insufficient information about neurodegenerative mechanisms no standard diagnostic tests for the detection of neurodegenerative disease could be develop to date, causes delayed diagnosis and disease worsening. So far the exploratory reports and clinical data have suggested the involvement of oxidative stress, mitochondrial impairment and apoptosis as major neurodegenerative mechanisms. Investigations have elicited that once initiated the degeneration of neurons could not be arrested therefore in the scarcity of curative therapy we should approach for the preventive neurodegenerative therapy. Since oxidative stress has noteworthy involvement in neuronal death solely, and in connection to other death pathways therefore, antioxidants as preventive therapeutics might provide beneficial effects in age related neurodegenerative diseases. With this hypothesis in this review we are discussing about the use of antioxidants as a preventive treatment of neurodegenerative diseases. Such therapies may work in the prodromal phase, or when given prophylactically. However, in the symptomatic patient there may be too much damage to the neuronal networks to restore functionality by reducing or even eliminating the primary stressor. As functional neuronal demise and excessive neuronal death are almost certainly the key factors that mediate the functional impairment, it is ostensible that preventing neuronal death and dysfunction at early stage may provide a huge clinical benefit.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658467","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}

引用次数: 15

Cocaine modulation of the mammalian circadian clock: potential therapeutic targets 可卡因对哺乳动物生物钟的调节:潜在的治疗靶点

Therapeutic targets for neurological diseases Pub Date : 2015-02-14 DOI: 10.14800/TTND.607

A. Stowie, R. Prosser, J. Glass

{"title":"Cocaine modulation of the mammalian circadian clock: potential therapeutic targets","authors":"A. Stowie, R. Prosser, J. Glass","doi":"10.14800/TTND.607","DOIUrl":"https://doi.org/10.14800/TTND.607","url":null,"abstract":"The circadian system plays an integral role in regulating physiological and behavioral responses to cocaine, which contribute to abuse and relapse. To date, however, little is known of the mechanism(s) underlying cocaine effects on biological timing, and in particular, how this drug may impact the regulation of the master circadian clock of the suprachiasmatic nucleus (SCN). This review summarizes our current research into the chronotypic actions of acute and chronic cocaine. In initial experiments, it was shown that acute systemic and in vitro cocaine blocks the nocturnal SCN photic phase-resetting response critical for circadian entrainment to the light-dark cycle (LD). Cocaine treatment at midday also advances circadian clock phase, showing that this drug possess non-photic circadian phase-resetting properties. Next, chronic (weeks-months) cocaine regimens were used to model human drug abuse patterns. Such long-term oral drug exposures caused dramatic alterations in intrinsic circadian period and entrainment to LD that persisted long after cocaine withdrawal, suggesting long-term (possibly permanent) circadian disruptive effects. Lastly, we found that the acute systemic cocaine effects described above are blocked using a serotonin receptor antagonist (metergoline) targeted to the SCN in vivo, as well as in vitro , suggesting involvement of a serotonergic mechanism. Consistent with this hypothesis, mutant mice with a cocaine-insensitive serotonin transporter exhibited little or no circadian response to cocaine. Collectively, these results indicate that cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence. Earmarking the serotonergic system in mediating these cocaine effects offers a potential chrono-pharmacological approach for the treatment of cocaine abuse and addiction.","PeriodicalId":90750,"journal":{"name":"Therapeutic targets for neurological diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66658784","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}

引用次数: 6