Using zebrafish to assess the impact of drugs on neural development and function

Background: Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype-based genetic and small molecule compound screening. Objective/method: The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by > 600 disorders in humans. I discuss the past, present and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease and neural system dysfunctions such as anxiety/depression and addiction. Conclusion: These studies hold promise to reveal fundamental mechanisms governing nervous system development and function, and to facilitate small molecule drug discovery for the many types of neurological disorders.     

Enviromimetics: exploring gene environment interactions to identify therapeutic targets for brain disorders

There is a growing awareness of the central role played by environmental factors in many of the most debilitating neural disorders. Epidemiological studies have suggested a complex balance between genetic and environmental factors in the pathogenesis of neurological and psychiatric conditions. The use of accurate animal models, combined with experimental manipulations such as environmental enrichment, has shown that increased sensory, cognitive and motor stimulation has beneficial effects in a range of CNS disorders, including Huntington's, Alzheimer's, Parkinson's and other neurodegenerative diseases. Various studies have identified molecular, structural and functional correlates of this experience-dependent plasticity. The authors propose that the molecular systems which mediate the therapeutic effects of environmental enrichment may provide novel targets for pharmacotherapies. More specifically, they elaborate a theoretical framework for the development of ‘enviromimetics’, therapeutics that mimic or enhance the beneficial effects of environmental stimulation, targeted towards a wide range of nervous system disorders.     

Assessment of heavy metals by ICP-OES and their impact on insulin stimulating hormone and carbohydrate metabolizing enzymes

Arsenic (As) and cadmium (Cd) have recently emerged as major health concerns owing to their strong association with diabetes mellitus (DM). We aimed to investigate the heavy metals exposure towards incidence of DM at various enzymatic and hormonal levels. Additionally, association of As and Cd with Zinc (Zn, essential metal) was also evaluated. Spot urine samples were collected to assess As, Cd and Zn through ICP-OES. Serum was analyzed by assay method for fasting blood glucose, liver and renal function biomarkers. ELISA was performed to investigate the impact of heavy metals on HbA1c, α-amylase, DPP-IV, IGF-1, leptin, GSH, MDA, SOD, HDL, FFA, TG and interleukin (IL)-6. Association of heavy metals with DM was measured by odds ratio (OR) and level of significance was assessed by Chi-squared test. Unpaired student's t-test was used to compare DM-associated risk factors in heavy metals-exposed and unexposed participants. As and Cd were detectable in 75.4% and 83% participants with mean concentration of 75.5 ppb and 54.5 ppb, respectively. For As exposure, OR in the third quartile was maximum ie 1.34 (95% CI, 0.80 to 2.23), however the result was not statistically significant (P > .05). For Cd exposure, OR in the fourth quartile was considerably high, 1.62 (95% CI, 1.00 to 2.61), with a significant probability value (P < .05). Urinary Cd was negatively associated with Zn. As and Cd exposure increases the incidence of DM in the general population. Impaired hormonal and enzymatic levels in diabetic and non-diabetic exposed participants reflect the multiple organ damage by heavy metal exposure.     

模式动物斑马鱼在神经退行性疾病研究中的应用

斑马鱼作为一种新型模式低等脊椎动物,具有发育周期短、体外受精、胚胎透明、突变种多等优势,被广泛应用于神经、心血管、消化等方面的研究中。神经退行性疾病包括帕金森病、阿尔茨海默病等,近年来发病率不断上升,且有年轻化的趋势,严重影响人们的身体健康和生活质量。因其发病机制复杂,至今仍缺乏治疗此类疾病的方法。本文综述近年来用斑马鱼制作神经退行性疾病模型的主要方式及可行性,为研究神经退行性疾病中斑马鱼模型的选择提供参考。     

Burden of cadmium in early childhood: Longitudinal assessment of urinary cadmium in rural Bangladesh

Chronic cadmium exposure is associated with many adverse health effects in adults, but little is known about the scenario early in life. This study assessed cadmium exposure and body burden in young children, born to women with known cadmium exposure via rice. As part of our ongoing population-based, longitudinal study of health effects of early-life toxicants exposure in rural Bangladesh, we measured cadmium in urine of about 350 children at 1.5 and 5 years of age, and in 92 children at 3 months of age. Median cadmium concentrations in urine were 0.30, 0.16 and 0.30 μg/L at 3 months, 1.5 and 5 years of age, respectively (0.6 μg/L in mothers). Cadmium concentrations in infant's urine correlated with concentrations in maternal breast milk, saliva, and urine. As expected, concentrations in urine increased from 1.5 to 5 years of age. Rice (median 47 μg Cd/kg) is most likely the main source of exposure. In conclusion, we found unexpectedly high cadmium exposure among children in rural Bangladesh. Urinary cadmium concentrations were particularly elevated at 3 months of age, indicating limited reabsorption and accumulation of cadmium in the kidneys, known to be the main site of cadmium burden in older children and adults.     

Recent applications of benchmark dose method for estimation of reference cadmium exposure for renal effects in man

The initial sign of cadmium (Cd)-induced renal effects is tubular damage, followed by glomerular damage. For the prevention of Cd-induced renal effects, it is essential to establish the reference exposure below which the risk of adverse health effects is low. In earlier Japanese studies, the estimated reference exposure of creatinine (cre)-adjusted urinary cadmium for renal tubular effect ranged from 1.6 to 4.0 μg/g cre in men and 2.3 to 4.6 μg/g cre in women. The benchmark dose (BMD) is defined as the exposure that corresponds to a certain response change from the background. The lower 95% confidence limit of the BMD (BMDL) can be used in risk assessment as a replacement for the no observed adverse effect level. This is a review of all relevant BMDL of Cd exposure for renal effects estimated so far. Based on studies in Japan, the best estimate is considered to be 1.5–3.2 μg/g cre for urinary Cd, 0.09–0.13 mg/kg for rice Cd concentration, and 0.9–1.4 g Cd for lifetime Cd intake. These BMDLs for renal effects were generally lower than the reference exposure expected from earlier studies, indicating the importance of further discussion regarding comprehensive measures to decrease the Cd exposure in the general population.     

The influence of cannabinoids on generic traits of neurodegeneration

In an increasingly ageing population, the incidence of neurodegenerative disorders such as Alzheimer''s disease, Parkinson''s disease and Huntington''s disease are rising. While the aetiologies of these disorders are different, a number of common mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support. Current therapies focus on treatment of the symptoms and attempt to delay the progression of these diseases but there is currently no cure. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB₁ and CB₂ receptors are known to be involved in the regulation of Ca²⁺ homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPARγ, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6     

槲皮素对阿尔茨海默病的作用机制研究新进展

阿尔茨海默病是老年人最常见的神经退行性疾病,由于世界人口老龄化的加快,阿尔茨海默病的发病率随之持续增长,中药或中药提取物对神经保护作用的研究不断增多.槲皮素是一种黄酮类化合物,能够保护神经元免受氧化损伤,减少脂质过氧化,抑制淀粉样蛋白的原丝形成.本文对槲皮素的来源、药代动力学、对阿尔茨海默病的作用机制的新进展进行了综述...     

Eugenol and its association with levodopa in 6‐hydroxydopamine‐induced hemiparkinsonian rats: Behavioural and neurochemical alterations

Parkinson's disease is a neurodegenerative disorder that affects the central nervous system and is mainly characterized by the loss of dopaminergic neurons and pro‐oxidant mechanisms. Eugenol has been widely studied due to its anti‐inflammatory and antioxidant activities, making it a promising neuroprotective agent. This study aimed to investigate the effects of eugenol and its combined action with levodopa in the 6‐hydroxydopamine‐induced Parkinson's disease model. Wistar rats were subjected to intrastriatal injection of 6‐hydroxydopamine (21 μg) and then treated with eugenol (0.1, 1, or 10 mg/kg), levodopa (25 mg/kg) or their combination (eugenol 10 mg/kg + levodopa 12.5 mg/kg) orally for 14 days. On the 14th day, the animals were subjected to behavioural tests, and after euthanization and dissection of the brain areas, neurochemical analyses were performed. The results showed that eugenol reduced the oxidative stress and behavioural disturbances induced by 6‐hydroxydopamine. The eugenol and levodopa combination was more effective in some behavioural parameters and body‐weight gain in addition to promoting an increase in reduced glutathione levels compared to levodopa alone. Thus, the neuroprotective activity of eugenol was observed against motor and neurochemical disorders. Additionally, the eugenol and levodopa combination was promising when compared to conventional treatment.     

白藜芦醇治疗阿尔茨海默病的研究进展

神经退行性疾病是一种慢性进展性疾病,其特点是中枢神经系统神经元的逐渐丧失。由于血脑屏障的存在,经典的抗炎药物如类固醇激素和非甾体类抗炎药,对神经系统疾病的治疗作用有限。因此,开发新的抗炎药物,对于预防和治疗神经系统疾病具有重要的意义。白藜芦醇是一种有很强活性的天然多酚类物质,目前研究已显示其具有心血管保护、神经保护、免疫调节、肿瘤的化学预防作用。近年来还发现其具有抗神经炎症作用,可用于治疗神经精神性疾病,如帕金森病、阿尔茨海默病(AD)和亨廷顿症等。综述白藜芦醇对AD的保护作用及其机制研究进展,为进一步推进白藜芦醇用于防治AD的研究提供参考。     

Arsenic exposure at low-to-moderate levels and skin lesions, arsenic metabolism, neurological functions, and biomarkers for respiratory and cardiovascular diseases: Review of recent findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh

The contamination of groundwater by arsenic in Bangladesh is a major public health concern affecting 35-75 million people. Although it is evident that high levels (> 300 μg/L) of arsenic exposure from drinking water are related to adverse health outcomes, health effects of arsenic exposure at low-to-moderate levels (10-300 μg/L) are not well understood. We established the Health Effects of Arsenic Longitudinal Study (HEALS) with more than 20,000 men and women in Araihazar, Bangladesh, to prospectively investigate the health effects of arsenic predominately at low-to-moderate levels (0.1 to 864 μg/L, mean 99 μg/L) of arsenic exposure. Findings to date suggest adverse effects of low-to-moderate levels of arsenic exposure on the risk of pre-malignant skin lesions, high blood pressure, neurological dysfunctions, and all-cause and chronic disease mortality. In addition, the data also indicate that the risk of skin lesion due to arsenic exposure is modifiable by nutritional factors, such as folate and selenium status, lifestyle factors, including cigarette smoking and body mass index, and genetic polymorphisms in genes related to arsenic metabolism. The analyses of biomarkers for respiratory and cardiovascular functions support that there may be adverse effects of arsenic on these outcomes and call for confirmation in large studies. A unique strength of the HEALS is the availability of outcome data collected prospectively and data on detailed individual-level arsenic exposure estimated using water, blood and repeated urine samples. Future prospective analyses of clinical endpoints and related host susceptibility will enhance our knowledge on the health effects of low-to-moderate levels of arsenic exposure, elucidate disease mechanisms, and give directions for prevention.     

Gene expression profiling and therapeutic interventions in neurodegenerative diseases: a comprehensive study on potentiality and limits

Introduction: Neurodegenerative diseases are incurable debilitating disorders of the nervous system that affect approximately 30 million people worldwide. Despite profuse efforts attempting to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. The novelty of their mechanisms represents a challenge to biology, to their related biomarkers identification and drug discovery. Because of their multifactorial aspects and complexity, gene expression analysis platforms have been extensively used to investigate altered pathways during degeneration and to identify potential biomarkers and drug targets.

Areas covered: This work offers an overview of the gene expression profiling studies carried out on Alzheimer's disease, Huntington's disease, Parkinson's disease and prion disease specimens. Therapeutic approaches are also discussed.

Expert opinion: Although many therapeutic approaches have been tested, some of them acting on several altered cellular pathways, no effective cures for these neurodegenerative diseases have been identified. Microarray technology must be associated with functional proteomics and physiology in an effort to identify specific and selective biomarkers and druggable targets, thus allowing the successful discovery of disease-modifying therapeutic treatments.     

西红花苷防治中枢神经系统疾病的研究进展

西红花苷是西红花中活性成分，具有多种药理作用。西红花苷具有出色的中枢神经系统保护作用，可以多维度、多途径地改善中枢神经系统疾病的神经功能，能抗抑郁、抗癫痫，对帕金森病、阿尔茨海默病、缺血性脑卒中、多发性硬化具有神经保护作用。综述了西红花苷防治中枢神经系统疾病的研究进展，以期提高西红花苷在临床治疗中的转化和应用。     

锰神经毒性机制研究进展

过量锰暴露可能会损害中枢神经系统,产生不可逆转的神经毒性,导致严重的神经退行性疾病。锰的神经毒性机制可能与转运稳态失调、氧化应激与线粒体损伤、自噬、蛋白质折叠错误、细胞凋亡、神经炎症有关,其中蛋白质错误折叠、线粒体损伤和神经炎症等又称锰神经毒性的3种主要损伤机制。本文对上述研究进展予以综述,以期为锰中毒防治提供科学依据。     

Uptake of silica nanoparticles: Neurotoxicity and Alzheimer-like pathology in human SK-N-SH and mouse neuro2a neuroblastoma cells

Growing concern has been raised over the potential adverse effects of engineered nanoparticles on human health due to their increasing use in commercial and medical applications. Silica nanoparticles (SiNPs) are one of the most widely used nanoparticles in industry and have been formulated for cellular and non-viral gene delivery in the central nerve system. However, the potential neurotoxicity of SiNPs remains largely unclear. In this study, we investigated the cellular uptake of SiNPs in human SK-N-SH and mouse neuro2a (N2a) neuroblastoma cells treated with 10.0 μg/ml of 15-nm SiNPs for 24 h by transmission electron microscopy. We found that SiNPs were mainly localized in the cytoplasm of the treated cells. The treatment of SiNPs at various concentrations impaired the morphology of SK-N-SH and N2a cells, characterized by increased number of round cells, diminishing of dendrite-like processes and decreased cell density. SiNPs significantly decreased the cell viability, induced cellular apoptosis, and elevated the levels of intracellular reactive oxygen species (ROS) in a dose-dependent manner in both cell lines. Additionally, increased deposit of intracellular β-amyloid 1-42 (Aβ_1-42) and enhanced phosphorylation of tau at Ser262 and Ser396, two specific pathological hallmarks of Alzheimer's disease (AD), were observed in both cell lines with SiNPs treatment. Concomitantly, the expression of amyloid precursor protein (APP) was up-regulated, while amyloid-β-degrading enzyme neprilysin was down-regulated in SiNP-treated cells. Finally, activity-dependent phosphorylation of glycogen syntheses kinase (GSK)-3β at Ser9 (inactive form) was significantly decreased in SiNP-treated SK-N-SH cells. Taken together, these data demonstrated that exposure to SiNPs induced neurotoxicity and pathological signs of AD. The pre-Alzheimer-like pathology induced by SiNPs might result from the dys-regulated expression of APP/neprilysin and activation of GSK-3β. This is the first study with direct evidence indicating that in addition to neurotoxicity induced by SiNPs, the application of SiNPs might increase the risk of developing AD.     

The monoamine oxidase inhibitory activity of essential oils obtained from Eryngium species and their chemical composition

Context Monoamine oxidase (MAO) inhibitors are used in the treatment of depression, anxiety disorders, and the symptomatic treatment of Parkinson's disease. Eryngium, the most representative of the Apiaceae family, is well known for the presence of essential oils (EOs), which have already demonstrated MAO inhibitory potential.

Objective The objective of this study is to evaluate the MAO inhibitory capacity of the EOs obtained from Eryngium floribundum Cham. & Schlecht. (EF), E. eriophorum Cham. & Schlecht. (EE), E. nudicaule Lam. (EN), E. horridum Malme (EH), and E. pandanifolium Cham. & Schlecht. (EP).

Materials and methods EOs were obtained from fresh whole plants by hydrodistillation (3?h). Chemical analyses were performed by GC/MS using apolar and polar columns, with oven temperature from 60 to 300?°C at 3?°C/min. The MAO-A and -B activities were evaluated in vitro by an end-point method using kynuramine as the substrate and mitochondrial suspension or human recombinant enzymes as the enzymatic source. DMSO 2%, clorgyline 10^?7 M, and pargyline 10^?6 M were used as controls.

Results and discussion EFEO, EEEO, ENEO, EHEO, and EPEO GC/MS analysis showed (E)-caryophyllene (4.9–10.8%), germacrene D (0.6–35.1%), bicyclogermacrene (10.4–17.2), spathulenol (0.4–36.0%), and globulol (1.4–18.6%) as main constituents. None of the EOs inhibited MAO-A activity (4 and 40?μg/mL). However, EHEO inhibited MAO-B activity with an IC₅₀ value of 5.65?μg/mL (1–200?μg/mL). Pentadecane (10?μM), its major constituent (53.5%), did not display significant MAO-B inhibition.

Conclusion The study demonstrates the promising application of Eryngium species as a source of potential central nervous system bioactive secondary metabolites, specially related to neurodegenerative disorders.     

阿尔茨海默病的纳米疗法研究进展

阿尔茨海默病(alzheimer's disease,AD)是一种中枢神经退行性疾病,在社会人口老龄化日益加剧的今天,AD患病率不断上升,其严重程度足以干扰人类的日常生活,危害人类的健康.目前AD的发病机制尚不明确,没有有效的药物可以治愈AD.血脑屏障(Blood brain barrier,BBB)是血液循环与中枢神经系统之间的生物屏障,药物不能穿过BBB,使其在治疗中枢神经系统疾病时有一定的局限性.纳米释药系统可以非侵入性地将药物递送至大脑,通过靶向药物递送,可以降低药物的毒性,增加药物的生物利用度.本文简述了AD发病的几种假说,介绍了与AD相关的纳米药物(Nanomedicines,NMs)种类和研究进展,对纳米递药技术在AD治疗策略中的应用进行阐述和列举,为AD的NMs研究提供思路和参考.     

淫羊藿苷改善中枢神经系统疾病的研究进展

淫羊藿苷是淫羊藿中主要活性成分,具有抗肿瘤、抗炎、增强免疫、抗肝毒性、抗氧化等多种药理活性。淫羊藿苷可通过多靶点、多途径对中枢神经系统疾病产生保护作用,如淫羊藿苷具有抗抑郁作用,对阿尔茨海默病、帕金森病、缺血性脑卒中、多发性硬化具有保护作用。为了进一步扩大淫羊藿苷在临床治疗中的应用,综述了淫羊藿苷改善中枢神经系统疾病及其作用机制。     

Environmental exposure to mercury and its toxicopathologic implications for public health

Mercury is a toxic and hazardous metal that occurs naturally in the earth's crust. Natural phenomena such as erosion and volcanic eruptions, and anthropogenic activities like metal smelting and industrial production and use may lead to substantial contamination of the environment with mercury. Through consumption of mercury in food, the populations of many areas, particularly in the developing world, have been confronted with catastrophic outbreaks of mercury-induced diseases and mortality. Countries such as Japan, Iraq, Ghana, the Seychelles, and the Faroe Islands have faced such epidemics, which have unraveled the insidious and debilitating nature of mercury poisoning. Its creeping neurotoxicity is highly devastating, particularly in the central and peripheral nervous systems of children. Central nervous system defects and erethism as well as arrythmias, cardiomyopathies, and kidney damage have been associated with mercury exposure. Necrotizing bronchitis and pneumonitis arising from inhalation of mercury vapor can result in respiratory failure. Mercury is also considered a potent immunostimulant and -suppressant, depending on exposure dose and individual susceptibility, producing a number of pathologic sequelae including lymphoproliferation, hypergammaglobulinemia, and total systemic hyper- and hyporeactivities. In this review we discuss the sources of mercury and the potential for human exposure; its biogeochemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences on its toxicity; as well as the important considerations in risk assessment and management of mercury poisoning.     

Uptake and disposition of 1,1-difluoroethane (HFC-152a) in humans

The aim of this study was to determine the toxicokinetics of inhaled 1,1-difluoroethane (HFC-152a) in humans. Healthy volunteers were exposed to 0, 200 or 1000 ppm 1,1-difluoroethane for 2 h at light exercise in an exposure chamber. Capillary blood, urine and exhaled air were sampled up to 22 h post-exposure and analyzed for 1,1-difluoroethane. Fluoride and other potential metabolites were analyzed in urine. Symptoms of irritation and central nervous system effects were rated and inflammatory markers were analyzed in blood. Within a few minutes of exposure to 200 and 1000 ppm, 1,1-difluoroethane increased rapidly in blood and reached average levels of 7.4 and 34.3 μM, respectively. The post-exposure decreases in blood were fast and parallel to those in exhaled air. The observed time courses in blood and breath agreed well with those obtained with the PBPK model. The PBPK simulations indicate a net uptake during exposure to 1000 ppm of 6.6 mmol (6.7%) which corresponds to the amount exhaled post-exposure. About 20 μmol excess fluoride (0.013% of inhaled 1,1-difluoroethane on a molar basis) was excreted in urine after exposure to 1000 ppm, compared to control. No fluorine-containing metabolites were detected in urine. Symptom ratings and changes in inflammatory markers revealed no exposure-related effects.