Neuronal models for evaluation of proliferation in vitro using high content screening☆

Mundy, William R.; Radio, Nicholas M.; Freudenrich, Theresa M.

doi:10.1016/j.tox.2010.02.004

Cited by 46 publications

(30 citation statements)

References 41 publications

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“…PC12 cell is a very common and useful cell line widely employed to examine the effect of different chemicals on neuron protection due to its sensitivity and low variability (Mundy et al, 2010). Rat adrenal pheochromocytoma PC12 cell line, obtained from the American Type Culture Collection (ATCC; Manassas, Va., USA), was cultured in a growth medium consisting of Dulbecco's Modified Eagle Medium (DMEM), 5% fetal bovine serum (FBS), 10% horse serum (HS), 0.2% pyruvate and 0.5% gentamicin (50 mg/mL).…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

Protective properties of Salvia lavandulifolia Vahl. essential oil against oxidative stress-induced neuronal injury

Porres-Martínez

González-Burgos

Carretero

et al. 2015

Food and Chemical Toxicology

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Section: Cell Culture and Treatmentmentioning

confidence: 99%

Protective properties of Salvia lavandulifolia Vahl. essential oil against oxidative stress-induced neuronal injury

Porres-Martínez

González-Burgos

Carretero

et al. 2015

Food and Chemical Toxicology

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“…Application of a multiplex assay analogous to the quadprobe HCA assay with measurements for mitochondrial activity, apoptosis, plasma membrane permeability and DNA in human kidney cells (HK-2) revealed proximal tubule injury potential of compounds [34]. Several studies have demonstrated that neurotoxicity can be effectively screened for using HCA analysis of rat PC12, mouse N1E-115 and human SH-SY5Y neuronal cell lines for assessment of neurite outgrowth [35] and inhibition of cell proliferation [36].…”

Section: M72mentioning

confidence: 99%

High‐Content Analysis in Toxicology: Screening Substances for Human Toxicity Potential, Elucidating Subcellular Mechanisms and In Vivo Use as Translational Safety Biomarkers

O’Brien

2014

Basic Clin Pharma Tox

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High-content analysis (HCA) of in vitro biochemical and morphological effects of classic (small molecule) drugs and chemicals is concordant with potential for human toxicity. For hepatotoxicity, concordance is greater for cytotoxic effects assessed by HCA than for conventional cytotoxicity tests and for regulatory animal toxicity studies. Additionally, HCA identifies chronic toxicity potential, and drugs producing idiosyncratic adverse reactions and/or toxic metabolites are also identified by HCA. Mechanistic information on the subcellular basis for the toxicity is frequently identified, including various mitochondrial effects, oxidative stress, calcium dyshomeostasis, phospholipidosis, apoptosis and antiproliferative effects, and a fingerprinting of the sequence and pattern of subcellular events. As these effects are frequently non-specific and affect many cell types, some toxicities may be detected and monitored by HCA of peripheral blood cells, such as for anticancer and anti-infective drugs. Critical methodological and interpretive features are identified that are critical to the effectiveness of the HCA cytotoxicity assessment, including the need for multiple days of exposure of cells to drug, use of a human hepatocyte cell line with metabolic competence, assessment of multiple pre-lethal effects in individual live cells, consideration of hormesis, the need for interpretation of relevance of cytotoxicity concentration compared to efficacy concentration and quality management. Limitations of the HCA include assessment of drugs that act on receptors, transporters or processes not found in hepatocytes. HCA may be used in a) screening lead candidates for potential human toxicity in drug discovery alongside of in vitro assessment of efficacy and pharmacokinetics, b) elucidating mechanisms of toxicity and c) monitoring in vivo toxicity of drugs with known toxicity of known mechanism.Classic (small molecule) drug toxicity is one of the major challenges for the pharmaceutical industry, not only because of the associated loss of human life or health, but because of enormous financial loss of past investment and of future revenue potential. Attrition of drugs is progressively more costly the later it occurs. It costs almost two billion dollars to bring the average drug through discovery and development to registration [1]. Furthermore, typically 10-12 years of investment of time by hundreds of pharmaceutical staff will have been mis-spent.Drug safety has been an important cause of this attrition. Analysis of safety attrition of approved drugs over a 25-year period ending in 1999 indicated an annual average of 0.7 approved drugs was withdrawn and two drugs received black box warnings [2]. From 1994 to 2006, the average safety attrition was even higher with 2.1 drugs per year, with 38 drugs withdrawn from the market by the US Food and Drug Agency More than 80% of market withdrawals due to drug toxicity were due to cardiotoxicity and hepatotoxicity. In 2003, druginduced liver injury was found to be the most fr...

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“…Neurite loss is one of the core pathologies of AD and application of HCS to quantify neuronal outgrowth has already been achieved and proven to be faster than traditional manual tracing methods [41,43] . Assessment of chemical toxicity has also been demonstrated by HCS in three neuronal cell lines, whereby proliferation was detected by BrdU incorporation (an indicator of actively proliferating cells) and cell counts were obtained with Hoechst 33342 nuclear dye in a 96-well plate format [44] . HCS has applications in additional areas of neuroscience including neurogenesis, cell signalling and inclusion formation as reviewed by Dragunow [45] .…”

Section: High Throughput Screening Of Novel Therapeutics For Ad: Inmentioning

confidence: 99%

Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

Mohamet

Miazga²,

Ward³

2014

WJSC

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Alzheimer's disease (AD) is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks. Diagnosis of AD is difficult, particularly in early stages of the disease, and largely consists of cognitive assessments, with only one in four patients being correctly diagnosed. Development of novel therapeutics for the treatment of AD has proved to be a lengthy, costly and relatively unproductive process with attrition rates of > 90%. As a result, there are no cures for AD and few treatment options available for patients. Therefore, there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications. Here, we discuss the use of induced pluripotent stem cells (iPSCs), which can be derived from adult cells, as a method of recapitulation of AD phenotype in vitro . We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy, toxicology and disease modelling. At present, a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications. However, whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field, it is one with immense potential that is likely to reach fruition within the next few years.© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.Key words: Human induced pluripotent stem cells; Alzheimer's disease; Neurodegenerative diseases; Highthroughput screening assays; Cholinergic neurons; Drug discovery; Stratified medicine Core tip: Alzheimer's disease (AD) affects 36 million people worldwide and is set to double by 2030. Progress in understanding AD has been hindered by a lack of suitable in vitro and in vivo models reflected in > 90% drug attrition rates. Induced pluripotent stem cells are an alternative source of neural cells that can be derived from patients' somatic cells and exhibit AD pathophysiological phenotypes. These cells are amenable to HTS formats required for drug discovery applications. Harnessing this combined potential would provide an unprecedented opportunity to significantly reduce timeframes and costs associated with developing novel therapeutics, ultimately improving patient outcomes.Mohamet L, Miazga NJ, Ward CM. Familial Alzheimer's disease modelling using induced pluripotent stem cell technology. World J Stem Cells 2014; 6(2): 239-247 Available from:

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Neuronal models for evaluation of proliferation in vitro using high content screening☆

Cited by 46 publications

References 41 publications

Protective properties of Salvia lavandulifolia Vahl. essential oil against oxidative stress-induced neuronal injury

Protective properties of Salvia lavandulifolia Vahl. essential oil against oxidative stress-induced neuronal injury

High‐Content Analysis in Toxicology: Screening Substances for Human Toxicity Potential, Elucidating Subcellular Mechanisms and In Vivo Use as Translational Safety Biomarkers

Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

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