Application of In Vitro Models in Developmental Neurotoxicity and Pharmaceutics Research

doi:10.4172/2329-9053.1000e122

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…Whether MXE is as potent in a human in vitro model, is currently unknown. Since in vitro neurotoxicity testing is shifting towards using models of human origin (Wang, 2015;Shinde et al, 2016;Schmidt et al, 2017), we selected several models of human origin, including human embryonic kidney cells (HEK293), a human neuronal cell line (SH-SY5Y), human induced pluripotent stem cell (iPSC)-derived neurons and iPSC-derived astrocytes. Since MXE is a ketamine analogue, we also investigated neuropharmacological effects of ketamine.…”

Section: Introductionmentioning

confidence: 99%

Neuropharmacological characterization of the new psychoactive substance methoxetamine

et al. 2017

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a b s t r a c tThe use of new psychoactive substances (NPS) is steadily increasing. One commonly used NPS is methoxetamine (MXE), a ketamine analogue. Several adverse effects have been reported following MXE exposure, while only limited data are available on its neuropharmacological modes of action.We investigated the effects of MXE and ketamine on several endpoints using multiple in vitro models. These included rat primary cortical cells, human SH-SY5Y cells, human induced pluripotent stem cell (hiPSC)-derived iCell ® Neurons, DopaNeurons and astrocyte co-cultures, and human embryonic kidney (HEK293) cells. We investigated effects on several neurotransmitter receptors using single cell intracellular calcium [Ca 2þ ] i imaging, effects on neuronal activity using micro-electrode array (MEA) recordings and effects on human monoamine transporters using a fluorescence-based plate reader assay.In rat primary cortical cells, 10 mM MXE increased the glutamate-evoked increase in [Ca 2þ ] i , whereas 10 mM ketamine was without effect. MXE and ketamine did not affect voltage-gated calcium channels (VGCCs), but inhibited spontaneous neuronal activity (IC 50 0.5 mM and 1.2 mM respectively). In human SH-SY5Y cells, 10 mM MXE slightly inhibited the K Our combined in vitro data provide an urgently needed first insight into the multiple modes of action of MXE. The use of different models and different (neuronal) endpoints can be complementary in pharmacological profiling. Rapid in vitro screening methods as those presented here, could be of utmost importance for gaining a first mechanistic insight to aid the risk assessment of emerging NPS.

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Section: Introductionmentioning

confidence: 99%

Neuropharmacological characterization of the new psychoactive substance methoxetamine

et al. 2017

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“…NSCs response to the external stimuli varies with the age of the donor [7], site in the nervous system and due to the diversity in their local environment [8,9]. The SVZ presents the major niche of NSCs where primary and secondary neurogenesis occurs primarily [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Troxerutin flavonoid has neuroprotective properties and increases neurite outgrowth and migration of neural stem cells from the subventricular zone

et al. 2020

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Troxerutin (TRX) is a water-soluble flavonoid which occurs commonly in the edible plants. Recent studies state that TRX improves the functionality of the nervous system and neutralizes Amyloid-ß induced neuronal toxicity. In this study, an in vitro assay based upon Neural stem cell (NSCs) isolated from the subventricular zone of the postnatal balb/c mice was established to explore the impact of TRX on individual neurogenesis processes in general and neuroprotective effect against ß-amyloid 1-42 (Aß42) induced inhibition in differentiation in particular. NSCs were identified exploiting immunostaining of the NSCs markers. Neurosphere clonogenic assay and BrdU/Ki67 immunostaining were employed to unravel the impact of TRX on proliferation. Differentiation experiments were carried out for a time span lasting from 48 h to 7 days utilizing ß-tubulin III and GFAP as neuronal and astrocyte marker respectively. Protective effects of TRX on Aß42 induced depression of NSCs differentiation were determined after 48 h of application. A neurosphere migration assay was carried out for 24 h in the presence and absence of TRX. Interestingly, TRX enhanced neuronal differentiation of NSCs in a dose-dependent manner after 48 h and 7 days of incubation and significantly enhanced neurite growth. A higher concentration of TRX also neutralized the inhibitory effects of Aß42 on neurite outgrowth and length after 48 h of incubation. TRX significantly stimulated cell migration. Overall, TRX not only promoted NSCs differentiation and migration but also neutralized the inhibitory effects of Aß42 on NSCs. TRX, therefore, offers an interesting lead structure from the perspective of drug design especially to promote neurogenesis in neurological disorders i.e. Alzheimer's disease.

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“…Whether MXE is as potent in a human in vitro model, is currently unknown. Since in vitro neurotoxicity testing is shifting towards using models of human origin (Schmidt et al 2017;Shinde et al 2016;Wang 2015), we selected several models of human origin, including human embryonic kidney cells (HEK293), a human neuronal cell line (SH-SY5Y), human induced pluripotent stem cell (iPSC)-derived neurons and iPSC-derived astrocytes. Since MXE is a ketamine analogue, we also investigated neuropharmacological effects of ketamine.…”

Section: Introductionmentioning

confidence: 99%

Next Generation Risk Assessment of Chemicals

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Interspecies differences can be evaluated by comparing in vitro tests in rat tissue and human tissue, for example, to evaluate differences in toxicokinetics and toxicodynamics. These differences can then be applied to in vivo data and the UF for interspecies differences may be altered. PBK models can also evaluate interspecies differences, by incorporating species differences in metabolism, transporter expression, plasma protein binding, etc. (Punt et al. 2020).Second, in vitro and in silico approaches can also facilitate the evaluation of the intraspecies UF, both for toxicokinetic and toxicodynamic differences. The use of primary human hepatocytes, for example, can give information on human variability in biotransformation and refine the UF for toxicokinetics. However, human primary cells are difficult to obtain and they have a finite lifespan in culture (Grskovic et al. 2011).Moreover, not every human tissue is readily available for testing in vitro. On the contrary, stem cells can be differentiated into all kinds of cell types. Different types of stem cells (e.g. embryonic stem cells, adult human stem cells) are now being used in toxicology.Recently, a new class of stem cells have entered the toxicology arena: human induced pluripotent stem cells (hiPSCs). hiPSCs are generated from adult reprogrammed somatic cells and are ethically preferred over embryonic and foetal stem cells (Scott et al. 2013). These cells have the ability to be reprogrammed into specific types of cells, like cardiomyocytes, neurons and hepatocytes, which provides an opportunity for testing effects of chemicals on different cell types from specific (groups of) people (Anson et al. 2011). Human variability can be measured using hiPSCs from different donors (Anson et al. 2011;Caballero et al. 2016).In vitro approaches to better understand toxicodynamic processes are used to move away from the 'black box' animal system (see 'A shifting toxicological testing paradigm') and can also provide a refinement of the UF for toxicodynamics. For example, using cell systems like primary cultures or hiPSCs, not only variability in toxicokinetics can be quantified, but also variability in toxicodynamics. However, knowledge on toxicodynamics should capture all relevant biological targets and pathways, in order to be able to translate in vitro data to the in vivo situation using QIVIVE (Punt et al. 2020).

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Application of In Vitro Models in Developmental Neurotoxicity and Pharmaceutics Research

Cited by 3 publications

References 12 publications

Neuropharmacological characterization of the new psychoactive substance methoxetamine

Neuropharmacological characterization of the new psychoactive substance methoxetamine

Troxerutin flavonoid has neuroprotective properties and increases neurite outgrowth and migration of neural stem cells from the subventricular zone

Next Generation Risk Assessment of Chemicals

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