Effect of synthetic cannabinoids on spontaneous neuronal activity: Evaluation using Ca 2+ spiking and multi-electrode arrays

Tauskela, Joseph S.; Comas, Tanya; Hewitt, Melissa; Aylsworth, Amy; Zhao, Xigeng; Martina, Marzia; Costain, Willard J.

doi:10.1016/j.ejphar.2016.05.038

Cited by 12 publications

(5 citation statements)

References 47 publications

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“…Furthermore, JWH-210 can cause central nervous system depression, cerebral seizures, and sympathomimetic toxicity (Hermanns-Clausen et al, 2016; Hermanns-Clausen et al, 2013). MAM-2201 suppresses neurotransmission, alters energy metabolism, inhibits CYP1A activity in liver, and produces cytotoxicity in forebrain (Ashino et al, 2014; Irie et al, 2015; Tauskela et al, 2016; Tomiyama & Funada, 2014; Zaitsu et al, 2015a).…”

Section: 0 Introductionmentioning

confidence: 99%

Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists

et al. 2018

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Diversion of synthetic cannabinoids from the lab to drugs of abuse has become increasingly prevalent in recent years. Moreover, as earlier synthetic cannabinoids were banned, manufacturers introduced a new supply of novel compounds to serve as replacements. Hence, the chemical diversity of synthetic cannabinoid analogs has also rapidly increased. The present study examined 8 new synthetic cannabinoids: AM-1220, AM-2232, AM-2233, AM-679, EAM-2201, JWH-210, JHW-251, and MAM-2201. Each compound was assessed for binding affinity and functional activation of CB and CB receptors, and pharmacological equivalence with Δ-tetrahydrocannabinol (THC) in THC drug discrimination. All compounds bound to and activated CB and CB receptors, although efficacy at the CB receptor was reduced compared to that for the CB receptor. Similarly, all compounds stimulated [S]GTPγS binding through the CB receptor, and all compounds except AM-1220 and AM-2233 stimulated [S]GTPγS binding through the CB receptor. Furthermore, these compounds, along with CP55,940, substituted for THC in THC drug discrimination. Rank order of potency in drug discrimination was correlated with CB receptor binding affinity. Together, these results suggest that all test compounds share the THC-like subjective effects of marijuana. Interestingly, the most potent compounds in CB binding in the present study were also the compounds that have been found recently in the U.S., MAM-2201, EAM-2201, JWH-210, AM-2233, and AM-1220. These results indicate that the evolution of the synthetic cannabinoid drug market may be focused toward compounds with increased potency. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

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Section: 0 Introductionmentioning

confidence: 99%

Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists

et al. 2018

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“…The tested MAM-2201 concentrations (1–30 μM) were selected based on literature findings from in vitro studies carried out on brain cultures (rodent) that evidenced early cytotoxic effects (2–24 h, from 10 to 30 μM MAM-2201 treatment): MAM-2201 acted as a CB1R agonist and induced acute cytotoxicity by the involvement of caspase cascade-mediated apoptosis [ 24 , 25 , 27 , 28 , 29 ]. Moreover, we recently demonstrated MAM-2201 cytotoxicity in a human astrocyte line cultured in a monolayer (2D), in which the density decrease was noticeable at 30 μM after 24 h and at 10 μM after 48, and the caspase-3/7 activity impairment was evidenced at 5–30 μM, although transitorily (i.e., after 3 h of exposure only) [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

“…Currently, toxicity data on SCs and in particular on MAM-2201, which has been frequently identified in herbal blends or in powder products, are mainly obtained from studies performed on in vitro rodent cells and in vivo animal models [ 24 , 25 , 26 ]. The limited experimental evidence on neuronal cultures (rodent) indicate that MAM-2201 exposure can cause impairments of neuronal function and activity, as well as the inhibition of neurotransmitter release, which are effects likely mediated by the CB1 receptor [ 25 , 27 , 28 , 29 ]. Moreover, abnormal behaviors have been observed in animal models [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS

Simone

Pignatti

Villani

et al. 2023

IJMS

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There is growing concern about the consumption of synthetic cannabinoids (SCs), one of the largest groups of new psychoactive substances, its consequence on human health (general population and workers), and the continuous placing of new SCs on the market. Although drug-induced alterations in neuronal function remain an essential component for theories of drug addiction, accumulating evidence indicates the important role of activated astrocytes, whose essential and pleiotropic role in brain physiology and pathology is well recognized. The study aims to clarify the mechanisms of neurotoxicity induced by one of the most potent SCs, named MAM-2201 (a naphthoyl-indole derivative), by applying a novel three-dimensional (3D) cell culture model, mimicking the physiological and biochemical properties of brain tissues better than traditional two-dimensional in vitro systems. Specifically, human astrocyte spheroids, generated from the D384 astrocyte cell line, were treated with different MAM-2201 concentrations (1–30 µM) and exposure times (24–48 h). MAM-2201 affected, in a concentration- and time-dependent manner, the cell growth and viability, size and morphological structure, E-cadherin and extracellular matrix, CB1-receptors, glial fibrillary acidic protein, and caspase-3/7 activity. The findings demonstrate MAM-2201-induced cytotoxicity to astrocyte spheroids, and support the use of this human 3D cell-based model as species-specific in vitro tool suitable for the evaluation of neurotoxicity induced by other SCs.

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“…Comparatively, differently from hNLCs, human SH‐SY5Y‐neurons, a cancer‐derived cell line, were not susceptible to MAM 2201 tested under the same conditions (Coccini et al., 2021). So far, the in vitro neurotoxicity of MAM 2201 has been predominantly evaluated on rodent brain cultures (Costain et al., 2016; Irie et al., 2015; Tomiyama & Funada, 2011, 2014; Tauskela et al., 2016). By comparing in vitro animal data with that obtained from hNLCs after MAM 2201 treatment, higher susceptibility was observed in the human NLCs, suggesting that human cells may be more susceptible than animal models (Coccini et al., 2021).…”

Section: Commentarymentioning

confidence: 99%

Human Umbilical Cord Mesenchymal Stem Cell–Based in vitro Model for Neurotoxicity Testing

et al. 2022

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Neurotoxicity (NT) testing for regulatory purposes is based on in vivo animal testing. There is general consensus, however, about the need for the development of alternative methodologies to allow researchers to more rapidly and cost effectively screen large numbers of chemicals for their potential to cause NT, or to investigate their mode of action. In vitro assays are considered an important source of information for making regulatory decisions, and human cell-based systems are recommended as one of the most relevant models in toxicity testing, to reduce uncertainty in the extrapolation of results from animal-based models. Human neuronal models range from various neuroblastoma cell lines to stem cell-derived systems, including those derived from mesenchymal stem/stromal cells (hMSC). hMSCs exhibit numerous advantages, including the fact that they can be obtained in high yield from healthy human adult tissues, can be cultured with a minimal laboratory setup and without genetic manipulations, are able of continuous and repeated self-renewal, are nontumorigenic, and can form large populations of stably differentiated cells representative of different tissues, including neuronal cells. hMSCs derived from human umbilical cord (hUC) in particular possess several prominent advantages, including a painless, non-invasive, and ethically acceptable collection procedure, simple and convenient preparation, and high proliferation capacity. In addition, hMSCs can be efficiently differentiated into neuron-like cells (hNLCs), which can then be used for the assessment of neuronal toxicity of potential neurotoxic compounds in humans. Here, we describe a step-by-step procedure to use hMSCs from the umbilical cord for in vitro neurotoxicity testing. First, we describe how to isolate, amplify, and store hMSCs derived from the umbilical cord. We then outline the steps to transdifferentiate these cells into hNLCs, and then use the hNLCs for neurotoxicity testing by employing multiple common cytotoxicity assays after treatment with test compounds. The approach follows the most updated guidance on using human cell-based systems. These protocols will allow investigators to implement an alternative system for obtaining primary NLCs of human origin, and support advancement in neurotoxicity research.

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Effect of synthetic cannabinoids on spontaneous neuronal activity: Evaluation using Ca 2+ spiking and multi-electrode arrays

Cited by 12 publications

References 47 publications

Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists

Finding order in chemical chaos - Continuing characterization of synthetic cannabinoid receptor agonists

Human Astrocyte Spheroids as Suitable In Vitro Screening Model to Evaluate Synthetic Cannabinoid MAM2201-Induced Effects on CNS

Human Umbilical Cord Mesenchymal Stem Cell–Based in vitro Model for Neurotoxicity Testing

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