Hazard Characterization of Synthetic Cathinones Using Viability, Monoamine Reuptake, and Neuronal Activity Assays

Zwartsen, Anne; Olijhoek, Michiel E.; Westerink, Remco H.S.; Hondebrink, Laura

doi:10.3389/fnins.2020.00009

Cited by 19 publications

(18 citation statements)

References 54 publications

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“…The increased symptoms were associated with a statistically and clinically significant decrease in CBF compared to HC. Extending these findings, we show that working memory function, as assessed by the n -back test, decreased immediately after HUT ( 35 ). Furthermore, we show a decrease in pressure pain thresholds (PPT) immediately after orthostatic stress similar to PPT changes in ME/CFS patients after an exercise stressor ( 36 ).…”

Section: Discussionsupporting

confidence: 72%

Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Campen¹,

Rowe

Verheugt

et al. 2021

Front. Med.

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Introduction: Muscle pain, fatigue, and concentration problems are common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These symptoms are commonly increased as part of the phenomenon of postexertional malaise (PEM). An increase in the severity of these symptoms is described following physical or mental exercise in ME/CFS patients. Another important symptom of ME/CFS is orthostatic intolerance, which can be detected by head-up tilt testing (HUT). The effect of HUT on PEM has not been studied extensively. For this purpose, we assessed numeric rating scales (NRS) for pain, fatigue, and concentration pre- and post-HUT. As pain is a core symptom in fibromyalgia (FM), we subgrouped ME/CFS patients by the presence or absence of FM.Methods and Results: In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days posttest. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM. In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT.Conclusion: NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM.

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Section: Discussionsupporting

confidence: 72%

Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Campen¹,

Rowe

Verheugt

et al. 2021

Front. Med.

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“…Plates, covered in aluminum foil, were placed on a plate shaker for approximately 30 min before fluorescence was measured at 530/645 nm. Cell viability was calculated according to Zwartsen, Hondebrink [30,31] and expressed as mean ± SEM of n wells from N plates . In total, 3.3% of the values were considered outliers.…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

Cardiotoxicity screening of illicit drugs and new psychoactive substances (NPS) in human iPSC-derived cardiomyocytes using microelectrode array (MEA) recordings

Zwartsen

Korte

Nacken³

et al. 2019

Journal of Molecular and Cellular Cardiology

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The use of recreational drugs, including new psychoactive substances (NPS), is paralleled by emergency department visits of drug users with severe cardiotoxicity. Drug-induced cardiotoxicity can be the (secondary) result of increased norepinephrine blood concentrations, but data on potential drug-induced direct effects on cardiomyocyte function are scarce. The presence of hundreds of NPS therefore calls for efficient screening models to assess direct cardiotoxicity.We investigated effects of four reference compounds (3-30 nM dofetilide, nifedipine and isoproterenol, and 1-10 μM mexiletine) and six recreational drugs (0.01-100 μM cocaine, 0.01-1000 μM amphetamine, MDMA, 4fluoroamphetamine, α-PVP and MDPV) on cardiomyocyte function (beat rate, spike amplitude and field potential duration (FPD ≈ QT interval in ECGs)), using Pluricyte® human-induced pluripotent stem cell (hiPSC)derived cardiomyocytes cultured on ready-to-use CardioPlate™ multi-well microelectrode arrays (mwMEAs). Moreover, the effects of exposure to recreational drugs on cell viability were assessed.Effects of reference compounds were in accordance with the literature, indicating the presence of hERG potassium (dofetilide), sodium (mexiletine) and calcium (nifedipine) channels and α-adrenergic receptors (isoproterenol). All recreational drugs decreased the spike amplitude at 10-100 μM. All amphetamine-type stimulants and α-PVP decreased the beat rate at 300 μM, while cocaine and MDPV did so at 10 μM and 30 μM, respectively. All drugs increased the FPD, however at varying concentrations. MDMA, MDPV and amphetamine affected cardiomyocyte function at concentrations relevant for human exposure, while other drugs affected cardiomyocyte function only at higher concentrations (≥ 10 μM). Cell viability was only mildly affected at concentrations well above the lowest concentrations affecting cardiomyocyte function.We demonstrate that MEA recordings of hiPSC-derived cardiomyocytes enable screening for acute, direct effects on cardiomyocyte function. Our data further indicate that tachycardia in patients exposed to recreational drugs is likely due to indirect drug effects, while prolonged repolarization periods (prolonged QT c interval) could (partly) result from direct drug effects on cardiomyocyte function. entered the drug market around a decade ago [1]. Currently, there are over 700 of these 'legal highs' and the lifetime prevalence of NPS use is comparable to or even higher than that of 'classic' illicit drugs in specific groups, especially in young adults (15-24 years) [2]. NPS are manufactured to induce effects comparable to illicit drugs by modifying their chemical structures, thereby making them legal when entering the

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“…MDPV impact on the vesicular/plasma transporters and the synaptic levels of monoamines, thermoregulation, oxidative stress, and cytotoxicity may represent an important mechanism of action [ 25 ]. However, data on the underlying mechanisms of MDPV induced neurotoxicity is not abundant [ 4 , 22 , 26 , 27 ] and mostly circumscribed to in vitro studies [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ], hampering proper risk characterization and adverse effect management [ 2 , 5 , 25 ]. Indeed, the scarce data available suggests that synthetic cathinones may exert differential neurotoxic properties on monoaminergic neurons and elicit more complex responses than non-keto amphetamines (e.g., METH) [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

et al. 2021

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3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, C57BL/6J mice were exposed to a binge MDPV or METH regimen (four intraperitoneal injections every 2 h, 10 mg/kg). Locomotor, exploratory, and emotional behavior, in addition to striatal neurotoxicity and glial signature, were assessed within 18–24 h, a known time-window encompassing classical amphetamine dopaminergic neurotoxicity. MDPV resulted in unchanged locomotor activity (open field test) and emotional behavior (elevated plus maze, splash test, tail suspension test). Additionally, striatal TH (METH neurotoxicity hallmark), Iba-1 (microglia), GFAP (astrocyte), RAGE, and TLR2/4/7 (immune modulators) protein densities remained unchanged after MDPV-exposure. Expectedly, and in sheer contrast with MDPV, METH resulted in decrease general locomotor activity paralleled by a significant striatal TH depletion, astrogliosis, and microglia arborization alterations (Sholl analysis). This comparative study newly highlights that binge MDPV-exposure comes without evident behavioral, neurochemical, and glial changes at a time-point where METH-induced striatal neurotoxicity is clearly evident. Nevertheless, neuropharmacological MDPV signature needs further profiling at different time-points, regimens, and brain regions.

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Hazard Characterization of Synthetic Cathinones Using Viability, Monoamine Reuptake, and Neuronal Activity Assays

Cited by 19 publications

References 54 publications

Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Cardiotoxicity screening of illicit drugs and new psychoactive substances (NPS) in human iPSC-derived cardiomyocytes using microelectrode array (MEA) recordings

Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

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