Molecular Toxicological Mechanisms of Synthetic Cathinones on C2C12 Myoblasts.

Xun Zhou,Matthias Liechti,Gerda Sanvee,Stephan Krähenbühl,Jamal Bouitbir,Dino Luethi

doi:10.3390/ijms20071561

Abstract

Synthetic cathinones are popular psychoactive substances that may cause skeletal muscle damage. In addition to indirect sympathomimetic myotoxicity, these substances could be directly myotoxic. Since studies in myocytes are currently lacking, the aim of the present study was to investigate potential toxicological effects by synthetic cathinones on C2C12 myoblasts (mouse skeletal muscle cell line). We exposed C2C12 myoblasts to 3-methylmethcathinone, 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone), 3,4-methylenedioxypyrovalerone (MDPV), alpha-pyrrolidinovalerophenone (α-PVP), and naphthylpyrovalerone (naphyrone) for 1 or 24 h before cell membrane integrity, ATP content, mitochondrial oxygen consumption, and mitochondrial superoxide production was measured. 3,4-Methylenedioxymethamphetamine (MDMA) was included as a reference compound. All investigated synthetic cathinones, as well as MDMA, impaired cell membrane integrity, depleted ATP levels, and increased mitochondrial superoxide concentrations in a concentration-dependent manner in the range of 50–2000 μM. The two pyrovalerone derivatives α-PVP and naphyrone, and MDMA, additionally impaired basal and maximal cellular respiration, suggesting mitochondrial dysfunction. Alpha-PVP inhibited complex I, naphyrone complex II, and MDMA complex I and III, whereas complex IV was not affected. We conclude that, in addition to sympathetic nervous system effects and strenuous muscle exercise, direct effects of some cathinones on skeletal muscle mitochondria may contribute to myotoxicity in susceptible synthetic cathinone drugs users.

Highlights

Synthetic cathinones are derivatives of cathinone, the naturally occurring alkaloid found in the Catha edulis shrub, and represent one of the largest groups of new psychoactive substances (NPS), with more than one hundred different substances detected by the European Union Early
The intracellular ATP content was determined for the assessment of mitochondrial function and
After exposure for 24 h, treatment for 24 h, all drugs proved to impair cell membrane integrity and to deplete ATP in a a significant depletion of ATP at 50 μM was observed for naphyrone, at 200 μM for mephedrone, at concentration-dependent manner in the range of 50–2000 μM (Figure 2)

Summary

Introduction

Synthetic cathinones are derivatives of cathinone, the naturally occurring alkaloid found in the Catha edulis shrub, and represent one of the largest groups of new psychoactive substances (NPS), with more than one hundred different substances detected by the European Union EarlyWarning System between 2005 and 2017 [1]. Synthetic cathinones are derivatives of cathinone, the naturally occurring alkaloid found in the Catha edulis shrub, and represent one of the largest groups of new psychoactive substances (NPS), with more than one hundred different substances detected by the European Union Early. Cathinones are structurally closely related to amphetamines, such as 3, 4-methylenedioxymethamphetamine (MDMA, “ecstasy”). The main difference is a β-keto group in the side chain of the cathinones, which is not present in the amphetamines [2]. Even though the frequent use of synthetic cathinones in a recreational setting is a relatively new phenomenon, several of these substances were first synthesized during the twentieth century. The first synthesis of the frequently abused 4-methylmethcathinone (mephedrone) was published in 1929 [3]. Many additional synthetic cathinones have since been developed, mostly as

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