The psychoactive drug of abuse mephedrone differentially disrupts blood-brain barrier properties

Tetyana P Buzhdygan,Cassidy R Rodrigues,Servio H Ramirez,Scott M Rawls,Allison M Andrews,Hannah M Mcgary,Jana A Khan

doi:10.1186/s12974-021-02116-z

Abstract

BackgroundSynthetic cathinones are a category of psychostimulants belonging to the growing number of designer drugs also known as “Novel Psychoactive Substances” (NPS). In recent years, NPS have gained popularity in the recreational drug market due to their amphetamine-like stimulant effects, low cost, ease of availability, and lack of detection by conventional toxicology screening. All these factors have led to an increase in NPS substance abuse among the young adults, followed by spike of overdose-related fatalities and adverse effects, severe neurotoxicity, and cerebral vascular complications. Much remains unknown about how synthetic cathinones negatively affect the CNS and the status of the blood-brain barrier (BBB).MethodsWe used in vitro models of the BBB and primary human brain microvascular endothelial cells (hBMVEC) to investigate the effects of the synthetic cathinone, 4-methyl methcathinone (mephedrone), on BBB properties.ResultsWe showed that mephedrone exposure resulted in the loss of barrier properties and endothelial dysfunction of primary hBMVEC. Increased permeability and decreased transendothelial electrical resistance of the endothelial barrier were attributed to changes in key proteins involved in the tight junction formation. Elevated expression of matrix metalloproteinases, angiogenic growth factors, and inflammatory cytokines can be explained by TLR-4-dependent activation of NF-κB signaling.ConclusionsIn this first characterization of the effects of a synthetic cathinone on human brain endothelial cells, it appears clear that mephedrone-induced damage of the BBB is not limited by the disruption of the barrier properties but also include endothelial activation and inflammation. This may especially be important in comorbid situations of mephedrone abuse and HIV-1 infections. In this context, mephedrone could negatively affect HIV-1 neuroinvasion and NeuroAIDS progression.

Highlights

Cathinone (2-amino-1-phenyl propanone) is the naturally occurring psychostimulant and the major active constituent of khat, the leaf of the Catha edulis bush that has been chewed recreationally in East Africa and Middle East for centuries
Using in vitro models of the blood-brain barrier (BBB), we found that mephedrone decreases transendothelial electrical resistance (TEER) and increases paracellular permeability of the endothelial barrier
Mephedrone does not induce cellular toxicity in human brain endothelial cells To date, no published information is available regarding whether mephedrone impacts viability of human endothelial cells

Summary

Introduction

Cathinone (2-amino-1-phenyl propanone) is the naturally occurring psychostimulant and the major active constituent of khat, the leaf of the Catha edulis bush that has been chewed recreationally in East Africa and Middle East for centuries. Growing number of reports on the synthetic cathinone abuse highlights the serious physical and psychological risks. Synthetic cathinones are a category of psychostimulants belonging to the growing number of designer drugs known as “Novel Psychoactive Substances” (NPS). NPS have gained popularity in the recreational drug market due to their amphetamine-like stimulant effects, low cost, ease of availability, and lack of detection by conventional toxicology screening. All these factors have led to an increase in NPS substance abuse among the young adults, followed by spike of overdose-related fatalities and adverse effects, severe neurotoxicity, and cerebral vascular complications. Much remains unknown about how synthetic cathinones negatively affect the CNS and the status of the blood-brain barrier (BBB)

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