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

Abstract

Background Synthetic 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). Methods We 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. Results We 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. Conclusions In 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.

Extracellular Microvesicles Released From Brain Endothelial Cells are Detected in Animal Models Of HIV-1 Signifying Unresolved Inflammation

“…hBMVECs were plated (20,000/well) on collagen I coated 96-well electrode arrays (96W20idf, Applied Biophysics, Troy, NY, USA) and grown until confluent. Trans-endothelial electrical resistance (TEER) was measured at 2 kHz every 600 s using the Electrical Cell-Substrate Impedance Sensing (ECIS) system (Applied Biophysics, Troy, NY, USA) as described previously (Buzhdygan et al 2021 ). Cells were grown until a constant baseline resistance was obtained and then media was replaced with lack of growth factors.…”

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review

“…Alteration of the blood-brain barrier is a common effect of SCs consumption reflected in in vitro human models. The experiments conducted by Buzhdygan et al on the effects of mephedrone on human brain microvascular endothelial cells (hBMVEC) showed that the treatment with mephedrone caused a charge-dependent disruption of the endothelial barrier and an increase of barrier permeability [ 106 ], demonstrating the ability of mephedrone to regulate the tight junction complex.…”

Activation of CB2R by synthetic CB2R agonist, PM289, improves brain endothelial barrier properties, decreases inflammatory response and enhances endothelial repair

“…To examine gene expression via qRT-PCR, total Ribonucleic acid (RNA) was isolated as previously described [ 29 , 30 ]. Briefly, 1 mL TRIzol reagent was added to isolated microvessel tissue to dissociate total RNA from the samples.…”

“…The paracellular permeability assay was conducted as previously described [ 30 ]. Briefly, cells were plated in 200 µL of EGM-2 media at a density of 20,000 cells per well on the apical portion of semi-permeable trans-well inserts (Fisher Scientific, 0.4 µm pore size).…”