Human Neuronal Cell Lines as An In Vitro Toxicological Tool for the Evaluation of Novel Psychoactive Substances

Abstract

Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures

“…In particular, after 4-days of exposure to fentanyl, levels of the LDH enzyme in the culture supernatant, a measure of membrane integrity and/or indirectly cell death, in the high dose condition was comparable to untreated cultures, and similarly the total number of cells and estimated proportion of cells (e.g., neurons, astrocytes, and oligodendrocyte precursor cells or oligodendrocyte) from age-matched treated cultures was also comparable to untreated cultures. The doses used in the present study did not appear to induce cytotoxicity at the 4-day time point, as expected, since >250 μM of fentanyl has been previously shown to induce toxicity in neurons after 24 h of exposure ( Sogos et al, 2021 ).…”

A Scientometric Visualization Analysis for Molecular Mechanisms of Substance Abuse and Its Neurotoxicity From 1997 to 2021

“…Considering its global harm, there has been a significant increased hot topic research and collaborative projects in countries, such as the United States, Germany, and Canada (Fujáková-Lipski et al, 2017;Costa et al, 2021;Sogos et al, 2021). Based on legalized marijuana policies in the United States and Canada, similar domestic and international situations and potential cooperative opportunities increased exponentially; additionally, the United States provides attractive financial grants to facilitate efficient cooperation and productivity (Goundar et al, 2021;Isfandyari-Moghaddam et al, 2021).…”

2-Phenethylamines in Medicinal Chemistry: A Review

“…Additionally, in addition to their prominent therapeutic applications, it is worth mentioning the recreational use of a long list of alkaloids incorporating the aforementioned moiety (“designer drugs”) [ 2 ], responsible for drug abuse-related conditions [ 3 , 4 , 5 , 6 , 7 , 8 ]. Surprisingly, the literature lacks a comprehensive summary that bundles up 2-phenethylamine-based structures and known therapeutic targets, including basic hits or advanced leads.…”