Abstract
4,4’-Dimethylaminorex (4,4’-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1–60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4′-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers’ co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity.
Highlights
IntroductionSynthetic stimulants are one of the largest classes of novel psychoactive substances Synthetic stimulants areeach one of theby largest classes of novel substances (NPS) seized and identified year law enforcement andpsychoactive forensic laboratories [1]. (NPS)seized and identified each year by law enforcement and forensic laboratoriesAmong the latter, in recent years 4,4′-dimethylaminorex (4-Methyl-5-(4-methylphenyl)Among the latter, in recent years (4-Methyl-5-(4-methylphenyl)-4,54,5-dihydrooxazol-2-amine), commonly known as 4,4′-DMAR, has been both seized in dihydrooxazol-2-amine), commonly known as-DMAR, has been both various various European countries and associated with of poisoning and seized deathsin [2,3,4,5].European countries and with cases of poisoningof and deaths [2,3,4,5].4,4′-DMAR may beassociated considered a methyl-derivative4-methylaminorex (4-MAR)0 -DMAR may be considered a methyl-derivative of 4-methylaminorex (4-MAR)[6], two synthetic stimulants known for their anorexic properties [7]
The effect was significant in the dose range of 3–60 mg/kg; both the latency of the appearance of the effect (one-way analysis of variance (ANOVA); F (3.20) = 66.56, p < 0.0001) and its duration (one-way ANOVA showed F (3.20) = 66.56, p < 0.0001) were dose-dependent
Histological Histological analyses showed onlyshowed a slightonly oedema in the cerebral cortex
Summary
Synthetic stimulants are one of the largest classes of novel psychoactive substances Synthetic stimulants areeach one of theby largest classes of novel substances (NPS) seized and identified year law enforcement andpsychoactive forensic laboratories [1]. (NPS)seized and identified each year by law enforcement and forensic laboratoriesAmong the latter, in recent years 4,4′-dimethylaminorex (4-Methyl-5-(4-methylphenyl)Among the latter, in recent years (4-Methyl-5-(4-methylphenyl)-4,54,5-dihydrooxazol-2-amine), commonly known as 4,4′-DMAR, has been both seized in dihydrooxazol-2-amine), commonly known as-DMAR, has been both various various European countries and associated with of poisoning and seized deathsin [2,3,4,5].European countries and with cases of poisoningof and deaths [2,3,4,5].4,4′-DMAR may beassociated considered a methyl-derivative4-methylaminorex (4-MAR)0 -DMAR may be considered a methyl-derivative of 4-methylaminorex (4-MAR)[6], two synthetic stimulants known for their anorexic properties [7]. Synthetic stimulants are one of the largest classes of novel psychoactive substances Synthetic stimulants areeach one of theby largest classes of novel substances (NPS) seized and identified year law enforcement andpsychoactive forensic laboratories [1]. Seized and identified each year by law enforcement and forensic laboratories. Among the latter, in recent years 4,4′-dimethylaminorex (4-Methyl-5-(4-methylphenyl)Among the latter, in recent years (4-Methyl-5-(4-methylphenyl)-4,54,5-dihydrooxazol-2-amine), commonly known as 4,4′-DMAR, has been both seized in dihydrooxazol-2-amine), commonly known as. -DMAR, has been both various various European countries and associated with of poisoning and seized deathsin [2,3,4,5]. 0 -DMAR may be considered a methyl-derivative of 4-methylaminorex (4-MAR). Inand aminorex [6],the two synthetic stimulants known forthe their anorexic properties
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