Worsening of the Toxic Effects of (±) Cis -4,4′-DMAR Following Its Co-Administration with (±) Trans -4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice

Micaela Tirri, Paolo Frisoni, Sabrine Bilel, Raffaella Arfè, Claudio Trapella, Anna Fantinati, Giorgia Corli, Beatrice Marchetti, Fabio De-Giorgio, Cristian Camuto, Monica Mazzarino, Rosa Maria Gaudio, Giovanni Serpelloni, Fabrizio Schifano, Francesco Botrè, Matteo Marti

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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.
Original languageEnglish
Article number8771
Number of pages25
JournalInternational Journal of Molecular Sciences (IJMS)
Volume22
Issue number16
DOIs
Publication statusPublished - 16 Aug 2021

Keywords

  • 4-4′-DMAR
  • immunohistochemistry
  • drug metabolism
  • hyperthermia
  • novel psychoactive substances
  • stimulant
  • oxidative/nitrosative stress
  • apoptosis
  • neurotoxicity
  • cortex
  • Immunohistochemistry
  • Novel psychoactive substances
  • Stimulant
  • Cortex
  • Neurotoxicity
  • 4-4 -DMAR
  • Oxidative/nitrosative stress
  • Drug metabolism
  • Hyperthermia
  • Apoptosis
  • Stereoisomerism
  • Male
  • Psychotropic Drugs/classification
  • Behavior, Animal/drug effects
  • Mice, Inbred ICR
  • Animals
  • Oxazoles/classification
  • Mice
  • Psychophysiologic Disorders/chemically induced

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