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
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.
Item Type | Article |
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Uncontrolled 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 |
Subjects |
Biochemistry, Genetics and Molecular Biology(all) > Molecular Biology Chemistry(all) > Spectroscopy Chemical Engineering(all) > Catalysis Chemistry(all) > Inorganic Chemistry Computer Science(all) > Computer Science Applications Chemistry(all) > Physical and Theoretical Chemistry Chemistry(all) > Organic Chemistry |
Date Deposited | 26 Jul 2024 14:08 |
Last Modified | 26 Jul 2024 14:08 |
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Read more research from the creator(s):
- Tirri, Micaela
- Frisoni, Paolo
- Bilel, Sabrine
- Arfè, Raffaella
- Trapella, Claudio
- Fantinati, Anna
- Corli, Giorgia
- Marchetti, Beatrice
- De-Giorgio, Fabio
- Camuto, Cristian
- Mazzarino, Monica
- Gaudio, Rosa Maria
- Serpelloni, Giovanni
- Schifano, Fabrizio
- Botrè, Francesco
- Marti, Matteo
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- Department of Clinical, Pharmaceutical and Biological Science
- Centre for Health Services and Clinical Research
- Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Unit
- School of Life and Medical Sciences
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