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-kappa B), 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.