Activation of Antioxidant and Proteolytic Pathways in the Nigrostriatal Dopaminergic System After 3,4-Methylenedioxymethamphetamine Administration: Sex-Related Differences
Giulia Costa, Francesca Felicia Caputi, Marcello Serra, Nicola Simola, Laura Rullo, Serena Stamatakos, Fabrizio Sanna, Marc Germain, Maria-Grazia Martinoli, Sanzio Candeletti, Micaela Morelli, Patrizia Romualdi
Frontiers in Pharmacology August 27, 2021 DOI: 10.3389/fphar.2021.713486 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Male and female mice |
| Intervention | MDMA |
| Dose | 4 × 20 mg/kg, 2 h apart |
| Topics | MDMA |
| Key findings | The authors suggest that MDMA's neurotoxic effects on the nigrostriatal dopamine system are sex-dependent, with male dopaminergic neurons potentially more sensitive to SOD2- and ubiquitin-proteasome-mediated toxicity, based on sex-specific increases in SOD2 and reductions in ubiquitin-proteasome subunit activity. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is an amphetamine-related drug that may damage the dopaminergic nigrostriatal system. To investigate the mechanisms that sustain this toxic effect and ascertain their sex-dependence, we evaluated in the nigrostriatal system of MDMA-treated (4 × 20 mg/kg, 2 h apart) male and female mice the activity of superoxide dismutase (SOD), the gene expression of SOD type 1 and 2, together with SOD1/2 co-localization with tyrosine hydroxylase (TH)-positive neurons. In the same mice and brain areas, activity of glutathione peroxidase (GPx) and of β2/β5 subunits of the ubiquitin-proteasome system (UPS) were also evaluated. After MDMA, SOD1 increased in striatal TH-positive terminals, but not nigral neurons, of males and females, while SOD2 increased in striatal TH-positive terminals and nigral neurons of males only. Moreover, after MDMA, SOD1 gene expression increased in the midbrain of males and females, whereas SOD2 increased only in males. Finally, MDMA increased the SOD activity in the midbrain of females, without affecting GPx activity, decreased the β2/β5 activities in the striatum of males and the β2 activity in the midbrain of females. These results suggest that the mechanisms of MDMA-induced neurotoxic effects are sex-dependent and dopaminergic neurons of males could be more sensitive to SOD2- and UPS-mediated toxic effects.