MPTP‐induced dopamine neuron degeneration and glia activation is potentiated in MDMA‐pretreated mice

Abstract

Clinical observations report a greater propensity to develop Parkinson's disease (PD) in amphetamine users. 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is an amphetamine-related drug that is largely consumed by adolescents and young adults, which may have neuroinflammatory and neurotoxic effects. Here, the objective was to evaluate in mice whether consumption of MDMA during adolescence might influence the neuroinflammatory and neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin known to induce PD in humans. The activation of astroglia and microglia by glial fibrillary acidic protein (GFAP) and complement receptor type 3 (CD11b) immunohistochemistry and the degeneration of dopaminergic neurons by tyrosine hydroxylase (TH) immunohistochemistry were evaluated. MPTP (20 mg/kg × 4) was administered to mice treated from ages 8 weeks to 17 weeks with MDMA (10 mg/kg twice daily, two times a week). In mice that were chronically treated with MDMA, administration of MPTP induced a higher microglial and astroglial response in both the striatum and the substantia nigra pars compacta (SNc) compared with vehicle-treated or vehicle + MPTP-treated mice. Inflammatory changes were associated with a decrease in TH immunoreactivity in the SNc of MDMA-treated mice and with a further decrease in the striatum and the SNc of MDMA + MPTP-treated mice compared with vehicle-treated, MDMA-treated, and MPTP-treated mice. The results demonstrate that chronic administration of MDMA during late adolescence in mice exacerbates the neurodegeneration and neuroinflammation caused by MPTP, suggesting that MDMA may constitute a risk factor for dopaminergic neuron degeneration.

Protection effect of piperine and piperlonguminine from Piper longum L. alkaloids against rotenone-induced neuronal injury

“…The current study investigated the mechanism underlying these effects by inducing a PD-like syndrome using rotenone, as evidenced by the diminished performance on the rotarod test and loss of dopaminergic neurons in the midbrain (Fig. 1), which was consistent with results of previous studies that used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to induce PD (Costa et al, 2013;Toy et al, 2013;Lee et al, 2014). An assessment of gait using catwalk analysis revealed that rotenone caused a shortening of print width and length, which is consistent with published reports of 6-OHDAinduced PD (Chuang et al, 2010), (Hsieh et al, 2011) and comparable to what is observed in PD patients who experience rigidity of the muscles that consequently limits movement.…”

Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory Deficits

“…The highest dose used was notably lower than the dose established as toxic in binge regimens [6], but we used a more extended treatment. Costa et al [37] also used a prolonged and intermittent exposure (10 mg/kg two times in a day, twice per week during 9 weeks); nevertheless, we thought that once per week and administering increasing doses simulates better the pattern of consumption in adolescents. This treatment produced an initial reduction in TH-immunoreactivity in the SN, which agreed with the results of Costa et al There were no previous reports of longer-term effects of MDMA on mice, but our results here indicate an irreversible effect on dopaminergic neurons in SN or, alternatively, suggest that recovery from dopaminergic damage in mice takes more than three months.…”

Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms

“…Moreover, and most importantly, MDMA produces long-term degeneration of dopaminergic nerve terminals (Brodkin et al, 1993;Colado et al, 2001;Izco et al, 2010;Costa et al, 2013) and a decrease in tyrosine hydroxylase (TH), the rate-limiting enzyme for DA synthesis, in the striatum Costa et al, 2013). A study by Granado and coworkers has provided significant insight into the elucidation of the effects of MDMA on the nigrostriatal system of mice (Granado et al, 2008b).…”