Long‐lasting neuroprotective effect of sildenafil against 3,4‐methylenedioxymethamphetamine‐ induced 5‐hydroxytryptamine deficits in the rat brain

Abstract

Sildenafil, given shortly before 3,4-methylenedioxymethamphetamine (MDMA), affords protection against 5-hydroxytryptamine (5-HT) depletions caused by this amphetamine derivative by an acute preconditioning-like mechanism. Because acute and delayed preconditionings do not share the same mechanisms, we investigated whether sildenafil would also protect the 5-HT system of the rat if given 24 hr before MDMA. For this, MDMA (3 × 5 mg/kg i.p., every 2 hr) was administered to rats previously treated with sildenafil (8 mg/kg p.o.). One week later, 5-HT content and 5-HT transporter density were measured in the striatum, frontal cortex, and hippocampus of the rats. Our findings indicate that sildenafil afforded significant protection against MDMA-induced 5-HT deficits without altering the acute hyperthermic response to MDMA or its metabolic disposition. Sildenafil promoted ERK1/2 activation an effect that was paralleled by an increase in MnSOD expression that persisted 24 hr later. In addition, superoxide and superoxide-derived oxidants, shown by ethidium fluorescence, increased after the last MDMA injection, an effect that was prevented by sildenafil pretreatment. Similarly, MDMA increased nitrotyrosine concentration in the hippocampus, an effect not shown by sildenafil-pretreated rats. In conclusion, our data demonstrate that sildenafil produces a significant, long-lasting neuroprotective effect against MDMA-induced 5-HT deficits. This effect is apparently mediated by an increased expression of MnSOD and a subsequent reduced susceptibility to the oxidative stress caused by MDMA.

Modulation of the ASK1–MKK3/6–p38/MAPK signalling pathway mediates sildenafil protection against chemical hypoxia caused by malonate

“…In an attempt to understand the mechanisms underlying the protective effects afforded by sildenafil, we analysed the effect of this PDE5 inhibitor on ROS production. As expected, malonate increased ROS production; but, in contrast to previous reports (Koupparis et al, 2005;Muzaffar et al, 2005;Bivalacqua et al, 2009;Puerta et al, 2012), sildenafil failed to…”

“…In an attempt to understand the mechanisms underlying the protective effects afforded by sildenafil, we analysed the effect of this PDE5 inhibitor on ROS production. As expected, malonate increased ROS production; but, in contrast to previous reports (Koupparis et al ., ; Muzaffar et al ., ; Bivalacqua et al ., ; Puerta et al ., ), sildenafil failed to prevent malonate‐induced rise in ROS production. Furthermore, sildenafil also failed to reduce the increased NT concentrations found 72 h after malonate.…”

Treadmill exercise attenuates 3,4‐methylenedioxymethamphetamine‐induced memory impairment through a decrease apoptosis in male rat hippocampus

“…Administration of 3,4-methylenedioxymethamphetamine (MDMA) or ecstasy affects the serotonin system (Parrott, 2002;Puerta et al, 2012) in the hippocampus, and prefrontal cortex, which are important structures known to be involved in learning and memory (Bergstrom and Pinard, 2017).…”

Pharmacokinetic investigation of sildenafil using positron emission tomography and determination of its effect on cerebrospinal fluid cGMP levels

“…Neuroprotection by inhibitors is afforded in methylenedioxymethamphetamine‐induced 5‐hydroxytryptamine depletion (Puerta et al . , ), in 3‐nitropropionic acid neurotoxicity (Puerta et al . ) and in malonate‐induced chemical hypoxia (Barros‐Miñones et al .…”