Long‐lasting neuroprotective effect of sildenafil against 3,4‐methylenedioxymethamphetamine‐ induced 5‐hydroxytryptamine deficits in the rat brain
Elena Puerta, Lucía Barros-Miñones, Isabel Hervias, Violeta Gomez‐Rodriguez, Lourdes Orejana, Neus Pizarro, Rafael de la Torre, Joaquı́n Jordán, Norberto Aguirre
Journal of Neuroscience Research September 21, 2011 DOI: 10.1002/jnr.22759 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal experiment Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Sildenafil MDMA |
| Dose | Sildenafil 8 mg/kg p.o.; MDMA 3 × 5 mg/kg i.p. |
| Duration | MDMA injections every 2 hr; measurements one week later |
| Measures | 5-HT content, 5-HT transporter density, ERK1/2 activation, MnSOD expression, ethidium fluorescence, nitrotyrosine concentration |
| Topics | MDMA |
| Citations | 17 |
| Key findings | Sildenafil given 24 hours before MDMA significantly protected against MDMA-induced 5-HT depletion in rat striatum, frontal cortex, and hippocampus without altering MDMA's acute hyperthermia or metabolic disposition. The authors attribute this protection to increased ERK1/2 activation and MnSOD expression, with reduced oxidative stress markers (superoxide-derived oxidants and hippocampal nitrotyrosine). |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cites 16
- Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Journal of Neuroscience August 1, 1988
- Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Journal of Neuroscience June 15, 1999
- In vivo evidence for free radical involvement in the degeneration of rat brain 5‐HT following administration of MDMA (‘ecstasy’) and p‐chloroamphetamine but not the degeneration following fenfluramine British Journal of Pharmacology July 1, 1997
- Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[11C]DASB and structural brain imaging study Brain May 17, 2010
- Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT Synapse 2001
and 11 more in the library