title: 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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Puerta
authors.forename: Lucia
authors.initials: L
authors.lastname: Barros-Miñones
authors.forename: Isabel
authors.initials: I
authors.lastname: Hervias
authors.forename: Violeta
authors.initials: V
authors.lastname: Gomez-Rodriguez
authors.forename: Lourdes
authors.initials: L
authors.lastname: Orejana
authors.forename: Neus
authors.initials: N
authors.lastname: Pizarro
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
authors.forename: Joaquín
authors.initials: J
authors.lastname: Jordán
authors.forename: Norberto
authors.initials: N
authors.lastname: Aguirre
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000172:deficiency* / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D012701:Serotonin; D000068677:Sildenafil Citrate; D018817:N-Methyl-3,4-methylenedioxyamphetamine