Influence of sildenafil on the anticonvulsant action of selected antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice

Dorota Nieoczym,Jarogniew J Łuszczki,Stanisław J Czuczwar,Piotr Wlaź,Katarzyna Socała

doi:10.1007/s00702-012-0767-1

Dorota Nieoczym, Jarogniew J Łuszczki + Show 3 more

Open Access

https://doi.org/10.1007/s00702-012-0767-1

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Abstract

The aim of the present study was to investigate the effect of sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, on threshold for clonic seizures in mice. In addition, the effects of sildenafil on the anticonvulsant activity of selected antiepileptic drugs (AEDs), i.e., clonazepam (CZP), valproate (VPA), phenobarbital (PB), ethosuximide (ETS) and tiagabine (TGB), were also evaluated. The subcutaneous pentylenetetrazole (PTZ) test was used to determine the effects of sildenafil on convulsive susceptibility and the anticonvulsant activity of the studied AEDs in mice, while the acute side effects of sildenafil and its combinations with the studied AEDs were evaluated in the chimney test, step-through passive-avoidance task and grip-strength test in mice. Total brain concentrations of AEDs were also determined. Sildenafil (5–40 mg/kg) did not influence the threshold for PTZ-induced clonic seizures in mice, but increased the anticonvulsant activity of ETS in this test without any significant changes in the total brain concentration. The activity of the remaining AEDs was not significantly changed by sildenafil. Neither sildenafil alone nor its combinations with the studied AEDs produced any changes in the motor coordination, long-term memory and muscular strength in mice. Co-administration of sildenafil with ETS in male epileptic patients with co-existing erectile dysfunctions might lead to the pharmacodynamic interactions that may be beneficial for the patients. Combinations of sildenafil with CZP, VPA, PB and TGB appear to be neutral in terms of their influence on seizures.

Highlights

Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, is the active ingredient of ViagraÒ used in the treatment of erectile dysfunction of various etiologies
The subcutaneous pentylenetetrazole (PTZ) test was used to determine the effects of sildenafil on convulsive susceptibility and the anticonvulsant activity of the studied antiepileptic drugs (AEDs) in mice, while the acute side effects of sildenafil and its combinations with the studied AEDs were evaluated in the chimney test, step-through passive-avoidance task and grip-strength test in mice
Cyclic GMP is considered an important secondary messenger in the brain and its intracellular level is regulated by guanyl cyclase (GC) isoforms, which take part in its synthesis, and by phosphodiesterases (PDEs), which hydrolyze cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP)

Summary

Introduction

Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, is the active ingredient of ViagraÒ used in the treatment of erectile dysfunction of various etiologies. Its pharmacological activity is connected with nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. Cyclic GMP is considered an important secondary messenger in the brain and its intracellular level is regulated by guanyl cyclase (GC) isoforms, which take part in its synthesis, and by phosphodiesterases (PDEs), which hydrolyze cGMP to guanosine monophosphate (GMP). The ability of sildenafil to cross the blood–brain barrier and the presence of PDE5 in different brain areas predispose this drug to exert some direct central nervous system effects, which were previously noted in both humans and rodents. Among the numerous central nervous system effects of sildenafil, antinociceptive potential was noted (Kim et al 2010; Huang et al 2010). Dizziness, depression, headache, light-headedness, visual changes, nervousness, insomnia, abnormal dreams and substance abuse behaviors were noted in humans who used sildenafil (Moreira et al 2000; Crosby and Diclemente 2004)

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