Sildenafil influences the anticonvulsant activity of vigabatrin and gabapentin in the timed pentylenetetrazole infusion test in mice.
Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has recently been reported to affect convulsant activity in some animal models of seizures and epilepsy. Moreover, its influence on the protective activity of some antiepileptic drugs (AEDs) was also noted. The aim of the present study was to investigate the effect of sildenafil on the anticonvulsant potential of gabapentin (GBP) and vigabatrin (VGB) in the timed intravenous (i.v.) pentylenetetrazole (PTZ) test in mice. The chimney test, the passive avoidance task and the grip strength test were used to estimate some possible side effects caused by the studied AEDs and their combinations with sildenafil. Total brain and free plasma concentrations of GBP and VGB were determined to evaluate the characteristics of interactions. Our studies revealed that GBP (25-100 mg/kg) increases the threshold for the forelimb tonic extension, whereas VGB raises thresholds both, for myoclonic (200-600 mg/kg) and generalized clonic (400-600 mg/kg) seizures in the used model of seizures. GBP at sub-effective dose of 12.5 mg/kg co-administered with sildenafil at doses of 10 and 20 mg/kg significantly increases the threshold for tonic seizures in the i.v. PTZ test in mice. Combination of sub-effective dose of VGB (200 mg/kg) with sildenafil at a dose of 5mg/kg also showed significant anticonvulsant activity against clonic seizures. The studied AEDs and their combinations with sildenafil did not produce any changes in the motor coordination, long-term memory and muscular strength in mice. Sildenafil did not influence total brain and free plasma concentrations of GBP and VGB. Interactions between the studied AEDs and sildenafil were pharmacodynamic in nature and for that reason they are worthy of consideration in the clinical practice.
Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Skłodowska University, Lublin, Poland.
Dorota
D
Nieoczym
Katarzyna
K
Socała
Jarogniew J
JJ
Luszczki
Stanisław J
SJ
Czuczwar
Piotr
P
Wlaź
D000588:Amines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077206:Gabapentin; D018737:Hand Strength; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000187:drug effects; D010433:Pentylenetetrazole; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D020888:Vigabatrin / Q000494:pharmacology* / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000068677:Sildenafil Citrate; D020888:Vigabatrin; D010433:Pentylenetetrazole