Effects of sildenafil on pentylenetetrazol-induced convulsions in mice and amygdala-kindled seizures in rats.
Sildenafil is the first marketed phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction and recently, for pulmonary hypertension. While the treatment was found to be highly effective, several adverse effects are associated with this compound. Among numerous central nervous system-related untoward effects, proconvulsant activity was reported. The purpose of this study was to assess the effect of sildenafil on seizure threshold in rodents. Two seizure models/tests were used: the timed intravenous (iv) pentylenetetrazol (PTZ) infusion test in mice and the amygdala-kindling model in rats. Sildenafil was administered intraperitoneally 30 min before induction of seizures. In the iv PTZ paradigm, the first myoclonic twitch, generalized clonus with loss of the righting reflex, and forelimb tonus were recorded. In the amygdala-kindling model in rats, the following parameters were analyzed: threshold for induction of epileptiform discharges in the stimulated amygdala (afterdischarge threshold, ADT), seizure severity, seizure duration, and afterdischarge duration. Sildenafil (dosage range of 5-40 mg/kg) did not significantly affect the threshold for myoclonic twitches in the timed iv PTZ infusion test in mice but significantly decreased the threshold for clonic seizures at a dose of 20 mg/kg. Sildenafil at all doses tested neither significantly influenced the focal seizure threshold in the amygdala-kindling model of epilepsy in rats nor influenced seizure severity. Sildenafil significantly shortened afterdischarge duration and seizure duration recorded at the ADT current, indicative of a weak anticonvulsant activity. Our results show that sildenafil may have both pro- and anticonvulsant activity, which depends on the experimental model of epilepsy, on animal species and the dose of sildenafil. Based on these data and in view of the clinical observations, sildenafil should be used in patients suffering from epilepsy with caution and only based on a careful individual risk/benefit evaluation.
Nieoczym
Dorota
D
Department of Animal Physiology, Institute of Biology, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland. piotr.wlaz@umcs.lublin.pl
Socała
Katarzyna
K
Rundfeldt
Chris
C
Wlaź
Piotr
P
D000679:Amygdala / Q000502:physiology*; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology; D010433:Pentylenetetrazole; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*
D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; D010433:Pentylenetetrazole