title: Effect of sildenafil, a selective phosphodiesterase 5 inhibitor, on the anticonvulsant action of some antiepileptic drugs in the mouse 6-Hz psychomotor seizure model.
abstract: Sildenafil, a selective phosphodiesterase 5 inhibitor (PDE5), has been recently reported to have both pro- and anticonvulsant action in various experimental models of seizures and epilepsy. Furthermore, it affects anticonvulsant action of some antiepileptic drugs (AEDs) in mice seizure tests and both pharmacodynamic and pharmacokinetic interactions were noted. The present study was carried out to investigate influence of sildenafil on the threshold for 6 Hz-induced psychomotor seizures in mice. Effect of sildenafil on activity of some AEDs, i.e., phenobarbital (PB), clonazepam (CZP), ethosuximide (ETS), valproic acid (VPA), tiagabine (TGB), oxcarbazepine (OXC) and levetiracetam (LEV), in 6 Hz test was also examined. Moreover, combination of sildenafil with LEV was investigated in terms of influence on motor coordination (determined by the chimney test), muscular strength (evaluated in the grip-strength test) and long-term memory (assessed in the passive avoidance task) in mice. To determine the type of pharmacological interaction between sildenafil and LEV, free plasma and total brain concentrations of this AED were determined by LC-MS/MS method. Sildenafil at a dose ranging from 10 to 40 mg/kg statistically increased psychomotor seizure threshold in mice. Moreover, sildenafil enhanced the anticonvulsant action of all the studied AEDs in this test. Interactions between this PDE5 inhibitor and PB, CZP, ETS, TGB and OXC seem to be pharmacodynamic. Since sildenafil increased free plasma and total brain concentration of LEV, interactions between these drugs have pharmacokinetic nature. This kind of interaction was also noted between sildenafil and VPA. Neither LEV (2.32 mg/kg) nor its co-administration with sildenafil (40 mg/kg) produced any significant changes in motor coordination, muscular strength and long-term memory in mice.
authors.affiliation: Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Skłodowska University, Lublin, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Nieoczym
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Socała
authors.forename: Piotr
authors.initials: P
authors.lastname: Jedziniak
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Olejnik
authors.forename: Piotr
authors.initials: P
authors.lastname: Wlaź
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000932:Antiemetics / Q000097:blood / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects*; D018737:Hand Strength / Q000502:physiology; D008297:Male; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors / Q000097:blood / Q000627:therapeutic use*; D010879:Piperazines / Q000097:blood / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D011687:Purines / Q000097:blood / Q000627:therapeutic use; D012640:Seizures / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000932:Antiemetics; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate
keywords: 6Hz psychomotor seizure test; AED; Antiepileptic drugs; CBZ; CZP; ETS; GBP; GC; LC–MS/MS; LEV; MES; MEST; Mice; NO; NOS; OXC; PB; PDE; PKG; PTZ; Sildenafil; TGB; TPM; VGB; VPA; antiepileptic drug; cGMP; cGMP-dependent protein kinase; carbamazepine; clonazepam; cyclic guanosine 3′,5′-monophosphate; ethosuximide; gabapentin; guanylate cyclase; levetiracetam; liquid chromatography-tandem mass spectrometry; maximal electroshock seizure threshold; maximal electroshock seizures; nitric oxide; nitric oxide synthase; oxcarbazepine; pentylenetetrazole; phenobarbital; phosphodiesterase; tiagabine; topiramate; valproate; vigabatrin