Anticonvulsant effect of flutamide on seizures induced by pentylenetetrazole: involvement of benzodiazepine receptors.

Abstract:

PURPOSE:There is some structural similarity between the androgen receptor antagonist, flutamide (Flut) and benzodiazepines (BZDs). We evaluated the possible anticonvulsant effect and interaction of Flut with BZD receptors in common seizure models. METHODS:(a) Different groups of mice each were pretreated i.p. with Flut, and after 0.5 h, they received chemoconvulsants [pentylenetetrazole (PTZ), bicuculline, aminophylline, strychnine or kainic acid]. Latency and incidence of a clonic seizure were recorded. (b) Mice were pretreated i.p. with Flut, and after 0.5 h, transauricular electroshock was applied. Occurrence of a tonic seizure was observed. (c) Amygdala-kindled rats were pretreated i.p. with Flut, and 0.5, 1, or 2 h later, they were stimulated at afterdischarge threshold. Then the seizure parameters (afterdischarge duration, seizure severity, and stage 5 duration) were recorded. (d) The effect of Flut on clonic seizure threshold was determined by i.v. infusion of bicuculline or PTZ to different groups of Flut-receiving mice. To determine the possible interaction of Flut with BZD receptors, the flumazenil (FMZ)+Flut effect on clonic seizure threshold was compared with the effect of Flut. (e) Neurotoxicity of Flut was evaluated by rotarod test at 30 min after administration. RESULTS:Flut produced a dose-dependent anticonvulsant effect against PTZ-induced seizures [median effective dose (ED50), 67.0 mg/kg]. Moreover, Flut elevated the clonic seizure threshold induced by bicuculline or PTZ. FMZ reversed the effect of Flut on the threshold of PTZ seizures. A median toxic dose (TD50) value of 124.8 mg/kg was obtained for Flut. CONCLUSIONS:Flut both blocks PTZ-induced clonic seizures and elevates the threshold of PTZ or bicuculline-induced clonic seizures, through interaction with BZD receptors.

journal_name

Epilepsia

journal_title

Epilepsia

authors

Ahmadiani A,Mandgary A,Sayyah M

doi

10.1046/j.1528-1157.2003.36402.x

subject

Has Abstract

pub_date

2003-05-01 00:00:00

pages

629-35

issue

5

eissn

0013-9580

issn

1528-1167

pii

epi36402

journal_volume

44

pub_type

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