Cholecystokinin-8 sulfate modulates the anticonvulsant efficacy of vigabatrin in an experimental model of partial complex epilepsy in the rat.
OBJECTIVE
We evaluated the possible additive effect induced by the administration of the anticonvulsant vigabatrin (VGB) and cholecystokinin-8 sulfate (CCK-8S) on an experimental model of partial complex seizures (maximal dentate gyrus activation, MDA). Moreover, the functional involvement of gamma-aminobutyric acid (GABA) neurotransmission was tested by iontophoretically administering bicuculline (GABA receptor antagonist) in the dentate gyrus.


METHODS
Urethane anesthetized rats were pretreated with VGB (50, 100 or 200 mg/kg, i.p.) or CCK-8S (8 nmol/kg, i.p.) alone or coadministered with VGB (50 mg/kg, i.p.). Dentate gyrus epileptic activity was obtained through the repetitive electrical stimulation of the angular bundle. MDA latency, duration, and poststimulus afterdischarge (AD) duration were evaluated. The extracellular activity of some dentate neurons was recorded before and during bicuculline iontophoresis.


RESULTS
Only the higher dose of VGB reduced the mean duration of dentate MDA and AD. CCK-8S significantly decreased the number of animals exhibiting MDA responses, characterized by increased latency and shorter duration. The coadministration of CCK-8S and VGB (50 mg/kg) significantly increased the anticonvulsant effects, either reducing the number of responding animals or decreasing both MDA and AD durations. During bicuculline iontophoresis, all the modifications induced on the MDA-related activity of dentate neurons by the pretreatments (VGB and/or CCK-8S) were abolished.


CONCLUSIONS
The results indicate that CCK-8S significantly enhances the VGB-induced anticonvulsant effect in the MDA model of partial epilepsy, probably through an increase of GABA cerebral levels. Such increased anticonvulsant effect becomes evident by using VGB at a lower dose.
Ferraro
Giuseppe
G
Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana G Pagano, Universitàd degli Studi di Palermo, Palermo, Italy. giuseppe.ferraro@unipa.it
Sardo
Pierangelo
P
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001640:Bicuculline / Q000009:adverse effects; D003292:Convulsants / Q000009:adverse effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004558:Electric Stimulation / Q000009:adverse effects; D017029:Epilepsy, Complex Partial / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D012844:Sincalide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020888:Vigabatrin / Q000627:therapeutic use*
C090019:8-sulfocholecystokinin octapeptide; D000927:Anticonvulsants; D003292:Convulsants; D018697:Nootropic Agents; D020888:Vigabatrin; D012844:Sincalide; D001640:Bicuculline