Intracerebroventricular pertussis toxin enhances sensitivity to chemical convulsants and decreases the protective efficacy of carbamazepine in mice.
The effects of pretreatment with pertussis toxin on pentylenetetrazole-, bicuculline-, aminophylline- and pilocarpine-induced seizures were investigated in mice. In animals treated intracerebroventricularly with pertussis toxin (0.5 microgram animal-1 120 h prior to testing), the CD50 (convulsive dose in 50%) values were considerably decreased in comparison with the CD50 in sham-treated animals. CD50 values of pentylenetetrazole, bicuculline, pilocarpine and aminophylline were calculated to be 39.9, 2.0, 262 and 141 mg kg-1, whereas they were calculated to be 57.7, 2.7, 324 and 230 mg kg-1 in sham-treated animals. The observations suggest that the enhanced sensitivity to a number of chemical convulsants irrespective of their mode of action possibly results from a functional suppression of inhibitory transmission at receptors coupled to pertussis toxin sensitive G proteins, rather than a direct action on G protein linked excitatory neurotransmission. Pertussis toxin significantly decreased the protective action of carbamazepine, increasing its ED50 (effective dose in 50%) from 14.8 to 20.1 mg kg-1 in a maximal electroshock convulsive test. It influenced the ED50 of neither diphenylhydantoin nor diazepam. The diminution of carbamazepine's efficacy might result from a summation effect of adenosine receptor antagonist properties of the drug and a suppression of transmission at adenosine receptors coupled to G proteins sensitive to pertussis toxin. Pertussis toxin pretreatment remained without any significant influence on the total plasma levels of carbamazepine, diphenylhydantoin and diazepam. This may lead to the conclusion that the interaction between pertussis toxin and carbamazepine does not seem to be of a pharmacokinetic nature and occurs probably at neuronal level.
Korolkiewicz
R
R
Department of Pharmacology, Medical University of Gdańsk, Poland.
Kleinrok
Z
Z
Mlynarczyk
M
M
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D002220:Carbamazepine / Q000097:blood / Q000627:therapeutic use*; D003292:Convulsants / Q000633:toxicity*; D003975:Diazepam / Q000097:blood; D004357:Drug Synergism; D019204:GTP-Binding Proteins / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D037342:Pertussis Toxin; D010672:Phenytoin / Q000097:blood; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D012680:Sensitivity and Specificity; D010566:Virulence Factors, Bordetella / Q000633:toxicity*
D000927:Anticonvulsants; D003292:Convulsants; D010566:Virulence Factors, Bordetella; D002220:Carbamazepine; D010672:Phenytoin; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D003975:Diazepam