The benzodiazepine receptor partial agonist Ro 19-8022 suppresses generalized seizures without impairing motor functions in developing rats

Naunyn Schmiedebergs Arch Pharmacol. 1999 Nov;360(5):565-74. doi: 10.1007/s002109900126.

Abstract

The action of a partial benzodiazepine receptor agonist Ro 19-8022 [(R)-1-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbo nyl] -2-pyrrolidine-methanol] in doses from 0.01 to 150 mg/kg was studied using motor seizures induced by pentylenetetrazol (PTZ) in rats 7, 12, 18, 25 and 90 days old. Generalized tonic-clonic seizures were suppressed in all age groups, the three youngest groups being more sensitive than older animals. The highest dose of Ro 19-8022 did not exhibit anticonvulsant action in the 25-day-old rats. The other types of seizures (minimal clonic) induced by PTZ were suppressed by Ro 19-8022 only in 18-day-old and older rats in which PTZ reliably elicited these types of seizures. The doses of 50, 100 and 150 mg/kg were ineffective against minimal seizures. On the contrary, incidence of minimal seizures was significantly increased by Ro 19-8022 in 7-and 12-day-old rat pups. Motor performance of rat pups was not compromised by Ro 19-8022 (0.5 and 50 mg/kg) in contrast to the full agonist midazolam (1 and/or 2 mg/kg). The duration of anticonvulsant effects studied with a dose of 0.5 mg/kg was longer in 12-day-old than in adult rats. This dose of Ro 19-8022 resulted in a rebound proconvulsant effect 24 and 48 h after the administration in 12-day-old rats only. Ro 19-8022 exhibited an excellent anticonvulsant action especially against generalized tonic-clonic seizures; this action was lost with very high doses. It did not compromise the motor system, but in some tests motivation was probably lost.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Anticonvulsants / pharmacology*
  • Anticonvulsants / toxicity
  • Convulsants
  • Dose-Response Relationship, Drug
  • GABA-A Receptor Antagonists*
  • Male
  • Midazolam / pharmacology
  • Motor Skills / drug effects*
  • Pentylenetetrazole
  • Pyrrolidines / pharmacology*
  • Pyrrolidines / toxicity
  • Quinolizines / pharmacology*
  • Quinolizines / toxicity
  • Rats
  • Rats, Wistar
  • Seizures / chemically induced
  • Seizures / physiopathology
  • Seizures / prevention & control*
  • Time Factors

Substances

  • Anticonvulsants
  • Convulsants
  • GABA-A Receptor Antagonists
  • Pyrrolidines
  • Quinolizines
  • Ro 19-8022
  • Midazolam
  • Pentylenetetrazole