Anticonvulsive profile of two GABAB receptor antagonists on acute seizure mice models

Introduction: DL-3-hydroxy-3-phenylpentanamide (HEPP) and DL-3-hydroxy-3-(4 ' chlorophenyl)-pentanamide (Cl-HEPP) are phenyl-alcohol-amides that are metabotropic GABAB receptor (MGBR) antagonists and protective against absence seizures. This study aims to further characterize the anticonvulsant profile of these drugs. Methods: HEPP and Cl-HEPP were evaluated in various standardized acute seizure and toxic tests in female SwissOF1 mice. Results: Toxicities of HEPP and Cl-HEPP were limited; doses up to 30 mg/kg did not result in hypothermia, reduced spontaneous locomotor activity, or failure of the rotarod test, with doses >15 mg/kg potentiating pentobarbital-induced sleep. In maximal electroshock-induced seizures, 20 mg/kg Cl-HEPP protected 100 % of mice; lower doses shortened post-ictal recovery. Seizure protection occurred against subcutaneous pentylenetetrazole and picrotoxin, being limited against N-methyl-D-aspartate. In bicuculline test, clonic or fatal tonic seizures were decreased, onset delayed, and recovery improved; ED50 values (dose protecting 50 % of the animals) were 37.5 and 25 mg/kg for HEPP and Cl-HEPP, respectively. In magnesium deficiency-dependent audiogenic seizures (MDDAS), ED50 values were 3 and 8 mg/kg for Cl-HEPP and HEPP, respectively. The components of MDDAS (latency, wild running, seizure, and recovery phases) in unprotected animals were only minimally affected by near ED50 doses of Cl-HEPP and HEPP. Discussion: HEPP and, to a greater extent, Cl-HEPP provide anti-seizure protections in several acute seizure tests in mice at nontoxic doses. These results are consistent with the action of these drugs on diverse molecular targets directly resulting from their MGBR antagonistic properties. However, other mechanisms might occur possibly for the protection given in the MES test. Finally, a similarity in the modulation of MDDAS components between the two phenyl alcohol amides and ethosuximide could also be based on the MGBR antagonistic properties of the former, given the recently re-evaluated therapeutic relevant targets of the latter.

Automated summary

HEPP and Cl-HEPP demonstrate anti-seizure protection in mice against acute seizures at non-toxic doses, likely through their MGBR antagonistic properties. Other mechanisms may also be involved, particularly in providing protection in the MES test. The modulation of MDDAS components by these drugs shows similarities with ethosuximide.