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 Swiss-OF1 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.

Anticonvulsant; DL-3-hydroxy-3-(4’chlorophenyl)-pentanamide; DL-3-hydroxy-3-phenylpentanamide; Ethosuximide; Magnesium deficiency-dependent audiogenic seizures (MDDAS test); Metabotropic GABA(B) receptor; Minimal neurotoxicity; Modulation profile of MDDAS components; Neuroprotection; Phenyl alcohol amides; Seizure tests.