trans-2-en-valproate and Epilepsy

Valproic acid is one of the major antiepileptic drugs. In animal models, valproate showed less anticonvulsant potency than the other three established antiepileptic drugs: phenobarbital, phenytoin and carbamazepine. In addition, two major side-effects, teratogenicity and hepatotoxicity, have been associated with valproate therapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial need to develop improved derivatives of valproate. This paper analyses three kinds of valproate derivatives: valpromide, the primary amide of valproate, and its analogues; monoester prodrugs of valproate and an active metabolite of valproate, 2-n-propyl-2-pentenoate. The comparative evaluation was carried out by pharmacokinetic and pharmacodynamic analyses in animals. From the data accumulated so far, we can conclude that 2-n-propyl-2-pentenoate and/or a valpromide isomer, which does not undergo amide-acid biotransformation and preferably is not an epoxide hydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.

Topics: Animals; Anticonvulsants; Biotransformation; Drug Evaluation, Preclinical; Epilepsy; Fatty Acids, Monounsaturated; Prodrugs; Random Allocation; Stereoisomerism; Structure-Activity Relationship; Valproic Acid

Reducing the extracellular magnesium or calcium or increasing the extracellular potassium induces different patterns of epileptiform activity in the hippocampus and the entorhinal cortex. Although in the low Ca2+ and K+ models, seizure-like events (SLEs) develop in area CA1 of the hippocampus, only short recurrent discharges develop in the low Mg2+ model. In contrast, in low Mg2+, SLEs and late recurrent discharges (LRDs) are observed in the entorhinal cortex.. We compared the effects of valproate (VPA) and its major metabolite, trans-2-en-VPA (TVPA), on all these different model activities using extracellular field potential measurements. We also investigated the equilibration time course of VPA in the slice by using VPA-sensitive microelectrodes.. Both drugs reversibly blocked most forms of epileptiform activity. The only exception was the LRDs in the entorhinal cortex. In paired experiments, TVPA appeared to be more effective than VPA bath applied with the same concentration to the same slice. With our measurements of the VPA concentrations in slices, we showed that the concentrations used were close to therapeutic drug levels.. If TVPA stands the toxicological tests, it might be a useful alternative in the treatment of seizures.

Topics: Action Potentials; Animals; Anticonvulsants; Electroencephalography; Entorhinal Cortex; Epilepsy; Extracellular Space; Fatty Acids, Monounsaturated; Hippocampus; Magnesium; Microelectrodes; Neurons; Rats; Synaptic Transmission; Temporal Lobe; Valproic Acid

The anticonvulsant potency of 2-propyl-2-pentenoic acid (2-en-VPA; trans isomer), a major metabolite of the antiepileptic valproic acid (VPA), was evaluated in different animal models of epilepsy and compared with the respective data for VPA. Four models were used: the maximal electroshock seizure (MES) test in mice, the pentylenetetrazol seizure test in mice, gerbils with 'major' (generalized tonic-clonic) seizures in response to specific sensory stimulation, and rats with chronically recurring, spontaneous 'petit mal' seizures. The overall anticonvulsant profile of 2-en-VPA in these models compared favourably with that of VPA. Both drugs were considerably more potent to block seizures in epileptic rats and gerbils than in the traditional MES and pentylenetetrazol mouse models. As regards toxicity, no side-effects were observed with effective doses of 2-en-VPA in rats and gerbils, whereas in the doses necessary to block MES and pentylenetetrazol seizures in mice (200-300 mg/kg i.p.) 2-en-VPA was more sedative than VPA. LD50 values determined for both drugs were comparable. A major difference between 2-en-VPA and VPA was found with respect to embryotoxicity. Single doses of VPA administered to pregnant mice gave rise to significant teratogenic effects (exencephaly, embryolethality , growth retardation), whereas 2-en-VPA was not embryotoxic, even at extremely high doses (600 mg/kg). The data suggest that 2-en-VPA may be a valuable alternative antiepileptic drug.

Topics: Animals; Anticonvulsants; Electroshock; Epilepsy; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Gerbillinae; Lethal Dose 50; Male; Mice; Pentylenetetrazole; Pregnancy; Seizures; Species Specificity; Teratogens; Valproic Acid