The antiepileptic drug, valproic acid (VPA) is a simple branched-chain fatty acid with several notable pharmacologic properties. Unlike other antiepileptic drugs, anticonvulsant response to VPA is poorly correlated with plasma drug concentration. It has also been shown in clinical and animal studies that the time course of anticonvulsant activity is dissociated from the plasma kinetics of VPA. Maximal seizure control is not observed until long after the establishment of steady-state serum concentration of VPA. Also, the duration of anticonvulsant activity outlasts the presence of VPA in circulation. These unusual findings suggest that VPA has a distinctly different mechanism of antiepileptic action compared to other anticonvulsants. Despite considerable effort, the antiepileptic mechanism of valproic acid has not been identified. Recent evidence in literature together with preliminary animal studies in our laboratory now suggest that the unusual pharmacodynamics of VPA may be related to the selective accumulation and slow efflux of two unsaturated metabolites of the drug, Delta2-VPA and Delta4-VPA, in brain during chronic drug administration. The objective of this proposed research is to elucidate the role of these unsaturated metabolites in the antiepileptic activity of VPA.
The specific aims are: (i) to establish the contribution of Delta2-VPA and Delta4-VPA to the in vivo anticonvulsant activity of VPA; and (ii) to elucidate the pharmacokinetic mechanisms responsible for the slow uptake and efflux of these unsaturated branched-chain fatty acids in the CNS. The proposed pharmacodynamic studies will involve the comparison of anticonvulsant activity between VPA and directly administered synthetic Delta2-VPA and Delta4-VPA during chronic intravenous infusion in rats. A well established pentylenetetrazol rat seizure model will be used to assess anticonvulsant response. Three separate mechanisms, which may explain accumulation and slow clearance of Delta2-VPA and Delta4-VPA in brain, will be explored: (i) rate-limiting transport of unsaturated metabolite across blood-brain-barrier; (ii) in situ generation of metabolites in brain; and (iii) trapping of metabolites by the reversible formation of their CoA esters in brain. The long term goal of this research is to gain an understanding as to how CNS transport processes and brain metabolism modulate the anticonvulsant activity of the branched-chain fatty acids. Such knowledge will be useful in the development of more effective fatty acid like antiepileptic drugs.
