Membrane-disordering potency and anticonvulsant action of valproic acid and other short-chain fatty acids.

The cell membrane-disordering potencies of sodium valproate, the sodium salts of other short-chain fatty acids, and ethanol were compared using fluorescence polarization with the probe 1,6-diphenyl-1,3,5-hexatriene. Valproate was about 7 times more potent in fluidizing synaptosomal plasma membranes than ethanol, a prototypic disordering agent. The disordering potency of the straight-chain fatty acids pentanoate through octanoate increased by a factor of 2.2 with each additional methylene group. The sedative potencies of the drugs were assessed by determining the brain concentration at which Swiss Webster mice lost the ability to balance on a stationary wooden dowel. Relative anticonvulsant potency was measured by determining the ED50 for protection against pentylenetetrazol-induced seizures and then determining the brain levels of drug that were actually achieved at the time of seizure protection. The ability of the fatty acids and ethanol to disorder membranes in vitro correlated closely with their ability to cause sedation and protect mice against pentylenetetrazol-induced seizures. These data suggest that valproic acid might exert some of its effects by disordering brain cell membranes--the proposed mechanism of action of ethanol and the general anesthetics.