Background: The research on the improvement of epilepsy therapy is constantly growing. Valproyl-LPhenylalanine
(VPA-Phen) and N-valproyl-L-tryptophan (VPA-Tryp) were synthesized to increase the antiepileptic
efficacy of valproic acid.
Methods: VPA-Phen and VPA-Tryp were comparatively tested on CA1 hippocampal epileptiform bursting activity
obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing
rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 mM) of VPA-Phen or VPA-Tryp.
Both burst duration and interburst frequency, during and after treatment, were off-line compared with baseline
values. For both parameters, either the latency or the duration of drug-induced statistically significant responses
was calculated, as well as the response magnitude.
Results: VPA-Phen significantly reduced both burst frequency and duration. Comparative analyses show that
VPA-Phen and VPA-Tryp exert almost equivalent actions on both latency and magnitude of the observed inhibitory
effects. The main observed difference between the two tested molecules concerned the duration of inhibitory
effects, since VPA-Phen-dependent actions on both burst rate and duration were significantly shorter than the
VPA-Tryp-induced ones. In addition, in some slices the above reported inhibitory responses were preceded by a
“paradoxical” transient increase, more present at lower drug concentrations.
Conclusions: Both VPA-Phen and VPA-Tryp exert significant inhibitory effects on hippocampal burst activity
parameters. Although of comparable magnitude, VPA-Phen-dependent effects have a shorter duration than VPATryp-
induced ones. Nevertheless, the present results confirm that the conjugation between VPA and aminoacids
represents a valid tool to improve the efficacy of antiepileptic drugs and, as well as for VPA-Tryp, propose VPAPhen
as a novel VPA derivative with enhanced pharmacological features.