Comparative Study of the Effects Exerted by N-Valproyl-L-Phenylalanine and N-valproyl-L-tryptophan on CA1 Hippocampal Epileptiform Activity in Rat

Title:Comparative Study of the Effects Exerted by N-Valproyl-L-Phenylalanine and N-valproyl-L-tryptophan on CA1 Hippocampal Epileptiform Activity in Rat

Volume: 24 Issue: 17

Author(s): Fabio Carletti*, Valerio Rizzo, Giuditta Gambino, Viviana De Caro, Flavia Maria Sutera, Libero Italo Giannola, Giuseppe Ferraro and Pierangelo Sardo*

Affiliation:

• Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC), Sezione di Fisiologia umana, Universita degli Studi di Palermo, Corso Tukory, 129, 90134 Palermo,Italy

• Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC), Sezione di Fisiologia umana, Universita degli Studi di Palermo, Corso Tukory, 129, 90134 Palermo,Italy

Keywords: Amino-acidic derivative, antiepileptic drug, valproic acid, hippocampal epilepsy, interictal bursts, Valproyl-L-Phenylalanine (VPA-Phen).

Abstract: 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.

Cite this article as:

Carletti Fabio*, Rizzo Valerio , Gambino Giuditta , De Caro Viviana , Sutera Maria Flavia , Giannola Italo Libero, Ferraro Giuseppe and Sardo Pierangelo *, Comparative Study of the Effects Exerted by N-Valproyl-L-Phenylalanine and N-valproyl-L-tryptophan on CA1 Hippocampal Epileptiform Activity in Rat, Current Pharmaceutical Design 2018; 24 (17) . https://dx.doi.org/10.2174/1381612824666180409095530