N-valproyl-L-tryptophan for CNS-targeting: synthesis, characterization and efficacy in vitro studies of a new potential antiepileptic drug.

A new aminoacidic derivative of valproic acid (VPA) has been synthesized and characterized by analytical and spectral data. The rationale for the preparation of such potential antiepileptic agent is based on the observation that chemical combination of the anticonvulsant pharmacophore, VPA with essential aminoacids could afford more effective and less toxic actives. The synthesis, characterization, physico-chemical parameters functional for crossing Blood Brain Barrier of N-valproyl-L-tryptophan (4) are reported. The Log D pH7.4 (0.3) indicates that (4) is adequate to cross biological membranes. Its chemical and enzymatic stability were assessed. The experiments indicate high stability of c…

CNS-targeted valproic-aminoacid conjugate: preliminary studies on pharmacokinetic parameters and antiepileptic activity

Modulation of in vivo GABA-evoked responses by nitric oxide-active compounds in the globus pallidus of rat.

Nitric oxide (NO) is a gaseous molecule acting as a messenger in both the peripheral and the central nervous systems. NO affects synaptic activity by modulating neurotransmitter release and/or receptor function. We previously observed that NO-active compounds modify the bioelectric activity of basal ganglia (BG) units. In this study, we applied microiontophoresis to extracellular in vivo recordings to investigate the effect of NO-active compounds on GABA-evoked responses in the globus pallidus (GP) of anesthetized rats. The changes induced by NO-active drugs on the GABA-induced inhibition were used as indicators of NO modulation. The response to GABA release was tested on recorded GP neuron…

Nitric oxide-active compounds modulate the intensity of glutamate-evoked responses in the globus pallidus of the rat

Abstract Aim The effects of local applied NO-active compounds on glutamate (GLU)-evoked responses were investigated in globus pallidus (GP) neurons. Main methods Extracellularly recorded single units from anesthetized rats were treated with GLU before and during the microiontophoretic application of S-nitrosoglutathione (SNOG), a NO donor, and Nω-nitro- l -arginine methyl ester (L-NAME), a NOS inhibitor. Key findings Most GP cells were excited by SNOG whereas administration of L-NAME induced decrease of GP neurons activity. Nearly all neurons responding to SNOG and/or L-NAME showed significant modulation of their excitatory responses to the administration of iontophoretic GLU. In these cell…

SINTESI, CARATTERIZZAZIONE E STUDIO ELETTROFISIOLOGICO IN UN MODELLO SPERIMENTALE DI EPILESSIA DI NUOVI DERIVATI DELL’ACIDO VALPROICO

Nitric oxide-active compounds modulate glutamatergic and GABAergic transmission in globus pallidus of rat

The globus pallidus (GP) of rodents, homologous to the external globus pallidus of primates, plays a critical role in the expression of basal ganglia (BG) function. Glutamatergic and GABAergic inputs have been demonstrated to greatly modulate the spontaneous GP activity. In this study the effects of local applied NO-active compounds on glutamate (GLU)- and GABA-evoked responses were investigated in rat GP neurons. Extracellularly recorded single units from anesthetized rats were treated with GLU or GABA before and during the microiontophoretic application of S-nitrosoglutathione (SNOG), a NO donor, and Nω-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor. Most GP cells were excited by…

Comparison of effects of Valproate and the newly synthesized Valproil-L-Tryptophan on epileptiform activity in rat brain slices

Transbuccal delivery of methimazole: ex vivo permeation studies, histomorphological features and matrix system development

Effects of nitric oxide and cGMP-active compounds on neuronal activity of substantia nigra pars reticulata: a rat in vivo study

NITRIC OXIDE-ACTIVE COMPOUNDS MODULATE IN VIVO GABA-EVOKED RESPONSES IN THE GLOBUS PALLIDUS OF RAT

Nitric oxide (NO) acts as a messenger in the central nervous system; it affects the synaptic activity by modulating neurotransmitter release and/or receptor function. We previously observed that NO-active compounds modify the bioelectric activity of basal ganglia (BG) units. In this study, we applied microiontophoresis to extracellular in vivo recordings to investigate the effect of NO-active compounds on GABA-evoked responses in the globus pallidus (GP) of rats. The response to GABA release was tested on recorded GP neurons before and during the administration of S-nitroso-glutathione (SNOG, NO donor) and/or Nω-nitro-L-arginine methyl ester (L-NAME), inhibitor of nitric oxide synthase (NOS…

Buccal delivery in treatment of Alzheimer disease: enhancement of galantamine absorption

Sintesi di un nuovo derivato dell’acido valproico ed effetti in un modello sperimentale di epilessia ippocampale nel ratto

Evidences of cannabinoids-induced modulation of paroxysmal events in an experimental model of partial epilepsy in the rat

Different studies have been shown a clear anticonvulsant activity exerted by cannabinoids (CB) through the CB1 receptor activation. The purpose of this study was to evaluate, in an in vivo experimental model of temporal lobe epilepsy (maximal dentate gyrus activation - MDA) in the rat, the protective effect of (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN 55,212-2, CB agonist) alone or in combination with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, selective CB1 antagonist). Pre-treatment with AM251 (1 mg kg-1, 30 min interval) dramatically reduced the signif…

Inhibitory effects of N-valproyl-L-tryptophan on high potassium, low calcium and low magnesium-induced CA1 hippocampal epileptiform bursting activity in rat brain slices.

N-valproyl-l-tryptophan (VPA-Tryp), new antiepileptic drug, was 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 or 2 mM) of Valproate (VPA) or VPA-Tryp. Both burst duration and interburst frequency during and after treatment were off-line compared with baseline values. For both parameters, the latency and the length of statistically significant response periods as well as the magnitude of drug-induced responses were calculated. VPA-Tryp evoked fewer and weaker early excitatory effects than VPA on …