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The i.p. injection in rats of GABA (740 mg/Kg) after sonication with an equal amount of phosphatidylserine (PS) has an antiepileptic effect. The injection of plain GABA has no such an effect. Blood, brain and synaptosomal accumulation of exogenous labeled GABA under the two circumstances are evaluated. In the case of GABA/PS injection there is a higher passage of the exogenous labeled neurotransmitter into the blood and brain nerve endings (synaptosomes). A higher synaptosomal accumulation of the exogenous labeled neurotransmitter is found even when GABA and PS are injected separately. Since these accumulation increases occur at a time when there is the antiepileptic effect, they seem relevant to it. Our interpretation of the chain of the events resulting in the antiepileptic action is that the phospholipid facilitates from the beginning the first passage of the exogenous neurotransmitter form the peritoneum to the blood. Then a higher passage to the brain tissue and eventually to the GABA-ergic nerve endings ensues. The brisker accumulation of the exogenous neurotransmitter in the nerve endings could be at the basis of a more efficient GABA-ergic inhibitory control in the brain.

The permeation of labeled Cl- ions across single plasma membranes from Deiters' neurons has been studied in the presence of various concentrations of phosphatidylserine (PS) on their extracellular side. PS reduces significantly basal Cl- permeation only at 10(-5) M on the membrane exterior. No effect was found at other concentrations. GABA activable 36Cl- permeation is heavily reduced and almost abolished at 10(-11) - 10(-5) M phosphatidylserine. This exogenous phosphatidylserine effect is difficult to interpret in relation to the function of the endogenous phospholipid. However, it may be involved in the epileptogenic effect in vivo of exogenous phosphatidylserine administration to rats.

The interaction of the negatively-charged phosphatidylserine (PS) and gamma-Aminobutyric acid (GABA) is examined in black lipid membranes (BLM) and inverse micelles. GABA does not permeate through PS membranes and, in concentrations of 10(-5)-10(-4) M, it reduces the negative potential at the membrane-aqueous solution interface. The effect is owing to the adsorption of the GABA cationic species and the consequent decrease of the negative surface charge density of the membrane. When the intrinsic pH of the membrane-solution interface is considered, the Gouy-Chapman-Stern theory describes the GABA screening effect and makes it possible to calculate the GABA-PS binding constant. This value is compared with that obtained measuring the partition of 14C-GABA between an organic phase containing PS and the aqueous solution. The results presented strongly suggest that the electrostatic force plays a major role in GABA-PS interaction.

The effect of a suspension of GABA and phosphatidylserine (PS), phosphatidylcholine, or phosphatidylethanolamine was studied on penicillin-induced epileptic activity in rats. GABA-PS significantly reduced the number of spikes, in comparison with either the other phospholipid compounds or normal saline. No effect was observed after GABA or PS administration alone. We suggest that the different effects probably depend on extracellular and intracellular factors.

A sonicated liposome suspension of gamma-aminobutyric acid (GABA) and phosphatidylserine (liposome-entrapped GABA), intraperitoneally administered in rats, inhibited EEG epileptic activity induced by penicillin, whereas GABA did not. A significant increase (20.4%) in brain radioactivity accumulation occurred at 5 min after i.p. administration of [14C]GABA associated with phosphatidylserine in comparison with the administration of [14C]GABA; such an increase persisted after 20 min. However, the accumulation of radioactivity into brain synaptosomes demonstrated a 24.1% increase at 5 min and subsequently showed a 43.3% increase at 20 min after injection of liposome-entrapped GABA. The above findings suggest that phosphatidylserine stimulates exogenous GABA uptake into brain GABAergic nerve terminals.

To assess the relationships between the efficacy and blood levels of progabide (PGB) and its active acidic metabolite (PGA) in epileptics, observations were carried out on 89 adult patients with epilepsy of different types and severity in two groups at Paris and Genoa. The Paris group received progabide in addition to other antiepileptic drugs for 6 to 12 months, whereas the Genoa group received a polytherapy for the first two months then a monotherapy with progabide alone for up to 22 months. Blood levels from monthly or bimonthly samples were significantly higher in both surveys when there was a satisfactory therapeutic response and levels were also higher in those receiving monotherapy suggesting a synergism among antiepileptic drugs. It is concluded that therapeutic drug monitoring of PGB and PGA blood concentrations may be a useful technique in optimizing progabide treatment in epileptic patients.

A simple method for the determination of the proportion of true GABA within labeled "GABA" used for membrane binding assay is presented. The method is intended for the assessment of the integrity of refrigerator (+4 degrees C) stored labeled neurotransmitter. Its application allows a precise determination of the binding parameters.

An electrophoretic method for the separation of gamma-aminobutyric acid (GABA) from its metabolites after GABA-transaminase attack is presented. The method is based on the fact that at neutral pH GABA has no net electrical charge, whereas its major metabolites, succinic acid and Krebs cycle intermediates, are negatively charged. The method appears to be especially suitable for evaluation of true-labeled neurotransmitter within the radioactivity which is found in synaptosomes after labeled GABA-uptake studies.

Sprague-Dawley rats with interictal and ictal spike activity induced by intraperitoneally injected isoniazid (INH) were treated, 5 min before or 30 min later, with liposome-entrapped gamma-aminobutyric acid (GABA) (LEG) or GABA or phosphatidylserine. Crossover injections were given in random sequence and INH alone ws also injected in every animal as a control. LEG inhibited either seizures or interictal spikes in both groups. No decrease of epileptogenic activity was seen after GABA or phosphatidylserine treatment alone. It is suggested that LEG could contribute to the reconstitution of the GABA pool decreased by INH.

We studied Sprague-Dawley rats with spike activity and myoclonus after intraperitoneal injections of penicillin. Twenty minutes after penicillin injection, one group received a random crossover treatment by intraperitoneal GABA (gamma-aminobutyric acid) or liposome-entrapped GABA (LEG) or phosphatidylserine alone. The other group received GABA, LEG, or phosphatidylserine followed 15 minutes later by the injection of penicillin. LEG decreased or prevented the epileptic activity, whereas no significant changes were seen with either GABA or phosphatidylserine given alone. LEG may enhance penetration of GABA across the blood-brain barrier because of the carrier action of the liposomes.

Progabide (PGB), a gamma-amino-butyric acid receptor agonist, was administered, according to an open-label long-term design, to 40 adult patients suffering from complex partial seizures, with or without secondary generalization, whose response to carbamazepine (CBZ) monotherapy was unsatisfactory. A reference-baseline period of two months with carbamazepine monotherapy was followed by a two-month "add-on" period where increasing doses of progabide were added without modifying the CBZ regimen; then CBZ was withdrawn over 15-60 days and patients were followed up to 12 months' progabide treatment. Twenty-seven patients completed the trial but 12 of them had to be returned to CBZ + PGB bitherapy due to an increase of seizures following CBZ withdrawal. A definite therapeutic effect could be observed in nine patients on PGB monotherapy and in six patients on CBZ + PGB bitherapy. Side-effects of clinical relevance occurred in three cases and were represented by remarkable anxiety in two patients and a rise in serum glutamic oxalo-acetic acid and pyruvic transaminases with clinical symptoms of liver dysfunction in one, with rapid recovery following progabide discontinuation. In conclusion, progabide was effective against complex partial seizures in about 40% of patients not responding satisfactorily to available antiepileptic drugs. Although the withdrawal of previous antiepileptic drugs was not possible in all patients, progabide monotherapy was sometimes more effective than CBZ monotherapy, and several patients in whom bitherapy had to be restored benefited from the association of progabide.