Administration Of 3-mercaptopropionic Acid Research Articles

New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice

About 30% of the patients with epilepsy do not respond to clinically established anticonvulsants, despite having effective concentrations of the antiepileptic drug in plasma. Therefore, new preclinical models of epilepsy are needed to identify more efficacious treatments. We describe here a new drug-resistant seizure model in mice to be used at the early stages of pre-clinical trials. This model consists in inducing daily generalized seizures for 23 consecutive days by administration of 3-mercaptopropionic acid (MP). As a result, 100% of animals become resistant to phenytoin and 80% to phenobarbital. Such resistance is strongly associated with the overexpression of P-glycoprotein (Pgp), observed in cerebral cortex, hippocampus and striatum while resistance to Pgp nonsubstrate drugs such as carbamazepine, diazepam and levetiracetam is not observed.This model could be useful for screening novel anticonvulsant drugs with a potential effect on pharmacoresistant seizures treatment.

Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model

The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45 mg kg −1, i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30 mg kg −1, i.v.) 30 min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2 mg kg −1). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration, C max: 2.7 ± 0.3 μg ml −1, p < 0.05 versus C rats) than in C animals ( C max: 5.3 ± 0.9 μg ml −1). Control rats pre-treated with NIMO showed similar results ( C max: 4.5 ± 0.8 μg ml −1) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations ( C max: 6.8 ± 1.0 μg ml −1, p < 0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model.

Influence of convulsants on rat brain activities of alanine aminotransferase and aspartate aminotransferase.

There exist differences between 12-day-old and adult rats in the onset of seizures induced by some inhibitors of glutamate decarboxylase (GAD). The aim of study was to investigate if there are differences between both groups in activities of rat brain alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the enzymes involved in glutamate metabolism, after the administration of 3-mercaptopropionic acid as specific GAD inhibitor or isoniazid as less specific general inhibitor of pyridoxal enzymes. Activities of both aminotransferases in a supernatant 20,000 g of the whole brain (containing predominantly cytosolic isoforms of enzymes) were increased at the beginning of 3-mercaptopropionic acid-induced generalized tonic-clonic seizures. At isoniazid-induced generalized tonic-clonic seizures, a significant increase in both enzyme activities was observed in adult rat brain. In the 12-day-old rat brain, ALT and AST activities reached about 40% and about 50-60% of adult control levels, respectively. In in vitro experiments, no influence of 3-mercaptopropionic acid on transaminase activities was found and an inhibitory effect of isoniazid on the enzymes was confirmed. Increased aminotransferase activities might participate in the enhanced synthesis of excitatory amino acid neurotransmitters in the nervous system, which may take a part in the initiation of epileptic seizures. Alternatively, the increased AST activity may be connected with an increased transport of NADH from the cytosol to mitochondria, while the increased ALT activity would represent the transformation of pyruvate to alanine as a consequence of increased glycolysis.

The Effects of a Convulsant, 3‐Mercaptopropionic Acid, on the GABA Level in Rat Pancreatic Islets and Brain, In‐vivo and In‐vitro

To investigate the properties of the γ-aminobutyric acid (GABA)-synthesizing enzyme, glutamate decarboxylase (GAD), in the pancreatic islets and brain of the rat, GABA concentration in the pancreatic islets and brain was measured after administration of 3-mercaptopropionic acid (3-MP) in in-vivo and in-vitro studies. Fifteen and sixty minutes after administration of 3-MP at 25 mg kg−1 intraperitoneally, GABA concentration in the pancreatic islets decreased by 30–35% and GABA concentration in the hypothalamus, the superior colliculus and the hippocampus of the brain decreased by 25–30%. GABA concentration in the pancreatic isolated islets in-vitro was measured after incubation of 3-MP in the range 10−7-10−4 M for 60 min. GABA concentrations in the pancreatic islets decreased on stimulation by 3-MP in a dose-dependent manner. The activities of GAD in the pancreatic islets can be modified by a convulsant, in this case 3-MP, in-vivo and in-vitro. These results suggest that the properties of GAD may be similar in the pancreatic islets and brain.

A convulsant, 3-mercaptopropionic acid, decreases the level of GABA in pancreatic islets of rat as well as that of brain

To investigate the properties of the gamma-aminobutyric acid (GABA) synthesizing enzyme, glutamate decarboxylase (GAD), in the brain and the pancreatic islets of the rat, GABA concentration in the brain and the pancreatic islets was measured after administration of 3-mercaptopropionic acid (3-MP) at 25 mg/kg intraperitoneally. Sixty minutes after the administration of 3-MP, GABA concentration in the hypothalamus, the superior colliculus and the hippocampus of the brain decreased by 20–30% and in the pancreatic islets by 35 %. The activities of GAD in the pancreatic islets and brain can be modified by a convulsant, in this case 3-MP. These results suggest the properties of GAD may be similar in the pancreatic islets and brain.

A presumptive role for GABA in the stimulatory effects of desgly 10, [D-AlA 6]-LHRH-ethylamide and pimozide on the gonadotropin release in carp

To investigate the effect of endogenous γ-aminobutyric acid (GABA) on the blood maturating gonadotropin (GtH) levels, or to study its interaction with pimozide (dopamine antagonist) and a luteinizing hormone- releasing hormone analog (LHRH-a), sexually mature male and female carps were treated with drugs that may either inhibit GABA biosynthesis or GABA degradation. In females the irreversible inhibitor of GABA- transaminase, γ-vinyl GABA (GVG), which was to increase the endogenous GABA-ergic tone, had no influence on GtH release. On the other hand, the increased GtH response to the combination of pimozide (PIM) and LHRH-a was clearly enhanced by the administration of 3-mercaptopropionic acid (MPA), an inhibitor of the rate limiting enzyme of GABA-biosynthesis. In males the GABA-ergic compound, valproic acid (DPA) decreased LHRH-a stimulated GtH levels. In male carps that received PIM to diminish the dopaminergic inhibition of GtH release, the spermiating response to LHRH-a was increased by administration of MPA. These data suggest that GABA interacts with the action of dopamine and the gonadotropin releasing hormone (GnRH) on the release of GtH.

Cardiovascular effects of 3-mercaptopropionic acid and levels of GABA in regions of the brain of Guinea-pigs

3-Mercaptopropionic acid (3-MP), an inhibitor of the synthesis of γ-aminobutyric acid (GABA), was administered to anesthetized rats and guinea-pigs in order to examine the relationship between the effect of this agent on regional levels of GABA in the brain and cardiovascular function. After a latent period, 3-mercaptopropionic acid (0.16 ml/kg, i.p.) produced initial increases in blood pressure and heart rate in rats followed by vagal bradycardia and hypotension. Guinea-pigs treated with 3-mercaptopropionic acid developed one of three patterns of cardiovascular changes. The type I response consisted of a period of sympathetically-mediated hypertension and tachycardia followed by vagal bradycardia. Type II animals exhibited increased arterial pressure and heart rate, but no vagal activation. Type III and control animals exhibited no significant cardiovascular changes following administration of 3-mercaptopropionic acid or appropriate vehicle. Regional levels of GABA in brain, measured at 90 min after treatment were significantly lower than control in type I and II animals in 3 of 4 areas of the brain measured, but not in type III guinea-pigs. When decreases in levels of GABA were compared to the changes in cardiovascular parameters for individual animals, the decrease in heart rate at the time of sacrifice was directly correlated with the decrease in medullary levels of GABA in type I animals. Conversely, in type II guinea-pigs, decreases in hypothalamic levels of GABA correlated inversely with heart rate at sacrifice. These results suggest that activation of cardiac sympathetic and parasympathetic nervous pathways following the administration of 3-mercaptopropionic acid may result from decreased levels of GABA in different regions of the brain.

Baclofen as an anticonvulsant in experimental models of convulsions

The anticonvulsant activity of baclofen, a putative γ-aminobutyric acid agonist, was determined in four different models of experimentally induced convulsions. These convulsions were induced by (i) transcorneally administered electroconvulsive shock, (ii) pentylenetetrazol administration, (iii) ringing sound presented to animals during barbital abstinence syndrome, and (iv) administration of 3-mercaptopropionic acid. The results showed the drug to be active as an anticonvulsant whether convulsions were induced by electroshock, 3-mercaptopropionic acid, or auditory stimulation. No effect was seen on convulsions induced by pentylenetetrazol administration. The participation of mechanisms involving the neurotransmitter γ-aminobutyric acid is suggested, and possible mechanisms of baclofen action are discussed.