4-aminopyrrolidine-2-4-dicarboxylic-acid and Epilepsy

Epileptic seizure can increase the cell proliferation in dentate gyrus in brain, but the mechanism remains unclear.. In this study, using systemic bromodeoxyuridine (BrdU) to label the dividing cells, the inhibitory effect of group II metabotropic glutamate receptor (mGluR) agonist 2R, 4R-4-aminopyrrolidine-2, 4-dicarboxylate (2R, 4R-APDC) on cell proliferation in dentate gyrus in rats after pilocarpine-induced status epilepticus (SE) was investigated.. Results found that, 2R, 4R-APDC could significantly inhibit the behavioral seizure and block the seizure-induced increase of BrdU-positive cells in dentate gyrus, especially in hilus. Double-label immunofluorescence staining showed that, 2R, 4R-APDC did not affect the ability of newborn cells to differentiate into neurons or astrocytes.. 2R, 4R-APDC not only has anticonvulsant effect on adult rats with pilocarpine-induced SE, but also has neuroprotective effect by reducing the abnormal regeneration of nerves.

Topics: Animals; Anticonvulsants; Cell Proliferation; Dentate Gyrus; Epilepsy; Excitatory Amino Acid Agonists; Male; Neuroprotective Agents; Proline; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate

The present study has examined the anticonvulsant and neuroprotective effect of 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective agonist for group II metabotropic glutamate receptors (mGluRs) when given 10-15 min after the onset of seizures induced in 12-day-old rats by bilateral icv infusion of DL-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion of DL-HCA. Comparable time intervals were used for sacrificing the animals which received 2R,4R-APDC (0.05 nmol/side) or saline. The severity of seizures was influenced only slightly when the agonist was given after the onset of seizures, as evaluated both from the behavioral symptoms and from EEG recordings. A tendency to lower number and a shorter duration of seizures was outlined in animals posttreated with 2R,4R-APDC, but the differences did not reach the level of statistical significance. Cortical energy metabolite changes which normally accompany seizures in immature rats (large decrease of glucose and glycogen and a marked rise of lactate) were ameliorated only partially. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration in many brain regions, mainly in the hippocampus and thalamus, following infusion of DL-HCA alone was only partially attenuated after 2R,4R-APDC posttreatment. The present findings clearly indicate that both anticonvulsant and neuroprotective effect of 2R,4R-APDC against DL-HCA-induced seizures is substantially diminished when the agonist is given after the onset of seizures as compared with its efficacy after the pretreatment (Exp. Neurol.192, 420-436, 2005).

Topics: Aging; Animals; Brain; Convulsants; Cytoprotection; Drug Administration Schedule; Drug Interactions; Epilepsy; Excitatory Amino Acid Agonists; Hippocampus; Homocysteine; Male; Nerve Degeneration; Neuroprotective Agents; Proline; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Thalamus; Treatment Outcome

The anticonvulsant activity of the selective group II metabotropic glutamate receptor (mGlu) agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) has been evaluated in chemoconvulsant and sound-induced models of epileptic seizures in DBA/2 mice. 2R,4R-APDC (> or =10 nmol, intracerebroventricularly (i.c.v.), -15 min) transiently reduced sound-induced seizure activity including clonic seizures to 40% of vehicle at 20 nmol (i.c.v.) and 30% of vehicle at 100 mg/kg (intraperitoneally (i.p.), -15 min). 2R,4R-APDC inhibited clonic seizures induced by the group III mGlu antagonist (R,S)-alpha-methylserine-O-phosphate (2.5 micromol, i.c.v.) when co-injected at 20-40 nmol and inhibited limbic seizure activity induced by the mGlu(1/5) agonist (R,S)-3,5-dihydroxyphenylglycine (1.5 micromol, i.c.v.) when co-injected at 10-40 nmol. A reversal of the anticonvulsant activity of 2R,4R-APDC was observed at (>20 nmol) in each of the chemoconvulsant and sound-induced models of epileptic seizures. 2R,4R-APDC (0.1-1 micromol, i.c.v.) induced stimulus-independent, rapid and dose-dependent clonic seizures. Selective mGlu(2/3) agonists represent a novel class of potential anti-epileptic drugs, however due to the proconvulsant activity observed here, 2R,4R-APDC is obviously limited in this regard.

Topics: Animals; Anticonvulsants; Central Nervous System; Convulsants; Dose-Response Relationship, Drug; Epilepsy; Excitatory Amino Acid Agonists; Female; Male; Mice; Mice, Inbred DBA; Proline; Receptors, Metabotropic Glutamate; Sound

Previous studies demonstrated that selected agonists for metabotropic glutamate group II and group III receptors can provide protection against seizures in adult animals. The present study has examined the potential effect of some of these compounds on seizures induced in immature rats by intracerebroventricular infusion of DL-homocysteic acid (DL-HCA, 600 nmol/side). Rat pups were sacrificed during generalised clonic-tonic seizures, 50--60 min after infusion. Comparable time intervals were used for sacrificing the pups which had received the protective drugs. The anticonvulsant effect was evaluated according to the suppression of behavioural manifestations of seizures and the protection of energy metabolite changes which normally accompany these seizures (large decreases of glucose and glycogen, and approximately 7- to 10-fold accumulation of lactate). Partial protection was exhibited by group II mGluR agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV, 0.6 nmol) and this effect was abolished after pretreatment with an antagonist for group II mGluRs (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG, 100 nmol). In high doses (5--100 nmol), however, DCG IV evoked seizures which were prevented by AP7, suggesting that the convulsant effect was mediated by interaction with NMDA receptors. A pronounced anticonvulsant effect against DL-HCA-induced seizures was achieved with low doses of a highly selective group II mGluR agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC, 0.6 nmol), group II agonist and group I mGluR antagonist (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4-C3HPG, 0.6 nmol) and group III mGluR agonist (RS)-1-amino-3-(phosphonomethylene) cyclobutane-carboxylic acid (32 nmol). Generalised clonic--tonic seizures were completely suppressed and the metabolic changes were markedly ameliorated, there being only a 1.5-, 2- and 2.5-fold rise of lactate, respectively. Higher doses of (S)-4-C3HPG (1--100 nmol) were, however, less anticonvulsant than low doses. The present results have confirmed that mGluRs may be considered a potential target for treatment of epilepsy.

Topics: Animals; Animals, Newborn; Anticonvulsants; Brain; Cyclobutanes; Cyclopropanes; Dose-Response Relationship, Drug; Epilepsy; Excitatory Amino Acid Agonists; Glycine; Homocysteine; Male; Neuroprotective Agents; Organophosphorus Compounds; Proline; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Seizures