Anticonvulsant activity of a mGlu_4α receptor selective agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid

Abstract

The metabotropic Group III agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1), selective for the mGlu_4α receptor, suppresses sound-induced seizures in DBA/2 mice following its intracerebroventricular (i.c.v.) administration (ED₅₀ 5.6 [2.9–10.7], nmol i.c.v., 15 min, clonic phase) and in genetically epilepsy-prone (GEP) rats following focal administration into the inferior colliculus (ED₅₀ 0.08 [0.01–0.50], nmol, 60 min, clonic phase). ACPT-1 also protects against clonic seizures induced in DBA/2 mice by the Group I agonist, (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) (ED₅₀ 0.60 [0.29–1.2], nmol i.c.v.) and by the Group III antagonist, (RS)-α-methylserine-O-phosphate (MSOP) (ED₅₀ 49.3 [37.9–64.1], nmol i.c.v.). Another Group III agonist, (RS)-4-phosphonophenyl-glycine (PPG), preferentially activating the mGlu₈ receptor, previously shown to protect against sound-induced seizures in DBA/2 mice and GEP rats, also protects against seizures induced in DBA/2 by 3,5-DHPG (ED₅₀ 3.7 [2.4–5.7], nmol i.c.v.) and by the Group III antagonist, MSOP (ED₅₀ 40.2 [21.0–77.0], nmol i.c.v.). At very high doses (500 nmol i.c.v. and above), Group III antagonists have pro-convulsant and convulsant activity. The anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu₄ receptor agonist ACPT-1, is partially reversed by the co-administration of the Group III antagonists, MSOP, (RS)-α-methyl-4-phosphonophenylglycine (MPPG) or (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4), in the 20–50 nmol dose range. At doses of 50–200 nmol, MPPG and MAP4 cause further reversal of the ACPT-1 anticonvulsant protection, while the MSOP effect on ACPT-1 protection is abolished at higher doses. In contrast, the anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu₈ receptor agonist PPG, is not significantly affected by the co-administration of the same Group III antagonists, MSOP, MPPG or MAP4. We conclude that activation of either mGlu_4α or mGlu₈ receptors confer anticonvulsant protection in DBA/2 mice. Furthermore, the metabotropic Group III receptor antagonists, MSOP, MPPG, and MAP4 appear to be functionally selective for the mGlu₄ receptor in this system.

Introduction

Antagonists acting at Group III (and Group II) metabotropic receptors have previously been shown to suppress seizure activity in several animal epilepsy models Tizzano et al., 1995, Abdul-Ghani et al., 1997, Tang et al., 1997, Chapman et al., 1999, Gasparini et al., 1999, but it is not established which of the Group III receptors (mGlu₄, mGlu₆, mGlu₇ or mGlu₈) are involved in seizure modulation.

It is well established that l-(+)-2-amino-4-phosphonobutyric acid (LAP4) acts presynaptically to block neurotransmission at some but not all glutamatergic pathways Koerner and Cotman, 1981, Evans et al., 1982, and that LAP4 and the analogous endogenous compound l-serine-O-phosphate are broad-spectrum agonists at Group III glutamate metabotropic receptors, but lack action at other mGlu receptors Okamoto et al., 1994, Pisani et al., 1997, Schoepp et al., 1999. Each of these Group III receptors has a distinctive pattern of expression on glutamatergic pathways in the brain Conn and Pin, 1997, Saugstad et al., 1997, Shigemoto et al., 1997, Cartmell and Schoepp, 2000. At certain pathways, there is evidence for a presynaptic action of Group III agonists on γ-amino-butyrate (GABA)ergic transmission, e.g. in ventrobasal thalamus, hippocampus, striatum and somatosensory cortex Salt and Eaton, 1995, Salt and Turner, 1996, and the synaptic blockade of the lateral perforant path can be linked to action of LAP4 and l-serine-O-phosphate on mGlu₈ receptors.

Studies employing intracerebroventricular (i.c.v.) or focal intracerebral injection in rodents not only demonstrate anticonvulsant, but also some proconvulsant effects of Group III agonists in several epilepsy models, including sound-induced seizures in DBA/2 mice and genetically epilepsy-prone rats (GEP rats). Administration of l-serine-O-phosphate into the inferior colliculus of GEP rats produces an immediate excitatory effect followed by a delayed, very prolonged anticonvulsant effect (Tang et al., 1997).

Recently, metabotropic agonists have become available that are reasonably selective for individual receptors within Group III, such as (R,S)-4-phosphonophenylglycine (PPG) that has a moderate preferential action on mGlu₈ receptors (Gasparini et al., 1999), and (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1) that is a potent, selective agonist for mGlu_4α receptors (Acher et al., 1997).

We have earlier shown that PPG has a more powerful and prolonged anticonvulsant action against sound-induced seizures in DBA/2 mice than l-serine-O-phosphate and LAP4 (Chapman et al., 1999).

In this study, we show that the mGlu_4α receptor agonist, ACPT-1, likewise has potent anticonvulsant activity against sound-induced seizures in rodents. Furthermore, in order to investigate the relative roles played by mGlu₈ and mGlu_4α receptors in controlling seizures, we have also used three Group III receptor antagonists, (RS)-α-methylserine-O-phosphate (MSOP), (RS)-α-methyl-4-phosphonophenylglycine (MPPG), and (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) in combination with the agonists, PPG and ACPT-1, because there is evidence that these antagonists show some differential action with respect to the four receptors within Group III (Schoepp et al., 1999). We have also compared the anticonvulsant potencies of PPG and ACPT-1 against seizures induced by convulsant metabotropic ligands, (RS)-3,5-dihydroxy-phenylglycine (3,5-DHPG) and MSOP.