Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu₁ receptor antagonist BAY 36-7620

Abstract

This study characterized the neuroprotective and behavioral effects of (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), a novel, selective and systemically active metabotropic glutamate (mGlu)₁ receptor antagonist. In the rat, neuroprotective effects were obtained in the acute subdural hematoma model (efficacy of 40–50% at 0.01 and 0.03 mg/kg/h, i.v. infusion during the 4 h following surgery); whereas in the middle cerebral artery occlusion model, a trend for a neuroprotective effect was obtained after triple i.v. bolus application of 0.03–3 mg/kg, given immediately, 2 and 4 h after occlusion. Hypothermic effects were mild and only obtained at doses which were considerably higher than those at which maximal neuroprotective efficacy was obtained, indicating that the neuroprotective effects are not a consequence of hypothermia. BAY 36-7620 protected against pentylenetetrazole-induced convulsions in the mouse (MED: 10 mg/kg, i.v.). As assessed in rats, BAY 36-7620 was devoid of the typical side-effects of the ionotropic glutamate (iGlu) receptor antagonists phencyclidine and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801). Thus, BAY 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or facilitate intracranial self-stimulation behavior. Although behavioral stereotypies and disruption of sensorimotor gating induced by amphetamine or apomorphine were not affected by BAY 36-7620, the compound attenuated some behavioral effects of iGlu receptor antagonists, such as excessive grooming or licking, and their facilitation of intracranial self-stimulation behavior. It is concluded that mGlu₁ receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects resulting from antagonism of iGlu receptors.

Introduction

Drugs aimed at blocking the effects of glutamate at its receptors may be beneficial for the treatment of central nervous system (CNS) disorders characterized by an excessive release of glutamate, such as brain ischemia, traumatic brain injury and epilepsy Choi, 1988, Meldrum, 2000. Glutamate receptors can be divided into ionotropic glutamate (iGlu) receptors, which are directly linked to the opening of cationic channels, and metabotropic glutamate (mGlu) receptors, which are linked to second messengers systems. Although it has been demonstrated that compounds which block iGlu receptors, such as the noncompetitive NMDA receptor antagonists (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) and phencyclidine (PCP), have neuroprotective and anticonvulsive properties, clinical experience has revealed that they are endowed with serious CNS side-effects, including psychotomimetic effects, which preclude their therapeutic use (Troupin et al., 1986).

mGlu receptors may offer an alternative approach for the treatment of CNS disorders characterized by excessive release of glutamate Nicoletti et al., 1996, Schoepp and Conn, 1993. Thus far, eight mGlu receptor subtypes, which can be subdivided in three groups based on their sequence similarity, have been identified (Conn and Pin, 1997). Group I (mGlu₁ and mGlu₅ receptors), activates phospholipase C; whereas group II (mGlu₂ and mGlu₃ receptors) and group III (mGlu₆, mGlu₇ and mGlu₈ receptors) inhibit adenylyl cyclase activity. Despite the fact that the elucidation of the physiological (and therapeutic) role of the mGlu receptor subtypes has been hampered by the lack of selective compounds (for recent reviews on mGlu receptor ligands, see Pin et al., 1999, Schoepp et al., 1999), increasing evidence suggests that the mGlu₁ receptor subtype could be particularly attractive as a target for novel neuroprotectants and anticonvulsants. Thus, in epileptic patients, as well as in animal models of epilepsy, such as the amygdala-kindled rat, the expression and function of mGlu₁ receptors is augmented Akbar et al., 1996, Al-Ghoul et al., 1998, Blumcke et al., 2000, Keele et al., 1999; whereas a reduced expression of mGlu₁ receptors, induced by mGlu₁ receptor antisense, inhibits kindling (Greenwood et al., 2000). Also in animal models of cerebral ischemia, it was reported that expression of mGlu₁ receptors and their associated signaling pathways is altered Martin et al., 2000, Sommer et al., 2000. Consistent with these findings, compounds with agonist properties at mGlu₁ receptors have been shown to induce neurotoxic and proconvulsive or convulsive effects Camón et al., 1998, Chapman et al., 2000, Sacaan and Schoepp, 1992, Thomsen and Dalby, 1998, and compounds with antagonist properties at mGlu₁ receptors have anticonvulsive and neuroprotective effects Bruno et al., 1999, Chapman et al., 1999, Cozzi et al., 1997, Faden et al., 2001, Gong et al., 1995, Pellegrini-Giampietro et al., 1999, Rauca et al., 1998, Thomsen and Dalby, 1998.

Recently, (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620; Fig. 1)was characterized as a highly selective, lipophilic mGlu₁ receptor antagonist Carroll et al., 2000, Carroll et al., 2001. BAY 36-7620 can be considered as an appropriate compound to test the neuroprotective and anticonvulsant potential of mGlu₁ receptor blockade in vivo, as it is more selective for mGlu₁ receptors than most of the previously tested mGlu₁ receptor antagonists and it lacks their inappropriate pharmacokinetic properties or difficulty to cross the blood–brain-barrier. Therefore, it was the aim of the present study to assess the neuroprotective and anticonvulsive efficacy of BAY 36-7620 after systemic administration. In addition, it was tested whether BAY 36-7620 shares the typical side-effects of noncompetitive NMDA receptor antagonists. Thus, it was investigated to what extent BAY 36-7620 was able to induce (1) psychotomimetic-like effects (as assessed in rats trained to discriminate PCP from vehicle), (2) rewarding effects [tested in an intracranial self-stimulation paradigm], (3) hypothermic effects, (4) stereotypic behavior, and (5) disruption of sensorimotor gating [tested in a prepulse inhibition paradigm]. A preliminary account of the present data was presented at the 26th Annual Meeting of the Society for Neuroscience (Müller et al., 2000).