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European Journal of Pharmacology 428 2001 203–214
www.elsevier.comrlocaterejphar
Neuroprotective and behavioral effects of the selective metabotropic
glutamate mGlu receptor antagonist BAY 36-7620
1
Jean De Vry
)
, Ervin Horvath, Rudy Schreiber
´
CNS Research, Bayer AG, Aprather Weg 18a, D-42096, Wuppertal, Germany
Received 10 May 2001; received in revised form 7 August 2001; accepted 10 August 2001
Abstract
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This study characterized the neuroprotective and behavioral effects of 3aS,6aS -6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-
wx Ž. Ž.
cyclopenta c furan-1-on BAY 36-7620 , a novel, selective and systemically active metabotropic glutamate mGlu receptor antagonist.
1
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In the rat, neuroprotective effects were obtained in the acute subdural hematoma model efficacy of 40–50% at 0.01 and 0.03 mgrkgrh,
.
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 mgrkg, 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-in-
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duced convulsions in the mouse MED: 10 mgrkg, i.v. . As assessed in rats, BAY 36-7620 was devoid of the typical side-effects of the
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ionotropic glutamate iGlu receptor antagonists phencyclidine and q -5-methyl-10,11-dihydroxy-5H-dibenzo a,d cyclohepten-5,10-
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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 mGlu receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects
1
resulting from antagonism of iGlu receptors. q2001 Elsevier Science B.V. All rights reserved.
Keywords: Acute subdural hematoma; Amphetamine; Apomorphine; Behavioral stereotypy; Body temperature; Drug discrimination; Intracranial
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self-stimulation; Middle cerebral artery occlusion; MK-801; Mouse ; Phencyclidine; Pentylenetetrazol; Prepulse inhibition; Rat ; Sensorimotor gating
1. Introduction
Drugs aimed at blocking the effects of glutamate at its
receptors may be beneficial for the treatment of central
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nervous system CNS disorders characterized by an exces-
sive release of glutamate, such as brain ischemia, traumatic
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brain injury and epilepsy Choi, 1988; Meldrum, 2000 .
Glutamate receptors can be divided into ionotropic gluta-
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mate iGlu receptors, which are directly linked to the
opening of cationic channels, and metabotropic glutamate
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mGlu receptors, which are linked to second messengers
systems. Although it has been demonstrated that com-
pounds which block iGlu receptors, such as the noncom-
)
Corresponding author. Tel.: q49-202-365-105; fax: q49-202-365-
156.
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E-mail address: jean.vry.jv1@bayer-ag.de J. De Vry .
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petitive NMDA receptor antagonists q -5-methyl-10,11-
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dihydroxy-5H-dibenzo a,d cyclohepten-5,10-imine MK-
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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
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therapeutic use Troupin et al., 1986 .
mGlu receptors may offer an alternative approach for
the treatment of CNS disorders characterized by excessive
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release of glutamate Nicoletti et al., 1996; Schoepp and
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Conn, 1993 . Thus far, eight mGlu receptor subtypes,
which can be subdivided in three groups based on their
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sequence similarity, have been identified Conn and Pin,
.Ž .
1997 . Group I mGlu and mGlu receptors , activates
15
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phospholipase C; whereas group II mGlu and mGlu
23
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receptors and group III mGlu , mGlu and mGlu recep-
67 8
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tors inhibit adenylyl cyclase activity. Despite the fact that
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the elucidation of the physiological and therapeutic role
of the mGlu receptor subtypes has been hampered by the
0014-2999r01r$ - see front matter q2001 Elsevier Science B.V. All rights reserved.
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PII: S0014-2999 01 01296-1