Selective activation of group II mGluRs with LY354740 does not prevent neuronal excitotoxicity

Behrens, M. Margarita; Strasser, Uta; Heidinger, Valérie; Lobner, Doug; Yu, Shan Ping; McDonald, John W.; Won, Michelle; Choi, Dennis W.

doi:10.1016/s0028-3908(99)00098-2

Cited by 25 publications

(15 citation statements)

References 61 publications

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“…Data with "second generation" agonists on in vivo excitotoxicity are controversial. D 'Onofrio et al (2001) have shown that LY379268 protects striatal neurons against NMDA toxicity when injected locally or systemically, whereas no effect of LY354740 on striatal NMDA toxicity was reported by Behrens et al (1999). A greater potency of LY379268 at native mGlu2/3 receptors or, more likely, the different doses of drugs used in the two experiments (10 nmol of LY354740 vs. 25 nmol of LY379268) may account for this difference.…”

Section: Bruno Et Al 1024mentioning

confidence: 99%

“…More recently, neuroprotection studies have been extended to "second generation" mGlu2/3 receptor agonists, such as 2R,4R-APDC, LY354740, LY379268, and LY389795. All these drugs were proven to protect neurons against NMDA toxicity in culture (Battaglia et al, 1998;Kingston et al, 1999a,b;Behrens et al, 1999;D'Onofrio et al, 2001). However, the relatively low potency of LY354740 and LY379268 in the study of Behrens et al (1999) led to the suggestion that neuroprotection was mediated by the activation of mGlu4 or mGlu8 receptors, which can be recruited by micromolar concentrations of both compounds (Schoepp et al, 1999).…”

Section: Bruno Et Al 1022mentioning

confidence: 99%

“…All these drugs were proven to protect neurons against NMDA toxicity in culture (Battaglia et al, 1998;Kingston et al, 1999a,b;Behrens et al, 1999;D'Onofrio et al, 2001). However, the relatively low potency of LY354740 and LY379268 in the study of Behrens et al (1999) led to the suggestion that neuroprotection was mediated by the activation of mGlu4 or mGlu8 receptors, which can be recruited by micromolar concentrations of both compounds (Schoepp et al, 1999). An alternative explanation is that native mGlu2/3 receptors have a lower affinity to LY354740 or LY379268 or that some unknown factor limits the access of these compounds to mGlu2/3 receptors in cortical cells.…”

Section: Bruno Et Al 1022mentioning

confidence: 99%

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Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs

Bruno

Battaglia

Copani

et al. 2001

J Cereb Blood Flow Metab

291

168

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Summary: Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.

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Section: Bruno Et Al 1024mentioning

confidence: 99%

Section: Bruno Et Al 1022mentioning

confidence: 99%

Section: Bruno Et Al 1022mentioning

confidence: 99%

See 1 more Smart Citation

Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs

Bruno

Battaglia

Copani

et al. 2001

J Cereb Blood Flow Metab

291

168

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“…Data obtained with more potent and selective "second generation" agonists of mGlu2 and mGlu3 receptors, such as (1S, 2S, 5R, 6S)-(ϩ)-2-aminobicylco[3.1.0]-hexane-2,6-dicarboxylic acid (LY354740) and (Ϫ)-2-oxa-4-aminocyclo [3.1.0]hexane-4,6-dicarboxylic acid (LY379268), are less convincing. These drugs protect cultured neurons against excitotoxic death, but at concentrations that are 10-to 100-fold higher than the reported EC 50 values for mGlu2 and mGlu3 re-ceptors (Battaglia et al, 1998;Behrens et al, 1999;Kingston et al, 1999a,b;D'Onofrio et al, 2001). Although LY354740 and LY379268 are systemically active, their efficacy as neuroprotectants in in vivo studies is restricted to a few models of neurodegeneration.…”

Section: Introductionmentioning

confidence: 95%

“…Although LY354740 and LY379268 are systemically active, their efficacy as neuroprotectants in in vivo studies is restricted to a few models of neurodegeneration. For example, systemic administration of LY354740/LY379268 protects striatal neurons against excitotoxicity in one study but not in another (Behrens et al, 1999), is only partially effective in models of global ischemia (Bond et al, 1999), is ineffective in models of focal ischemia (Bond et al, 1999), and produces ambiguous effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of dopaminergic neuronal death . The overall modest effect of mGlu2/3 receptor agonists in in vivo studies is counterintuitive if one assumes that both mGlu2 and mGlu3 receptors contribute to mechanisms of neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection

Corti

Battaglia²,

Molinaro³

et al. 2007

J. Neurosci.

184

161

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Dual metabotropic glutamate 2/3 (mGlu2/3) receptor agonists have been examined with success in the clinic with positive proof of efficacy in several tests of anxiety and schizophrenia. Moreover, a large body of evidence has accumulated that these drugs have significant neuroprotective potential. An important discussion in the field deals with dissecting effects on mGlu2 versus effects on mGlu3 receptors, which is relevant for the potential use of subtype-selective agonists or allosteric activators. We addressed this issue using mGlu2 and mGlu3 receptor knock-out mice. We used mixed cultures of cortical cells in which astrocytes and neurons were plated at different times and could therefore originate from different mice. Cultures were challenged with NMDA for the induction of excitotoxic neuronal death. The mGlu2/3 receptor agonist, (Ϫ)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), was equally neuroprotective in cultures containing neurons from wild-type, mGlu2 ؊/؊ , or mGlu3 ؊/؊ mice. Neuroprotection was instead abolished when astrocytes lacked mGlu3 receptors, unless neuronal mGlu2 receptors were also absent. The latter condition partially restored the protective activity of LY379268. Cultures in which neurons originated from mGlu2 ؊/؊ mice were also intrinsically resistant to NMDA toxicity. In in vivo experiments, systemic administration of LY379268 protected striatal neurons against NMDA toxicity in wild-type and mGlu2 Ϫ/Ϫ mice but not in mGlu3 ؊/؊ mice. In addition, LY379268 was protective against nigrostriatal degeneration induced by low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only in mice lacking mGlu2 receptors. We conclude that neuroprotection by mGlu2/3 receptor agonists requires the activation of astrocytic mGlu3 receptors, whereas, unexpectedly, activation of mGlu2 receptors might be harmful to neurons exposed to toxic insults.

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