Effects of the selective metabotropic glutamate agonist LY354740 in a rat model of permanent ischaemia

doi:10.1016/S0304-3940(98)00651-X

Neuroscience Letters

Volume 254, Issue 2, 2 September 1998, Pages 121-123

https://doi.org/10.1016/S0304-3940(98)00651-X Get rights and content

Abstract

The neuroprotective effects of a systemically active, potent, group II selective metabotropic glutamate receptor agonist, LY354740, was assessed in the middle cerebral artery occlusion model of focal ischaemia in rats. LY354740 (0.3, 3.0 or 30.0 mg/kg) was administered subcutaneously (s.c.) 30 min prior to and 3 hours after the induction of ischaemia. Twenty four hours after the ischaemic insult, the brains were processed for the evaluation of infarct volumes. No significant reduction in infarct volumes were observed in treated animals at any of the doses investigated. These data provide no support for the view that group II metabotropic glutamate receptors have a major influence on ischaemic damage in this model.

References (15)

G. Battaglia et al.
In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY354740 in rats
Neurosci. Lett.
(1997)
A. Buisson et al.
The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death
Neuropharmacology
(1995)
K. Maiese et al.
Activation of metabotropic glutamate receptor is neuroprotective during nitric oxide toxicity in primary hippocampal neurons of rats
Neurosci. Lett.
(1995)
M. Miyamoto et al.
Aniticonvulsive and neuroprotective actions of a potent agonist (DCG-IV) for group II metabotropic glutamate receptors against intraventricular kainate in the rat
Neuroscience
(1997)
F. Nicoletti et al.
Metabotropic glutamate receptors: a new target for the therapy of neurodegenerative disorders?
Trends Neurosci.
(1996)
J.P. Pin et al.
The metabotropic glutamate receptors: structure and functions
Neuropharmacology
(1995)
D.D. Schoepp et al.
LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors
Neuropharmacology
(1997)

There are more references available in the full text version of this article.

Cited by (41)

Preconditioning effect of (S)-3,5-dihydroxyphenylglycine on ischemic injury in middle cerebral artery occluded Sprague-Dawley rats
2015, Neuroscience Letters
Citation Excerpt :
These observations are consistent with the serum NSE of 1 μM and 10 μM (S)-3,5-DHPG preconditioning which were significantly lower than in the untreated stroke rats. It has been proposed that necrosis, apoptosis and ischemic preconditioning shared similar initial signaling pathway which depend on the intensity of an ischemic insult that being posed to the brain [32,33]. The reduction of brain damages in 1 and 10 μM (S)-3,5-DHPG preconditioning has been evidenced by other studies that suggested medium intensity of a stimulus commits the pathway to programmed cell protection.
Glutamate receptors are the integral cellular components associated with excitotoxicity mechanism induced by the ischemic cascade events. Therefore the glutamate receptors have become the major molecular targets of neuroprotective agents in stroke researches. Recent studies have demonstrated that a Group I metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) preconditioning elicits neuroprotection in the hippocampal slice cultures exposed to toxic level of N-methyl-d-aspartate (NMDA). We further investigated the preconditioning effects of (S)-3,5-DHPG on acute ischemic stroke rats. One 10 or 100 μM of (S)-3,5-DHPG was administered intrathecally to Sprague–Dawley adult male rats, 2 h prior to induction of acute ischemic stroke by middle cerebral artery occlusion (MCAO). After 24 h, neurological deficits were evaluated by modified stroke severity scores and grid-walking test. All rats were sacrificed and infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining. The serum level of neuron-specific enolase (NSE) of each rat was analyzed by enzyme-linked immunosorbent assay (ELISA). One and 10 μM of (S)-3,5-DHPG preconditioning in the stroke rats showed significant improvements in motor impairment (P < 0.01), reduction in the infarct volume (P < 0.01) and reduction in the NSE serum level (P < 0.01) compared to the control stroke rats. We conclude that 1 and 10 μM (S)-3,5-DHPG preconditioning induced protective effects against acute ischemic insult in vivo.
Metabotropic glutamate receptors in neurodegeneration/neuroprotection: Still a hot topic?
2012, Neurochemistry International
Citation Excerpt :
It was logical to expect a robust protective activity of dual orthosteric mGlu2/3 receptor agonists against ischemic neuronal damage, which is largely mediated by extracellular glutamate (reviewed by Meldrum, 1990; Siesjö et al., 1995; Lipton, 1999). Neuroprotection was consistently seen in models of transient global ischemia (Henrich-Noack et al., 1998; Bond et al., 1998; Bond et al., 1999, 2000; Yoshioka et al., 2009), but, surprisingly, was completely absent in models of focal ischemia (Lam et al., 1998; Bond et al., 1999), where the role of extracellular glutamate in the pathophysiology of neuronal damage is more prominent. The ambiguity of these findings has stimulated an in-depth analysis of the individual role played by mGlu2 and mGlu3 receptors in mechanisms of neurodegeneration/neuroprotection.
Moving from early studies, we here review the most recent evidence linking metabotropic glutamate (mGlu) receptors to processes of neurodegeneration/neuroprotection. The use of knockout mice and subtype-selective drugs has increased our knowledge of the precise role played by individual mGlu receptor subtypes in these processes. Activation of mGlu1 and mGlu5 receptors may either amplify or reduce neuronal damage depending on the context and the nature of the toxic insults. In contrast, mGlu1 and mGlu5 receptors antagonists are consistently protective in in vitro and in vivo models of neuronal death. A series of studies suggest that mGlu1 receptor antagonists or negative allosteric modulators (NAMs) are promising candidates for the treatment of ischemic brain damage, whereas mGlu5 receptor NAMs, which have been clinically developed for the treatment of Parkinson’s disease (PD) and l-DOPA-induced dyskinesias, protect nigro-striatal dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice and monkeys. Activation of glial mGlu3 receptors promotes the formation of various neurotrophic factors, such as transforming growth factor-β (TGF-β), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). Hence, selective mGlu3 receptor agonists or positive allosteric modulators (PAMs) (not yet available) are potentially helpful in the treatment of chronic neurodegenerative disorders such as PD, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis. Selective mGlu2 receptor PAMs should be used with caution in AD patients because these drugs are shown to amplify β-amyloid neurotoxicity. Finally, mGlu4 receptor agonists/PAMs share with mGlu5 receptor NAMs the ability to improve motor symptoms associated with PD and attenuate nigro-striatal degeneration at the same time. No data are yet available on the role of mGlu7 and mGlu8 receptors in neurodegeneration/neuroprotection.
The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2
2010, Bioorganic and Medicinal Chemistry Letters
Regioselective synthesis of dispiro[1H-indene-2,3′-pyrrolidine-2′,3″-[3H]indole]-1,2″(1″H)-diones of potential anti-tumor properties
2009, European Journal of Medicinal Chemistry
Citation Excerpt :
Additionally, other derivatives were reported as allosteric potentiators of the metabotropic glutamate subtype 2 receptor (mGluR2) [31]. Agents targeting mGluR2 may have utility in a variety of clinical conditions [32–34], including epilepsy, anxiety and schizophrenia [35]. Reaction of 2-(arylmethylene)-2,3-dihydro-1H-inden-1-ones 1a–g with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of sarcosine (3) “as a representative example of α-amino acid” and isatins 2a,b in refluxing ethanol afforded only one product as indicated by TLC in a highly regioselective manner (Scheme 2).
1,3-Dipolar cycloaddition reaction of 2-(arylmethylene)-2,3-dihydro-1H-inden-1-ones 1a–g with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a,b and sarcosine (3) afforded dispiro[1H-indene-2,3′-pyrrolidine-2′,3″-[3H]indole]-1,2″(1″H)-diones 4a–n and not the isomeric forms dispiro[1H-indene-2,4′-pyrrolidine-2′,3″-[3H]indole]-1,2″(1″H)-diones 5 in a highly regioselective manner. Anti-tumor activity screening for the synthesized compounds (4c,d,i–l) at a dose of 10 μM utilizing 56 different human tumor cell lines representing, leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate and kidney was carried out. All the tested compounds exhibit promising anti-tumor activity against SK-MEL-2 (melanoma) cell line. Anti-inflammatory activity of the prepared compounds was determined in vivo by the acute carrageenan-induced paw oedema in rats. Many of the prepared compounds exhibit considerable anti-inflammatory properties “at a dose of 50 mg/kg body weight”, especially 4a and 4m which reveal remarkable activities relative to indomethacin which was used as a reference standard in this study.
Biphenyl-indanones: Allosteric potentiators of the metabotropic glutamate subtype 2 receptor
2005, Bioorganic and Medicinal Chemistry Letters
3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy} phenyl)propanoic acid: A brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2)
2005, Bioorganic and Medicinal Chemistry Letters

View all citing articles on Scopus

View full text

Effects of the selective metabotropic glutamate agonist LY354740 in a rat model of permanent ischaemia

Abstract

Neurosci. Lett.

Neuropharmacology

Neurosci. Lett.

Neuroscience

Trends Neurosci.

Neuropharmacology

Neuropharmacology