Neuroprotective action of group I metabotropic glutamate receptor agonists against oxygen–glucose deprivation-induced neuronal death

doi:10.1016/S0006-8993(99)02166-6

Brain Research

Volume 853, Issue 2, 24 January 2000, Pages 370-373

https://doi.org/10.1016/S0006-8993(99)02166-6 Get rights and content

Abstract

The metabotropic glutamate receptor (mGluR) non-selective agonist (1S,3R)-1-aminocycloheptane-trans-1,3-dicarboxylic acid [(1S,3R)ACPD] and group I selective receptor agonist 3,5-dihydrophenylglycine (DHPG) effectively attenuated oxygen–glucose deprivation (OGD)-induced death of the cultured cerebellar granule cells. Furthermore, (1S,3R)ACPD (100 μM) reduced the number of apoptotic cells. Antiapoptotic action of (1S,3R)ACPD was prevented by the group I selective antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 100 μM) and protein kinase C (PKC) inhibitor bisindolylmaleimide (BMI, 1 μM).

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Acknowledgements

This work was supported by grant from the Estonian Scientific Foundation. We are grateful to Mrs. U. Peterson for the skillful technical assistance.

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Citation Excerpt :
Further, they showed that neurogenesis in organotypic hippocampal cultures requires mGluR1 activation, raising a possibility that neurogenesis may be part of mGluR-dependent mechanism that regulates neuronal susceptibility to injury. Group I mGluRs have been implicated in both neurotoxic (e.g. see Bruno et al., 1995; Nicoletti et al., 1999; Allen et al., 2000; Pellegrini-Giampietro, 2003) and neuroprotective (Koh et al., 1991; Chiamulera et al., 1992; Kalda et al., 2000; Maiese et al., 2000; Blaabjerg et al., 2003a) actions. In the organotypic hippocampal culture model of NMDA-induced cell death, stimulation of group I mGluRs before the NMDA injury reliably and dose-dependently induced neuroprotection and this action was specific to mGluR1 activation (Adamchik and Baskys, 2000; Blaabjerg et al., 2003a; Arnett et al., 2004).
Group I metabotropic glutamate receptor (mGluR) agonist DHPG reduced nerve cell death caused by their exposure to NMDA (“neuroprotective effect”) and attenuated NMDA receptor-mediated currents [Blaabjerg, M., Baskys, A., Zimmer, J., Vawter, M. P., 2003b. Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors. Brain Research, Molecular Brain Research 117, 196–205.]. In the present study, we used organotypic hippocampal culture preparation to examine specific phospholipase C (PLC) inhibitor U73122 effects on DHPG-induced neuroprotection, changes in excitatory synaptic transmission associated with the neuroprotective DHPG treatment and a role of group I mGluR ligands in neurogenesis. Results show that short (10 min) DHPG treatment did not result in neuroprotection but significantly depressed field synaptic potentials (fEPSP) in the Schaffer collateral-CA1 pathway. The fEPSP depression was not affected by the PLC inhibitor U73122. In contrast, prolonged (2-h) treatment of cultures with DHPG induced a significant protective effect that was blocked by a PLC inhibitor U73122 but not by its inactive analog U73343. Voltage-clamp measurements of spontaneous miniature excitatory post-synaptic currents (EPSCs) recorded in CA1 neurons from cultures treated with DHPG (10 μM, 2 h) showed a significant reduction of the EPSC amplitude in DHPG-treated but not control (untreated) cultures. This reduction was completely abolished by U73122, suggesting a PLC involvement. Since activation of PLC is thought to be associated with cell proliferation, we investigated whether group I mGluR agonist DHPG or subtype antagonists LY367385 and MPEP have an effect on dentate granule cells expressing immature neuronal marker TOAD-64. DHPG (100 μM, 72 h) slightly but not significantly increased the number of TOAD-64 positive cells. The mGluR1 antagonists LY367385 (10 μM, 72 h) markedly decreased the number of TOAD-64 positive cells and mGluR5 antagonist MPEP (1 μM, 72 h) had no effect. These data suggest that (1) prolonged activation of group I mGluRs reduces nerve cell susceptibility to excitotoxic injury in a PLC-dependent manner; (2) this reduction is associated with a PLC-dependent depression of excitatory synaptic transmission; and (3) mGluR1 activation may facilitate neurogenesis.
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The neurotransmitter glutamate can have both excitotoxic and protective effects on neurons. The excitotoxic effects have been intensively studied, whereas the protective effects, including the involvement of metabotropic glutamate receptors (mGluRs), remain unclear. In the present study, we tested the protective effects of the group-I-mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) on organotypic hippocampal slice cultures exposed to excitotoxic concentrations of N-methyl-d-aspartate (NMDA). Effects of DHPG on electrophysiological responses induced by NMDA receptor activation were also recorded. Experiments were performed on organotypic hippocampal slice cultures derived from 7-day-old rats, with cellular uptake of propidium iodide as a marker for neuronal cell death. Slice cultures pretreated with DHPG (10 or 100 μM) for 2 h prior to exposure to 50 μM NMDA for 30 min displayed reduced propidium iodide uptake, compared to cultures exposed to NMDA only. The neuroprotective effect was confirmed by Hoechst 33342 staining, where the appearance of pycnotic nuclei after NMDA treatment was prevented by the DHPG pretreatment. Using caspase-3 activity to monitor the presence of apoptosis, failed to demonstrate this type of cell death in CA1 after NMDA application. The protective effect of DHPG was abolished by the mGluR1 selective antagonist (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385; 5 or 10 μM), whereas the mGluR5-selective antagonist 2-methyl-6-phenylethynylpyridine (MPEP; 1 μM) had no effect. Voltage-clamping of CA1 pyramidal cells in cultures treated with 10 μM DHPG for 2 h showed a significant depression of NMDA-induced inward currents compared to untreated controls. We conclude that neuroprotection induced by activation of group-I-mGluRs involve mGluR1 and is associated with decreased NMDA-stimulated currents.
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Short communicationNeuroprotective action of group I metabotropic glutamate receptor agonists against oxygen–glucose deprivation-induced neuronal death

Abstract

Section snippets

Acknowledgements

Mol. Cell. Neurosci.

Neuroscience

Neurosci. Lett.

Neuroscience

TINS

Neuroscience

Neuropharmacology

Neuropharmacology

Activation of metabotropic glutamate receptors delays apoptosis of chick embryonic motor neurons in vitro

NeuroReport

Short communication
Neuroprotective action of group I metabotropic glutamate receptor agonists against oxygen–glucose deprivation-induced neuronal death