Distinct influence of the group III metabotropic glutamate receptor agonist (R,S)-4-phosphonophenylglycine [(R,S)-PPG] on different forms of neuronal damage

Henrich‐Noack, Petra; Flor, Peter J.; Sabelhaus, Clemens F; Prass, Konstantin; Dirnagl, Ulrich; Gasparini, F.; Sauter, André; Rudin, Markus; Reymann, Klaus G.

doi:10.1016/s0028-3908(99)00256-7

Cited by 28 publications

(7 citation statements)

References 28 publications

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“…In fact, after 5–10 min of OGD, there is a progressive reduction in the amplitude of PF–EPSCs and a concomitant increase in the PPR. These data are comparable to those that Henrich-Noack et al (2000) obtained in acute hippocampal slices. They show that OGD reduces glutamatergic transmission at the Shaffer collateral – CA1 pyramidal cell synapse, an effect mediated by the activation of group III mGlu receptors.…”

Section: Discussionsupporting

confidence: 90%

“…We used an ex vivo model of ischemia, in which we studied neuronal responses of PCs in acute cerebellar slices, that were subjected to controlled periods of OGD. This protocol, widely adopted to investigate cellular responses to ischemia, results in significant increases in synaptic and extra-synaptic glutamate levels, principally due to a functional reversal of astrocyte glutamate transporters ( Henrich-Noack et al, 2000 ; Rossi et al, 2000 ; Hamann et al, 2005 ; Domin et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

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A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex

Bossi

Helleringer

Galante

et al. 2018

Front. Cell. Neurosci.

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Metabotropic glutamate receptors (mGlus) are G Protein coupled-receptors that modulate synaptic transmission and plasticity in the central nervous system. Some act as autoreceptors to control neurotransmitter release at excitatory synapses and have become attractive targets for drug therapy to treat certain neurological disorders. However, the high degree of sequence conservation around the glutamate binding site makes the development of subtype-specific orthosteric ligands difficult to achieve. This problem can be circumvented by designing molecules that target specific less well conserved allosteric sites. One such allosteric drug, the photo-switchable compound OptoGluNAM4.1, has been recently employed to reversibly inhibit the activity of metabotropic glutamate 4 (mGlu4) receptors in cell cultures and in vivo. We studied OptoGluNAM4.1 as a negative modulator of neurotransmission in rodent cerebellar slices at the parallel fiber – Purkinje cell synapse. Our data show that OptoGluNAM4.1 antagonizes pharmacological activation of mGlu4 receptors in a fully reversible and photo-controllable manner. In addition, for the first time, this new allosteric modulator allowed us to demonstrate that, in brain slices from the rodent cerebellar cortex, mGlu4 receptors are endogenously activated in excitotoxic conditions, such as the early phases of simulated cerebellar ischemia, which is associated with elevated levels of extracellular glutamate. These findings support OptoGluNAM4.1 as a promising new tool for unraveling the role of mGlu4 receptors in the central nervous system in physio-pathological conditions.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex

Bossi

Helleringer

Galante

et al. 2018

Front. Cell. Neurosci.

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“…(R,S)-4-Phosphonophenylglycine (PPG), an orthosteric agonist of mGlu4 receptors that also activates mGlu7 and mGlu8 receptors, is protective against excitotoxic neuronal death in culture (Bruno et al, 2000;Henrich-Noack et al, 2000), and improves the recovery of neuronal function in acutely isolated hippocampal slices subjected to oxygen-glucose deprivation (Henrich-Noack et al, 2000). However, PPG has no effect on neuronal damage in models of focal or global ischemia (Henrich-Noack et al, 2000). Perhaps the efficacy of PPG or other orthosteric agonists in vivo is limited by the high levels of ambient glutamate that saturate mGlu4 receptors during ischemia-reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

Moyanova

Mastroiacovo

Kortenska

et al. 2010

J Cereb Blood Flow Metab

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We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.

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“…Glutamate can act as an endogenous agonist to metabotropic glutamate receptors (mGluRs). It has been shown that the activation of metabotropic glutamate receptor-1 (mGluR-1) aggravates nerve injury resulting from cerebral ischemia (Henrich-Noack et al, 2000), and administration of mGluR-1 antagonist reduces the brain injury owing to cerebral artery occlusion (Bonde et al, 2005). These were confirmed by the in vivo research evidence revealing that the over-expression of mGluR-1 RNA was observed after cerebral ischemia/reperfusion, and that mGluR-1 RNA was involved in the process of ischemia/reperfusion injury (Zhang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effect of Buyang Huanwu Decoction against focal cerebral ischemia/reperfusion injury in rats – Time window and mechanism

Zhao

Wang

Jin

et al. 2012

Journal of Ethnopharmacology

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Distinct influence of the group III metabotropic glutamate receptor agonist (R,S)-4-phosphonophenylglycine [(R,S)-PPG] on different forms of neuronal damage

Cited by 28 publications

References 28 publications

A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex

A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex

Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

Neuroprotective effect of Buyang Huanwu Decoction against focal cerebral ischemia/reperfusion injury in rats – Time window and mechanism

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