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Neuroprotective effects of the allosteric agonist of metabotropic glutamate receptor 7 AMN082 on oxygen-glucose deprivation- and kainate-induced neuronal cell death.
Neurochem Int. 2015 Sep; 88:110-23.NI

Abstract

Although numerous studies demonstrated a neuroprotective potency of unspecific group III mGluR agonists in in vitro and in vivo models of excitotoxicity, little is known about the protective role of group III mGlu receptor activation against neuronal cell injury evoked by ischemic conditions. The aim of the present study was to assess neuroprotective potential of the allosteric agonist of mGlu7 receptor, N,N'-Bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (AMN082) against oxygen-glucose deprivation (OGD)- and kainate (KA)-evoked neuronal cell damage in primary neuronal cultures, with special focus on its efficacy after delayed application. We demonstrated that in cortical neuronal cultures exposed to a 180 min OGD, AMN082 (0.01-1 µM) in a concentration- and time-dependent way attenuated the OGD-induced changes in the LDH release and MTT reduction assays. AMN082 (0.5 and 1 µM) produced also neuroprotective effects against KA-evoked neurotoxicity both in cortical and hippocampal cultures. Of particular importance was the finding that AMN082 attenuated excitotoxic neuronal injury after delayed application (30 min after OGD, or 30 min-1 h after KA). In both models of neurotoxicity, namely OGD- and KA-induced injury, the neuroprotective effects of AMN082 (1 µM) were reversed by the selective mGlu7 antagonist, 6-(4-Methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP, 1 µM), suggesting the mGlu7-dependent mechanism of neuroprotective effects of AMN082. Next, we showed that AMN082 (0.5 and 1 µM) attenuated the OGD-induced increase in the number of necrotic nuclei as well inhibited the OGD-evoked calpain activation, suggesting the participation of these processes in the mechanism of AMN082-mediated protection. Additionally, we showed that protection evoked by AMN082 (1 µM) in KA model was connected with the inhibition of toxin-induced caspase-3 activity, and this effect was abolished by the mGlu7 receptor antagonist. The obtained results indicated that the activation of mGlu7 receptors may be a promising target for neuroprotection against ischemic and excitotoxic insults.

Authors+Show Affiliations

Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland. Electronic address: domin@if-pan.krakow.pl.Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25576184

Citation

Domin, Helena, et al. "Neuroprotective Effects of the Allosteric Agonist of Metabotropic Glutamate Receptor 7 AMN082 On Oxygen-glucose Deprivation- and Kainate-induced Neuronal Cell Death." Neurochemistry International, vol. 88, 2015, pp. 110-23.
Domin H, Jantas D, Śmiałowska M. Neuroprotective effects of the allosteric agonist of metabotropic glutamate receptor 7 AMN082 on oxygen-glucose deprivation- and kainate-induced neuronal cell death. Neurochem Int. 2015;88:110-23.
Domin, H., Jantas, D., & Śmiałowska, M. (2015). Neuroprotective effects of the allosteric agonist of metabotropic glutamate receptor 7 AMN082 on oxygen-glucose deprivation- and kainate-induced neuronal cell death. Neurochemistry International, 88, 110-23. https://doi.org/10.1016/j.neuint.2014.12.010
Domin H, Jantas D, Śmiałowska M. Neuroprotective Effects of the Allosteric Agonist of Metabotropic Glutamate Receptor 7 AMN082 On Oxygen-glucose Deprivation- and Kainate-induced Neuronal Cell Death. Neurochem Int. 2015;88:110-23. PubMed PMID: 25576184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective effects of the allosteric agonist of metabotropic glutamate receptor 7 AMN082 on oxygen-glucose deprivation- and kainate-induced neuronal cell death. AU - Domin,Helena, AU - Jantas,Danuta, AU - Śmiałowska,Maria, Y1 - 2015/01/06/ PY - 2014/09/12/received PY - 2014/12/07/revised PY - 2014/12/17/accepted PY - 2015/1/11/entrez PY - 2015/1/13/pubmed PY - 2016/6/1/medline KW - Calpains KW - Caspase-3 KW - Ischemia KW - MMPIP KW - Neuroprotection KW - mGluR7 SP - 110 EP - 23 JF - Neurochemistry international JO - Neurochem. Int. VL - 88 N2 - Although numerous studies demonstrated a neuroprotective potency of unspecific group III mGluR agonists in in vitro and in vivo models of excitotoxicity, little is known about the protective role of group III mGlu receptor activation against neuronal cell injury evoked by ischemic conditions. The aim of the present study was to assess neuroprotective potential of the allosteric agonist of mGlu7 receptor, N,N'-Bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (AMN082) against oxygen-glucose deprivation (OGD)- and kainate (KA)-evoked neuronal cell damage in primary neuronal cultures, with special focus on its efficacy after delayed application. We demonstrated that in cortical neuronal cultures exposed to a 180 min OGD, AMN082 (0.01-1 µM) in a concentration- and time-dependent way attenuated the OGD-induced changes in the LDH release and MTT reduction assays. AMN082 (0.5 and 1 µM) produced also neuroprotective effects against KA-evoked neurotoxicity both in cortical and hippocampal cultures. Of particular importance was the finding that AMN082 attenuated excitotoxic neuronal injury after delayed application (30 min after OGD, or 30 min-1 h after KA). In both models of neurotoxicity, namely OGD- and KA-induced injury, the neuroprotective effects of AMN082 (1 µM) were reversed by the selective mGlu7 antagonist, 6-(4-Methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP, 1 µM), suggesting the mGlu7-dependent mechanism of neuroprotective effects of AMN082. Next, we showed that AMN082 (0.5 and 1 µM) attenuated the OGD-induced increase in the number of necrotic nuclei as well inhibited the OGD-evoked calpain activation, suggesting the participation of these processes in the mechanism of AMN082-mediated protection. Additionally, we showed that protection evoked by AMN082 (1 µM) in KA model was connected with the inhibition of toxin-induced caspase-3 activity, and this effect was abolished by the mGlu7 receptor antagonist. The obtained results indicated that the activation of mGlu7 receptors may be a promising target for neuroprotection against ischemic and excitotoxic insults. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/25576184/Neuroprotective_effects_of_the_allosteric_agonist_of_metabotropic_glutamate_receptor_7_AMN082_on_oxygen_glucose_deprivation__and_kainate_induced_neuronal_cell_death_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(15)00002-9 DB - PRIME DP - Unbound Medicine ER -