Activation of group I metabotropic glutamate receptors reduces neuronal apoptosis but increases necrotic cell death in vitro.
Glutamate released during acute CNS insults acts at metabotropic glutamate receptors (mGluR), including group I mGluR. Blockade of group I mGluR during in vitro neuronal trauma provides neuroprotection, whereas activation exacerbates such injury. However, the effects of group I mGluR agonists or antagonists have been primarily studied in in vitro models characterized by necrotic cell death. We examined the role of group I mGluR in the modulation of neuronal injury induced during oxygen-glucose deprivation (OGD), a well-studied model of necrosis, and by application of two well established pro-apoptotic agents: staurosporine and etoposide. Inhibition of group I mGluR attenuated necrosis induced by OGD, whereas selective activation of group I mGluR exacerbated such injury. In contrast, activation of group I mGluR, including selective activation of mGluR5, significantly attenuated apoptotic cell death induced by both staurosporine and etoposide. This effect was completely reversed by co-application of a group I mGluR antagonist. Thus, group I mGluR appear to exhibit opposite effects on necrotic and apoptotic neuronal cell death. Our findings suggest that activation of mGluR1 exacerbates neuronal necrosis whereas both mGluR1 and mGluR5 play a role in attenuation of neuronal apoptosis.
Allen
J W
JW
Institute for Cognitive and Computational Sciences, Georgetown University Medical Center, Washington, DC 20007, USA.
Knoblach
S M
SM
Faden
A I
AI
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005047:Etoposide / Q000494:pharmacology; D008959:Models, Neurological; D009336:Necrosis; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000145:classification / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology
D018094:Receptors, Metabotropic Glutamate; D005047:Etoposide; D019311:Staurosporine