mGluR1 antagonist decreased NADPH oxidase activity and superoxide production after transient focal cerebral ischemia.
NADPH oxidase, which is activated by PKC and signaling via the NMDA receptor, is one of the crucial enzymes for superoxide production in the CNS. We showed earlier that the metabotropic glutamate receptor 1 (mGluR1) plays an important role in the activation of PKC and tyrosine phosphorylation of the NMDA receptor, which has been implicated in enhancement of the channel activity, after cerebral ischemia. In this study, we sought to determine the role of mGluR1 in the activation of NADPH oxidase and subsequent superoxide production after transient focal cerebral ischemia. The amounts of NADPH oxidase subunits in the membrane fraction were increased after the start of reperfusion. These changes were accompanied by increased NADPH oxidase activity followed by superoxide production. The administration of an mGluR1 antagonist attenuated NADPH oxidase activity, which was coincident with inhibition of superoxide production. We further showed that the increase in the amount of PKCδ, but not of PKCζ, as well as the increase in those of NADPH oxidase subunits, was attenuated by the mGluR1 antagonist. These results suggest that mGluR1 may be linked to the increase in NADPH oxidase activity that is mediated by PKCδ and subsequent superoxide production after cerebral ischemia.
Murotomi
Kazutoshi
K
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Takagi
Norio
N
Mizutani
Reiko
R
Honda
Taka-aki
TA
Ono
Megumi
M
Takeo
Satoshi
S
Tanonaka
Kouichi
K
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002462:Cell Membrane / Q000201:enzymology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors; D000099221:Protein Kinase C zeta
D001565:Benzoates; D005998:Glycine; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D010750:Phosphoproteins; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D011743:Pyrimidines; D018094:Receptors, Metabotropic Glutamate; D013481:Superoxides; D019061:src-Family Kinases; D000099221:Protein Kinase C zeta; C412373:AG 1879; C104077:metabotropic glutamate receptor type 1; C079789:neutrophil cytosol factor 67K; C079694:alpha-methyl-4-carboxyphenylglycine; C500593:Cybb protein, rat