title: Pyrroloquinoline quinone rescues  hippocampal neurons from glutamate-induced cell death through activation of  Nrf2 and up-regulation of antioxidant genes.
abstract: Pyrroloquinoline  quinone (PQQ) has been shown to protect primary cultured hippocampal neurons  from glutamate-induced cell apoptosis by scavenging reactive oxygen species  (ROS) and activating phosphatidylinositol-3-kinase (PI3K)/Akt signaling. We  investigated the downstream pathways of PI3K/Akt involved in PQQ protection of  glutamate-injured hippocampal neurons. Western blot analysis indicated that PQQ  treatment following glutamate stimulation triggers phosphorylation of glycogen  synthase kinase 3β,  accompanied by maintenance of Akt activation. Immunostaining and quantitative  RT-PCR revealed that PQQ treatment promotes nuclear translocation of nuclear  factor erythroid 2-related factor 2 (Nrf2), and up-regulates mRNA expression of  Nrf2 and the antioxidant enzyme genes, heme oxygenase-1 and glutamate cysteine  ligase catalytic in glutamate-injured hippocampal neurons; this is a process  dependent on the PI3K/Akt pathway, as evidenced by blocking experiments with  PI3K inhibitors. In addition, increased ROS production and decreased  glutathione levels in glutamate-injured hippocampal neurons were found to be  reduced by PQQ treatment. Collectively, our findings suggest that PQQ exerts  neuroprotective activity, possibly through PI3K/Akt-dependent activation of  Nrf2 and up-regulation of antioxidant genes. However, the ability of PQQ to  scavenge ROS was not totally regulated by PI3K/Akt signaling; possibly it is  governed by other mechanisms.
authors: School of Biology and Basic Medical Sciences, Soochow University, Suzhou, P.R. China.
authors: Q
authors: Q
authors: Zhang
authors: M
authors: M
authors: Ding
authors: X R
authors: XR
authors: Gao
authors: F
authors: F
authors: Ding
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005971:Glutamates; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D045542:PQQ Cofactor / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D000975:Antioxidants; D005971:Glutamates; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D045542:PQQ Cofactor; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat; D005978:Glutathione