Pyrroloquinoline quinone rescues hippocampal neurons from glutamate-induced cell death through activation of Nrf2 and up-regulation of antioxidant genes

• DOI: 10.4238/2012.june.27.3
• Publication Date: 2012-06-29T13:52:35Z
• Authors: Q. Zhang; M. Ding; X.R. Gao; F. Ding
• Keywords: Cell Nucleus; Neurons; 0303 health sciences; Cell Death; NF-E2-Related Factor 2; Glutamate-Cysteine Ligase; PQQ Cofactor; Glutathione; Hippocampus; Antioxidants; Rats; 3. Good health; Enzyme Activation; Phosphatidylinositol 3-Kinases; Protein Transport; 03 medical and health sciences; Glutamates; Cytoprotection; Animals; RNA, Messenger; Phosphorylation; Proto-Oncogene Proteins c-akt; Heme Oxygenase-1

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.