The neuroprotective action of pyrroloquinoline quinone against glutamate-induced apoptosis in hippocampal neurons is mediated through the activation of PI3K/Akt pathway

Toxicol Appl Pharmacol. 2011 Apr 1;252(1):62-72. doi: 10.1016/j.taap.2011.02.006. Epub 2011 Feb 12.


Pyrroloquinoline quinone (PQQ), a cofactor in several enzyme-catalyzed redox reactions, possesses a potential capability of scavenging reactive oxygen species (ROS) and inhibiting cell apoptosis. In this study, we investigated the effects of PQQ on glutamate-induced cell death in primary cultured hippocampal neurons and the possible underlying mechanisms. We found that glutamate-induced apoptosis in cultured hippocampal neurons was significantly attenuated by the ensuing PQQ treatment, which also inhibited the glutamate-induced increase in Ca²+ influx, caspase-3 activity, and ROS production, and reversed the glutamate-induced decrease in Bcl-2/Bax ratio. The examination of signaling pathways revealed that PQQ treatment activated the phosphorylation of Akt and suppressed the glutamate-induced phosphorylation of c-Jun N-terminal protein kinase (JNK). And inhibition of phosphatidylinositol-3-kinase (PI3K)/Akt cascade by LY294002 and wortmannin significantly blocked the protective effects of PQQ, and alleviated the increase in Bcl-2/Bax ratio. Taken together, our results indicated that PQQ could protect primary cultured hippocampal neurons against glutamate-induced cell damage by scavenging ROS, reducing Ca²+ influx, and caspase-3 activity, and suggested that PQQ-activated PI3K/Akt signaling might be responsible for its neuroprotective action through modulation of glutamate-induced imbalance between Bcl-2 and Bax.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Female
  • Glutamic Acid / toxicity*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • PQQ Cofactor / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / physiology
  • Pregnancy
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-akt / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Neuroprotective Agents
  • Glutamic Acid
  • PQQ Cofactor
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt