Activation of Dopamine D4 Receptors Is Protective Against Hypoxia/Reoxygenation-Induced Cell Death in HT22 Cells

Several reports have shown that some dopamine receptor ligands modulate the ischemia-reperfusion injury in animal models; however, its underling mechanisms are still unclear. In this study, we sought to establish an in vitro experimental model of hypoxia/reoxygenation (H/R) using HT22 cells that originated from mouse hippocampal neurons and to examine protective the effect of dopamine-receptor ligands against H/R-induced cell injury. The treatment with hypoxia for 18 h followed by reoxygenation for 6 h induced the elevation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential; however, lactate dehydrogenase (LDH) release was not changed at this time point. LDH release was increased after reoxygenation for 18 h and longer, and this increase in LDH release was suppressed by dopamine receptor agonists such as apomorphine and apocodeine. The suppressive effects of these agonists were reversibly inhibited by L750667, a D(4)-receptor antagonist but not by D(2)- or D(3)-receptor antagonists. In addition, PD168077, a selective dopamine D(4)-receptor agonist, also protected against H/R-induced cell death. These results suggest that H/R causes oxidative stress-induced cell death and that the activation of dopamine D(4) receptors protects against H/R-induced cell death in HT22 cells.