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 d4-receptor antagonist but not by d2- or d3-receptor antagonists. in addition,pd168077,a selective dopamine d4-receptor agonist,also protected against h/rinduced cell death. these results suggest that h/r causes oxidative stress-induced cell death and that the activation of dopamine d4 receptors protects against h/r-induced cell death in ht22 cells. © 2010 the japanese pharmacological society.