Serotonin 5-HT2B receptor antagonism is fundamental for protecting PC12 cells exposed to hydrogen peroxide

Objectives: According to our previous work, aripiprazole exerted a protective effect on hydrogen peroxide (H2O2)-treated PC12 cells; haloperidol did not. Because aripiprazole has distinct affinities to a set of neurotransmitter receptor subtypes, this study aimed to clarify which subtype is responsible for rescuing cells from 0.25 mM H2O2 exposure. Methods: A set of compounds, which are more specific to each subset of G-protein coupled receptors, were examined for their ability to mimic the pharmacological effects of aripiprazole or haloperidol, including their Ki values. The viability of PC12 cells cultured with test compounds with or without H2O2 was assessed using WST-8 reagent. Results: Results from in vitro studies using PC12 cells showed that agonism at serotonin 5-HT2C-receptors based on the antagonism against 5-HT2B-receptors played a significant role in resistingH2O2-induced cell death. However, the use of a specific 5-HT2B-receptor agonist instead of a 5-HT2B-receptor antagonist completely negated the effect of a specific 5-HT2C-receptor agonist. Furthermore, unlike the dopamine D1-receptor specific antagonist, none of the agonists of dopamine D2-, D3-, and D4-receptors ameliorated the cytopathic effects of H2O2. Conclusion: Antagonism at 5-HT2B-receptors is fundamental for the protection of PC12 cells against the cytopathic effects caused by 0.25 mM H2O2. However, the role of negatively regulated cyclic adenosine monophosphate in this phenomenon requires further investigation.