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

抄録

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.