title: Antipsychotics, chlorpromazine and haloperidol inhibit voltage-gated proton currents in BV2 microglial cells.
abstract: Microglial dysfunction and neuroinflammation are thought to contribute to the pathogenesis of schizophrenia. Some antipsychotic drugs have anti-inflammatory activity and can reduce the secretion of pro-inflammatory cytokines and reactive oxygen species from activated microglial cells. Voltage-gated proton channels on the microglial cells participate in the generation of reactive oxygen species and neuronal toxicity by supporting NADPH oxidase activity. In the present study, we examined the effects of two typical antipsychotics, chlorpromazine and haloperidol, on proton currents in microglial BV2 cells using the whole-cell patch clamp method. Chlorpromazine and haloperidol potently inhibited proton currents with IC50 values of 2.2 μM and 8.4 μM, respectively. Chlorpromazine and haloperidol are weak bases that can increase the intracellular pH, whereby they reduce the proton gradient and affect channel gating. Although the drugs caused a marginal positive shift of the activation voltage, they did not change the reversal potential. This suggested that proton current inhibition was not due to an alteration of the intracellular pH. Chlorpromazine and haloperidol are strong blockers of dopamine receptors. While dopamine itself did not affect proton currents, it also did not alter proton current inhibition by the two antipsychotics, indicating dopamine receptors are not likely to mediate the proton current inhibition. Given that proton channels are important for the production of reactive oxygen species and possibly pro-inflammatory cytokines, the anti-inflammatory and antipsychotic activities of chlorpromazine and haloperidol may be partly derived from their ability to inhibit microglial proton currents.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 156-756, Republic of Korea. Electronic address: jinhos@cau.ac.kr.
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Song
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002460:Cell Line; D002746:Chlorpromazine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D011522:Protons
chemical_list: D014150:Antipsychotic Agents; D007473:Ion Channels; D011522:Protons; D006220:Haloperidol; D002746:Chlorpromazine
keywords: Antipsychotics; Chlorpromazine; Haloperidol; Microglia; Proton channel