Clozapine and olanzapine inhibit proton currents in BV2 microglial cells

Excessive reactive oxygen species produced by NADPH oxidase in over-activated microglia can lead to neuronal death. Some atypical antipsychotic drugs possibly have anti-inflammatory properties and suppress the production of pro-inflammatory cytokines and reactive oxygen species from microglia. Voltage-gated proton channels (Hv1) are expressed in microglia and are required for NADPH oxidase-dependent reactive oxygen species generation, which could contribute to neuronal death and ischemic brain damage. In the present study, we examined the effects of the atypical antipsychotics clozapine, olanzapine and risperidone on proton currents in microglial BV2 cells. Clozapine and olanzapine inhibited proton currents with IC50 values of 9.8 mu M and 84 mu M, respectively. Risperidone, however, showed very weak inhibition of proton currents. Clozapine-induced inhibition of proton currents was not accompanied by a positive shift in the activation voltage or reversal potential, indicating that the inhibition was not mediated through an increase in the intracellular pH. Clozapine binds to a multitude of receptors, including serotonin, dopamine and muscarinic receptors. Serotonin receptors, however, were not responsible for the proton current inhibition by clozapine. Of the three drugs, only clozapine could reach concentrations to inhibit microglial proton currents in the brain at therapeutic closes. Thus, the anti-inflammatory activity of clozapine may be partly attributable to its inhibition of microglial proton currents. (C)) 2015 Elsevier B.V. All rights reserved.