Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+ regulation in vitro.

Abstract

The activation of the inflammatory/immunological response system is suggested to be related to the pathophysiology of schizophrenia. Aripiprazole is a novel atypical antipsychotic, which is a high-affinity dopamine D(2) receptor partial agonist. Atypical antipsychotics, all of which have dopamine D(2) receptor antagonism, have recently reported to have significantly inhibitory effects on interferon (IFN)-gamma-induced microglial activation in vitro. In the present study, we investigated whether or not aripiprazole also has anti-inflammatory effect on IFN-gamma-induced microglial activation. Not quinpirole, dopamine D(2) full agonist, but aripiprazole significantly inhibited the generation of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha from IFN-gamma-activated microglia and suppressed the IFN-gamma-induced elevation of intracellular Ca(2+) concentrations ([Ca(2+)](i)) in murine microglial cells. Increased [Ca(2+)](i) has been reported to be required, but by itself not sufficient, for the release of NO and certain cytokines. As a result, we can speculate that aripiprazole may inhibit IFN-gamma-induced microglial activation through the suppression of IFN-gamma-induced elevation of [Ca(2+)](i) in microglia. Our results demonstrated that not only antipsychotics which have dopamine D(2) receptor antagonism but also aripiprazole have anti-inflammatory effects via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing the microglial inflammatory reactions.

• Authors: Takahiro Kato, Yoshito Mizoguchi, Akira Monji, Hideki Horikawa, Satoshi O Suzuki, Yoshihiro Seki, Toru Iwaki, Sadayuki Hashioka, Shigenobu Kanba
• Journal: Journal of neurochemistry (J Neurochem) Vol. 106 Issue 2 Pg. 815-25 (Jul 2008) ISSN: 1471-4159 [Electronic] England
• PMID: 18429930 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Dopamine Agonists
• Piperazines
• Quinolones
• Receptors, Dopamine D2
• Tumor Necrosis Factor-alpha
• Quinpirole
• Nitric Oxide
• Interferon-gamma
• Aripiprazole
• Calcium

Topics

• Analysis of Variance
• Animals
• Animals, Newborn
• Antipsychotic Agents (pharmacology)
• Aripiprazole
• Brain (cytology)
• Calcium (metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Dopamine Agonists (pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Enzyme-Linked Immunosorbent Assay (methods)
• Interferon-gamma (pharmacology)
• Mice
• Microglia (drug effects)
• Neurons
• Nitric Oxide (metabolism)
• Piperazines (pharmacology)
• Quinolones (pharmacology)
• Quinpirole (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine D2 (genetics, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)