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Inhibitory effects of aripiprazole on interferon-gamma-induced microglial activation via intracellular Ca2+
Takahiro Kato1, Yoshito Mizoguchi, Akira Monji
1Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
Aripiprazole, an atypical antipsychotic, demonstrates anti-inflammatory effects by inhibiting microglial activation. This suggests potential therapeutic benefits for schizophrenia by reducing neuroinflammation.
Area of Science:
- Neuroscience
- Psychiatry
- Immunology
Background:
- Schizophrenia pathophysiology may involve inflammatory and immunological responses.
- Atypical antipsychotics, including aripiprazole, interact with dopamine D(2) receptors.
- Previous studies suggest atypical antipsychotics inhibit interferon-gamma-induced microglial activation.
Purpose of the Study:
- To investigate the anti-inflammatory effects of aripiprazole on interferon-gamma-induced microglial activation.
- To determine if aripiprazole inhibits nitric oxide and tumor necrosis factor-alpha production in activated microglia.
Main Methods:
- Murine microglial cells were activated with interferon-gamma.
- Aripiprazole's effect on nitric oxide and tumor necrosis factor-alpha generation was measured.
- Intracellular calcium ion concentrations ([Ca(2+)](i)) were monitored in response to interferon-gamma and aripiprazole.
Main Results:
- Aripiprazole significantly inhibited nitric oxide and tumor necrosis factor-alpha generation from interferon-gamma-activated microglia.
- Aripiprazole suppressed the elevation of intracellular calcium ([Ca(2+)](i)) induced by interferon-gamma.
- Quinpirole, a dopamine D(2) full agonist, did not show these inhibitory effects.
Conclusions:
- Aripiprazole exhibits anti-inflammatory properties by inhibiting microglial activation, potentially via suppressing interferon-gamma-induced calcium signaling.
- These findings suggest that aripiprazole and other antipsychotics with dopamine D(2) antagonism may offer therapeutic benefits in schizophrenia by mitigating neuroinflammatory processes.
