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Bioenergetics and the Oxidative Burst: Protocols for the Isolation and Evaluation of Human Leukocytes and Platelets
Published on: March 27, 2014
Risperidone-induced bioenergetic disruption in the isolated human peripheral blood monocytes
Bandar Alenazi1, Huda A Al Doghaither2, Ayat B Al-Ghafari3
1Pharmacology Department, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia.
Abstract:
Risperidone (RIS) is a widely used antipsychotic drug with reported alteration in immune response. The current study investigated mitochondrial disruption as the underlying mechanism of RIS-induced immunotoxicity in isolated human peripheral blood monocytes (hPBM). RIS was cytotoxic to hPBM in exposure duration and concentration-dependent patterns. Functionally, RIS was shown to increase the release of IL-6, TNF-α, and IL-8 with a decrease in test particle phagocytosis in concertation and exposure time-based patterns. It was found that RIS decreased ATP production in isolated monocytes' mitochondria, with an estimated EC50 of around 70 μM after 24 h with parallel inhibition of mitochondrial complexes I and III activities and decreased mitochondrial membrane potential and oxygen consumption rates with increased lactate production from by the treated cells in comparison to controls. Structurally, RIS in 100 μM concentration significantly increased the mitochondrial membrane fluidity with significant increase in increased unsaturated/saturated fatty acids ratios of the mitochondrial membranes of the treated cells. Interestingly, water-soluble CoQ10 formulation significantly decreased the cytotoxic effect of RIS and improved the phagocytic activity of RIS-treated cells. To conclude, the current data suggests mitochondrial disruption as the underlying mechanism of RIS-induced immunotoxicity with shown protective effect of water-soluble CoQ10 formulation.
Insights
Risperidone (RIS) causes immune system damage by disrupting mitochondria in human monocytes. A CoQ10 formulation protected against this toxicity and improved cell function, suggesting a potential therapeutic approach.
Area of Science:
- Immunotoxicology
- Mitochondrial Biology
- Pharmacology
Background:
- Risperidone (RIS) is an antipsychotic known to affect immune responses.
- Mitochondrial dysfunction is implicated in various drug-induced toxicities.
- Human peripheral blood monocytes (hPBM) are key immune cells susceptible to drug effects.
Purpose of the Study:
- To investigate mitochondrial disruption as the mechanism behind risperidone-induced immunotoxicity in hPBM.
- To evaluate the functional and structural changes in monocytes exposed to risperidone.
- To assess the protective potential of a water-soluble CoQ10 formulation against risperidone's effects.
Main Methods:
- Cytotoxicity assays on isolated hPBM exposed to varying concentrations and durations of RIS.
- Measurement of cytokine release (IL-6, TNF-α, IL-8) and phagocytic activity.
- Assessment of mitochondrial function: ATP production, mitochondrial complex I and III activity, membrane potential, oxygen consumption, and lactate production.
- Analysis of mitochondrial membrane fluidity and fatty acid composition.
Main Results:
- Risperidone exhibited dose- and time-dependent cytotoxicity to hPBM.
- RIS increased pro-inflammatory cytokine release and decreased phagocytosis.
- Mitochondrial dysfunction was evident: reduced ATP production, inhibited complex I/III, decreased membrane potential, lower oxygen consumption, and increased lactate production.
- RIS altered mitochondrial membrane fluidity and fatty acid ratios.
- Water-soluble CoQ10 mitigated RIS-induced cytotoxicity and restored phagocytic activity.
Conclusions:
- Mitochondrial disruption is a key mechanism underlying risperidone-induced immunotoxicity in human monocytes.
- Risperidone impairs monocyte function through effects on mitochondrial bioenergetics and membrane integrity.
- Water-soluble CoQ10 demonstrates a protective effect against risperidone's immunotoxic effects, highlighting its therapeutic potential.
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