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Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia
Christopher J Henry1, Yan Huang, Angela Wynne
1Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 333 W, 10th Ave, Columbus, OH 43210, USA. henry.86@osu.edu
Background:
Activation of the peripheral innate immune system stimulates the secretion of CNS cytokines that modulate the behavioral symptoms of sickness. Excessive production of cytokines by microglia, however, may cause long-lasting behavioral and cognitive complications. The purpose of this study was to determine if minocycline, an anti-inflammatory agent and purported microglial inhibitor, attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia.
Methods:
In the first set of experiments the effect of minocycline pretreatment on LPS-induced microglia activation was assessed in BV-2 microglia cell cultures. In the second study, adult (3-6 m) BALB/c mice received an intraperitoneal (i.p.) injection of vehicle or minocycline (50 mg/kg) for three consecutive days. On the third day, mice were also injected (i.p.) with saline or Escherichia coli LPS (0.33 mg/kg) and behavior (i.e., sickness and anhedonia) and markers of neuroinflammation (i.e., microglia activation and inflammatory cytokines) were determined. In the final study, adult and aged BALB/c mice were treated with the same minocycline and LPS injection regimen and markers of neuroinflammation were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions.
Results:
Minocycline blocked LPS-stimulated inflammatory cytokine secretion in the BV-2 microglia-derived cell line and reduced LPS-induced Toll-like-receptor-2 (TLR2) surface expression on brain microglia. Moreover, minocycline facilitated the recovery from sickness behavior (i.e., anorexia, weight loss, and social withdrawal) and prevented anhedonia in adult mice challenged with LPS. Furthermore, the minocycline associated recovery from LPS-induced sickness behavior was paralleled by reduced mRNA levels of Interleukin (IL)-1beta, IL-6, and indoleamine 2, 3 dioxygenase (IDO) in the cortex and hippocampus. Finally, in aged mice, where exaggerated neuroinflammation was elicited by LPS, minocycline pretreatment was still effective in markedly reducing mRNA levels of IL-1beta, TLR2 and IDO in the hippocampus.
Conclusion:
These data indicate that minocycline mitigates neuroinflammation in the adult and aged brain and modulates the cytokine-associated changes in motivation and behavior.
Insights
Minocycline, an anti-inflammatory drug, reduces neuroinflammation and sickness behaviors in adult and aged mice. This microglial inhibitor mitigates cytokine-associated changes in motivation and behavior, offering potential therapeutic benefits.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Peripheral innate immune activation triggers central nervous system (CNS) cytokine release, influencing sickness behaviors.
- Excessive microglial cytokine production can lead to persistent behavioral and cognitive deficits.
- Minocycline, an anti-inflammatory agent, is investigated for its microglial inhibitory effects.
Purpose of the Study:
- To evaluate minocycline's efficacy in attenuating lipopolysaccharide (LPS)-induced neuroinflammation.
- To determine if minocycline reduces LPS-induced sickness behavior and anhedonia.
- To assess minocycline's effects on neuroinflammation markers in adult and aged mice.
Main Methods:
- Minocycline's effect on LPS-induced microglia activation was tested in BV-2 cell cultures.
- Adult and aged BALB/c mice received minocycline or vehicle, followed by LPS or saline injection.
- Behavioral changes (sickness, anhedonia) and neuroinflammation markers (microglia activation, cytokines) were quantified.
Main Results:
- Minocycline inhibited LPS-stimulated cytokine secretion and reduced Toll-like-receptor-2 (TLR2) expression in microglia.
- Minocycline treatment facilitated recovery from sickness behaviors and prevented anhedonia in adult mice.
- Reduced mRNA levels of Interleukin (IL)-1beta, IL-6, and indoleamine 2, 3 dioxygenase (IDO) were observed in minocycline-treated mice, including aged mice.
Conclusions:
- Minocycline effectively mitigates neuroinflammation in both adult and aged brains.
- The drug modulates cytokine-related alterations in motivation and behavior.
- Minocycline demonstrates potential as a therapeutic agent for neuroinflammatory conditions.
