Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia

By C. Henry, Yan Huang, Angela M Wynne, Mark L. Hanke, J. Himler, M. Bailey, J. Sheridan, Jonathan P. Godbout. Journal of Neuroinflammation, 2008

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BackgroundActivation 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.MethodsIn 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.ResultsMinocycline 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)-1β, 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-1β, TLR2 and IDO in the hippocampus.ConclusionThese data indicate that minocycline mitigates neuroinflammation in the adult and aged brain and modulates the cytokine-associated changes in motivation and behavior.

Subfields: Biological Psychiatry, Developmental Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/631d7b8bf6c9eeaf2e24bf6727feac896f7c8b20

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Citations in the corpus

Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness (2016, background): “Moreover, anti-inflammatory medication has been found to reduce depression-like behavioural deficits and reduce microglial activity (Burke et al. 2014; Hinwood et al. 2012; Henry et al. 2008), providing further support for a mechanistic link between microglial activity and psychiatric symptoms.”
Minocycline: far beyond an antibiotic (2013, background): “Minocycline also attenuated the mRNA expression of inflammatory genes, including IL-6, IL-1b, major histocompatibility complex (MHC) II and TLR-2 (Nikodemova et al., 2006; Henry et al., 2008).”
Inflammation: The Common Pathway of Stress-Related Diseases (2017, background): “Antidepressant drug and nonsteroidal anti-inflammatory drugs (NSAIDs) like minocycline, decrease blood levels of IL-6, attenuate microglial activation and central cytokine secretion and behavioral changes (Henry et al., 2008).”
Depression as a microglial disease. (2015, result): “However, another study found no antidepressant-like effects of minocycline (albeit at somewhat lower doses) in the forced swim test [87]; (ii) in the LPS model of depression in rats, administration of minocycline completely prevented the development of depression-like symptoms, as well as the LPS-in”
Normal aging induces A1-like astrocyte reactivity (2018, background): “We observed by qPCR that LPS treatment induces an up-regulation of A1 reactive genes in astrocytes from the hippocampus, striatum, and cortex (Fig.”
β-Adrenergic Receptor Antagonism Prevents Anxiety-like Behavior and Microglial Reactivity Induced by Repeated Social Defeat (2011, methodology): “Staining of microglia surface antigens was performed as previously described (Henry et al., 2008, 2009).”