Abstract
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.
Highlights
Activation of the peripheral innate immune system stimulates the secretion of central nervous system (CNS) cytokines that modulate the behavioral symptoms of sickness
Activation of peripheral innate immune cells elicits the secretion of inflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNFα.), that use neural [2,3], humoral [4] and blood brain barrier pathways [5] to relay this signal to the CNS
Plasma samples were assayed for IL-6 using a customized Enzyme Linked Immmunosorbent Assay (ELISA) that we have described in detail [52] and for IL-1β using a commercial ELISA kit (R&D Systems, Minneapolis, MN)
Summary
Activation of the peripheral innate immune system stimulates the secretion of CNS cytokines that modulate the behavioral symptoms of sickness. Activation of peripheral innate immune cells elicits the secretion of inflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNFα.), that use neural [2,3], humoral [4] and blood brain barrier pathways [5] to relay this signal to the CNS. This inflammatory signal, in turn, induces CNS macrophages and microglia to produce the same cytokines [6], which target neuronal substrates and elicit a sickness behavior syndrome that is normally adaptive and beneficial to the host [1]. We and others have reported that a biological consequence of this reactive glial profile is an exaggerated neuroinflammatory response to innate immune challenge [9,10,12,13,14,27,28]
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