Abstract
Inflammatory changes, characterized by an increase in pro-inflammatory cytokine production and up-regulation of the corresponding signaling pathways, have been described in the brains of aged rats and rats treated with the potent immune modulatory molecule lipopolysaccharide (LPS). These changes have been coupled with a deficit in long-term potentiation (LTP) in hippocampus. The evidence suggests that anti-inflammatory agents, which attenuate the LPS-induced and age-associated increase in hippocampal interleukin-1beta (IL-1beta) concentration, lead to restoration of LTP. Here we report that atorvastatin, a member of the family of agents that act as inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, exerts powerful anti-inflammatory effects in brain and that these effects are mediated by IL-4 and independent of its cholesterol-lowering actions. Treatment of rats with atorvastatin increased IL-4 concentration in hippocampal tissue prepared from LPS-treated and aged rats and abrogated the age-related and LPS-induced increases in pro-inflammatory cytokines, interferon-gamma (IFNgamma) and IL-1beta, and the accompanying deficit in LTP. The effect of atorvastatin on the LPS-induced increases in IFNgamma and IL-1beta was absent in tissue prepared from IL-4(-/-) mice. The increase in IL-1beta in LPS-treated and aged rats is associated with increased microglial activation, assessed by analysis of major histocompatibility complex II expression, and the evidence suggests that IFNgamma may trigger this activation. We propose that the primary effect of atorvastatin is to increase IL-4, which antagonizes the effects of IFNgamma, the associated increase in microglial activation, and the subsequent cascade of events.
Highlights
In concentration of the pro-inflammatory cytokine, interleukin-1 (IL-1), have been observed in aged rats [1, 2] and in rats treated with lipopolysaccharide (LPS [3, 4]) or -amyloid peptides (A [5])
Because atorvastatin failed to attenuate the LPS-induced increases in cytokine concentrations in tissue prepared from IL-4Ϫ/Ϫ mice, we propose that the primary action of atorvastatin may be to trigger production of IL-4 and thereby prevent the IFN␥-induced microglial activation
Atorvastatin Attenuates LPS-induced Inflammatory Changes— MHCII mRNA expression and IL-1 concentration were significantly increased in hippocampal tissue prepared from LPSinjected rats, compared with controls (*, p Ͻ 0.05, analysis of variance (ANOVA), Fig. 1, a and b); both changes were attenuated in hippocampal tissue prepared from atorvastatin-treated rats so that mean values were similar in tissue prepared from control-treated rats and LPS-treated rats, which received atorvastatin
Summary
Animals—Twenty-four, 2- to 3-month-old male Wistar rats (BioResources Unit, Trinity College, Dublin, Ireland), were used in the first study, and 18 aged (22–24 months) and 12 young (3– 4 months) animals (Bantham and Kingman, UK) were used in the second study. At the end of the treatment period, mice were killed by cervical dislocation, the brain was rapidly removed, dissected on ice, sliced (350 ϫ 350 m) using a McIlwain tissue chopper, and stored in Krebs buffer containing CaCl2 (1.13 mM) and 10% Me2SO at Ϫ80 °C as previously described [1] until required for analysis. To assess phosphorylation of c-Jun, nitrocellulose membranes were blocked in TBS containing 5% BSA overnight at 4 °C and immunoblotted with a mouse monoclonal antibody (1:300 dilution in phosphate-buffered salineTween containing 2% nonfat dried milk, Cell Signaling) for 2 h at room temperature. In the case of NFB, nitrocellulose membranes were blocked in 5% BSA in TBS overnight at 4 °C and immunoblotted with a rabbit monoclonal antibody (1:300 dilution in TBS-Tween containing 0.1% BSA, Cell Signaling Technology) for 2 h at room temperature. Data are expressed as means with standard errors and deemed statistically significant when p Ͻ 0.05
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