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Inflammatory changes, characterized by an increase in proinflammatory 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-1␤ (IL-1␤) 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 cholesterollowering actions. Treatment of rats with atorvastatin increased IL-4 concentration in hippocampal tissue prepared from LPStreated and aged rats and abrogated the age-related and LPSinduced increases in pro-inflammatory cytokines, interferon-␥ (IFN␥) and IL-1␤, and the accompanying deficit in LTP. The effect of atorvastatin on the LPS-induced increases in IFN␥ and IL-1␤ was absent in tissue prepared from IL-4 ؊/؊ mice. The increase in IL-1␤ 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 IFN␥ may trigger this activation. We propose that the primary effect of atorvastatin is to increase IL-4, which antagonizes the effects of IFN␥, the associated increase in microglial activation, and the subsequent cascade of events.The adverse effects of inflammation in the brain have been shown to include down-regulation of synaptic function. One manifestation of this is a decrease in the ability of rats to sustain long-term potentiation (LTP), 3 a form of synaptic plasticity that is considered to be a potential biological substrate for learning and/or memory. Inflammatory changes, typified by an increase 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)). In each of these conditions, LTP is impaired and, in some cases, the impairment is abrogated by strategies that restore IL-1␤ concentration to the lower values observed in control conditions (4). A role for IL-4 in modulating IL-1␤ production has been demonstrated (6), and we have observed that two treatments with anti-inflammatory properties, the polyunsaturated fatty acid, eicosapentaenoic acid (6) and rosiglitazone, 4 abrogate age-and LPS-induced neuroinflammation by increasing IL-4 concentration in hippocampus. These data highlight the potential of anti-inflammatory treatments to restore functional deficits associated with inflammation and draw an interesting parallel with the observation that the incidence of Alzheimer disease is reduced in individuals undergoing anti-inf...

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Neuroinflammation is a significant and consistent feature of many neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). The greatest risk factor for neurodegenerative disorders is age and a proinflammatory phenotype in the aged brain is believed to contribute to these neurodegenerative conditions. In animal models, neuroinflammatory changes, characterized by increased microglial activation, have been associated with a loss of synaptic plasticity and here we show that treatment of aged rats with the PPAR␥ agonist, rosiglitazone, modulates the inflammatory changes and restores synaptic function. The evidence presented highlights an important role for astrocytes in inducing inflammatory changes and suggests that the age-related astrogliosis and astrocytosis is responsible for the increase in the proinflammatory cytokine, tumor necrosis factor alpha (TNF-␣). Magnetic resonance (MR) imaging revealed an age-related increase in T1 relaxation time and, importantly, treatment of aged rats with rosiglitazone reversed the age-related increases in astrogliosis and astrocytosis, TNF-␣ concentration and T1 relaxation time. The evidence indicates that the site of action for rosiglitazone is endothelial cells, and suggests that its effect on astrocytes is secondary to its effect on endothelial cells.

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