Rejuvenation Res 2009 (Dec); 12 (6): 445–453 ~ FULL TEXT
Abraham J, Johnson RW.
Division of Nutritional Sciences,
University of Illinois,
Urbana, Illinois 61801, USA.
Aged mice treated peripherally with lipopolysaccharide (LPS) show an exaggerated neuroinflammatory response and cognitive deficits compared to adults. Considerable evidence suggests resveratrol, a polyphenol found in red grapes, has potent antiinflammatory effects in the periphery, but its effects on the central inflammatory response and cognitive behavior are unknown. Therefore, the current study investigated if resveratrol dietary supplementation would inhibit neuroinflammation as well as behavioral and cognitive deficits in aged mice given LPS to mimic a peripheral infection. In initial studies, adult (3-6 months) and aged (22-24 months) mice were provided control or resveratrol-supplemented diet for 4 weeks and then injected intraperitoneally (i.p.) with saline or LPS, and locomotor activity and spatial working memory were assessed. As anticipated, deficits in locomotor activity and spatial working memory indicated aged mice are more sensitive to LPS compared to adults. More importantly, the LPS-induced deficits in aged animals were mitigated by dietary supplementation of resveratrol. In addition, resveratrol consumption reduced LPS-induced interleukin-1beta (IL-1beta) in plasma and the IL-1beta mRNA in the hippocampus of aged mice. Finally, pretreatment of BV-2 microglial cells with resveratrol potently inhibited LPS-induced IL-1beta production. These data show that aged mice are more sensitive than adult mice to both the inflammatory and cognitive effects of peripheral immune stimulation and suggest that resveratrol may be useful for attenuating acute cognitive disorders in elderly individuals with an infection.
From the FULL TEXT Article:
Interleukin-1β (il-1β), a proinflammatory cytokine produced in the brain predominantly by microglia, plays a dual role in hippocampal-dependent learning and memory processes. A basal level of IL-1β and IL-1 receptor type 1 signaling is essential for hippocampal learning and memory.  However, if IL-1β activity exceeds a normal physiological range, hippocampal neurogenesis is reduced and the consolidation of hippocampal-dependent memories is inhibited. [2, 3]. The potential role of IL-1β in cognitive aging is of growing interest because the gene expression profile of cognitively impaired aged animals is indicative of increased brain inflammation. [4–6] In addition, the constitutive expression of IL-1β in the brain of old, but otherwise healthy, animals is often higher than young cohorts. [7, 8] Evidence further suggests the aging process sensitizes microglia to signals from the peripheral immune system. [9–11] For example, after isolating microglia from whole brain and staining for CD11b and IL-1β, Henry et al.  found a higher percentage of IL-1β–positive microglia in aged mice compared to adults following peripheral injection of lipopolysaccharide (LPS). Moreover, after peripheral injection of LPS, old mice expressed higher levels of IL-1β in the hippocampus and had greater deficits in spatial working memory compared to young adults.  Recently, the exaggerated sickness behavior in aged mice caused by peripheral injection of LPS was attenuated by intracerebroventricular injection of IL-1 receptor antagonist (IL-1RA).  Therefore, inhibiting IL-1β production by microglial cells may be useful for slowing cognitive aging or preventing infection-related cognitive disorders.
Resveratrol, (3,5,4′-trihydroxy-trans-stilbene), is a polyphenol found mainly in grapes and red wine and has diverse biological activities that confer protection against oxidative stress, inflammation, cardiovascular disease, and cancer. [13–19] Resveratrol is of particular interest for modulating diseases with an inflammatory component because several studies found it to inhibit production of reactive oxygen species (ROS) by neutrophils, monocytes, and macrophages [20–24] as well as activation of several transcription factors including nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). [25, 26] Recently, a number of animal studies have focused on the neuroprotective effects of resveratrol, showing it to slow the neuropathology associated with Alzheimer  and Parkinson disease  and to protect against injury from brain trauma  and cerebral ischemia.  It was further shown to modulate cholinergic neurotransmission and improve cognition in diabetic rats. 
That all of the aforementioned conditions are associated with increased expression of IL-1β and other inflammatory cytokines in the brain presents the distinct possibility that the beneficial effects of resveratrol are conferred through its antiinflammatory properties. Despite the number of studies that show resveratrol inhibits the production of inflammatory molecules by stimulated microglial cells in vitro, [32–35] there have been no studies in aged animals investigating the potential for dietary resveratrol to reduce IL-1β in the brain during infection and protect against deficits in cognition.
Therefore, the purpose of the present study was to determine if resveratrol dietary supplementation would inhibit IL-1β expression in the hippocampus as well as behavioral and cognitive deficits in aged mice given LPS to mimic a peripheral infection. The results suggest infection-related neuroinflammation and cognitive deficits in elderly subjects can be minimized by resveratrol supplementation.
Recent evidence indicates aging sensitizes microglial cells to signals from the peripheral immune system, resulting in an exaggerated neuroinflammatory response and behavioral pathology during peripheral infection. [5, 8, 11] Thus, to promote healthy aging and facilitate recovery after peripheral infection, it is vital that new strategies be envisioned to mitigate the dysregulated communication between the immune system and brain in elderly subjects. Therefore, the goal of the present study was to determine if consuming a diet supplemented with the polyphenol resveratrol afforded aged mice protection from the excessive production of IL-1β in the brain and severe behavioral and cognitive deficits that occur during infection. The significant results showed that dietary supplementation of resveratrol inhibited the production of IL-1β in the periphery and brain as well as the deficits in spatial working memory when LPS was administered to aged mice to mimic a peripheral infection. Resveratrol was further shown to inhibit IL-1β production by LPS-stimulated microglia in vitro. Thus, the present findings in aged mice suggest dietary resveratrol can constrain the central response to signals from the peripheral immune system and promote recovery after peripheral infection.
Markers of inflammation have been reported to increase in both the peripheral blood [39, 40] and brain  with advancing age. In the periphery, this is due in part to the increased capacity of mononuclear cells in elderly subjects to produce proinflammatory cytokines.  This is also the case in the brain as microglia, which are derived from mononuclear myeloid progenitors, from aged mice produced higher levels of proinflammatory cytokines both in the absence and presence of immune stimuli. [41, 43] Peripheral injection of LPS has been found to cause an exaggerated inflammatory cytokine response in the aged brain. [5, 8] Moreover, anorexia, depression-like behavior, and deficits in hippocampal-dependent learning and memory are more evident in old mice than in young adults after peripheral LPS administration. [5, 8, 44] Importantly, this was confirmed in the present study, because aged mice compared to young adults had:
(1) higher circulating levels of IL-1β in the absence and presence of LPS stimulation;
(2) higher levels of IL-1β mRNA in the hippocampus in the absence and presence of LPS stimulation;
(3) LPS-induced sickness behavior of a greater magnitude and duration; and
(4) LPS-induced deficits in spatial working memory.
Thus, the model appeared to be optimal for assessing the ability of resveratrol to mitigate the interaction between the peripheral immune system and brain in aged subjects.
In this study we adopted a pragmatic approach by delivering resveratrol as a dietary supplement. Similar to other polyphenols, the oral bioavailability of resveratrol is low due to rapid excretion and extensive metabolism into various glucuronide and sulfate conjugates. [45, 46] Nonetheless, moderate consumption of red wine, where resveratrol is highly concentrated, is associated with reduced risk of cardiovascular disease and cancer. [47, 48] Moreover, several reports have confirmed orally administered resveratrol to be absorbed and cross the blood–brain barrier and incorporate into the brain. [49–52] The antiinflammatory effects of resveratrol in aged mice could be linked to its ability to inhibit factors involved in gene transcription such as mitogen-activated protein kinase (MAPK), AP-1, and NF-κB.  Resveratrol affects NF-κB by inhibiting Iκ-B kinase, thereby preventing translocation of NF-κB into the nucleus. [25, 53] How this occurs is not clear; however, it may be that resveratrol activates SIRT1, an enzyme of the sirtuin class of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases, which deacetylates NF-κB, thereby inactivating the transcription factor. [54, 55]
Recently, Adler et al.  demonstrated that inhibition of NF-κB signaling in old mice reverted the tissue characteristics and global gene expression to those of young mice. This kind of “rejuvenation” suggests that the continuous activation of NF-κB signaling could promote the aging process. Several studies have indicated that SIRT1 is a potent inhibitor of NF-κB transcription. [32, 54] The signaling link between SIRT1 and NF-κB is especially interesting with respect to aging because according to a number of studies SIRT1 acts to extend lifespan by inhibiting NF-κB signaling, and this is sufficient to reverse gene expression changes associated with age in mice. [54, 56, 57] It is important to note that resveratrol did not inhibit the effects of LPS in young adults. This is important because immunological and behavioral responses to infection are intended to help the host contend against infective agents. However, in LPS-treated old mice, resveratrol reduced IL-1β in the periphery and brain and improved locomotor behavior and hippocampal-dependent spatial working memory. Accordingly, resveratrol may prove to be neuroprotective against age-related neuroinflammation by downregulating NF-κB signaling and restoring the response to LPS to that of their younger cohorts.
Regardless of the mechanism, the current findings suggest that dietary supplementation with resveratrol may play an important role in reversing the deleterious effects of infection on behavior and cognition in elderly subjects. These findings may also support the role of natural compounds as a possible preventative and/or complementary therapy for several neurodegenerative diseases caused by neuroinflammation.