Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice

Abstract

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.

FIG. 1.

Resveratrol protected aged mice but not adult mice from lipopolysaccharide (LPS)-induced deficits in locomotor behavior. Adult and aged mice were provided control or resveratrol-supplemented diet for 4 weeks and then injected peripherally with saline or LPS. Locomotor activity was measured for both adult and aged mice at 8 h (A) and 24 h (B) after LPS injection. Bars represent the mean ± standard error of the mean (SEM) (n = 10–11). Means with different letters (a, b, or c) are significantly different (p < 0.05) from each other.

FIG. 2.

Performance of adult and aged mice during a 5-day acquisition phase in the Morris water maze. Adult and aged mice were provided control or resveratrol-supplemented diet for 4 weeks, and during the fourth week of diet supplementation animals were trained in a 5-day acquisition phase. Distance swam (A), latency to platform (B), and swim speed (C) were measured for both adult and aged mice. Data points represent the mean ± standard error of the mean (SEM) (n = 11–13). Means marked with and asterisk (*) or number sign (#) are significantly different (p < 0.05) from aged treatment-matched baseline controls, respectively.

FIG. 3.

Resveratrol improves impaired spatial working memory in aged mice 4 h post LPS injection. After 5 days of acquisition training, mice were evaluated in a reversal test 4 h after lipopolysaccharide (LPS) injection. Distance swam to platform (A), latency to find the platform (B), and swim speed (C) were evaluated for both adult and aged mice. Bars represent the mean ± standard error of the mean (SEM) (n = 11–13). Means with different letters (a or b) are significantly different (p < 0.05) from each other.

FIG. 4.

Resveratrol improves impaired spatial working memory in aged mice 24 h post LPS injection. After 5 days of acquisition training, mice were evaluated in a reversal test 24 h after lipopolysaccharide (LPS) injection. Distance swam to platform (A), latency to find the platform (B), and swim speed (C) were evaluated for both adult and aged mice. Bars represent the mean ± standard error of the mean (SEM) (n = 11–13). Means with different letters (a or b) are significantly different (p < 0.05) from each other.

FIG. 5.

Dietary supplementation with resveratrol inhibited the LPS-induced increase in interleukin-1β (IL-1β) in periphery of aged mice. Adult and aged mice were provided control or resveratrol-supplemented diet for 4 weeks and then injected peripherally with saline or lipopolysaccharide (LPS). After the final behavioral test or cognitive test (24 h after injection), blood was collected and IL-1β production was measured by an IL-1β Quantikine assay. Bars represent means ± standard error of the mean (SEM) (n = 11–13). Means with different letters (a, b, or c) are significantly different (p < 0.05) from each other.

FIG. 6.

Dietary supplementation with resveratrol inhibited the lipopolysaccharide (LPS)-induced increase in interleukin-1β (IL-1β) mRNA in aged mice. Adult and aged mice were provided control or resveratrol-supplemented diet for 4 weeks and then injected peripherally with saline or LPS. After the final behavioral test or cognitive test (24 h after injection), hippocampal tissue was collected and IL-1β mRNA was measured by quantitative real-time PCR. Bars represent means ± standard error of the mean (SEM) (n = 11–13). Means with different letters (a, b, or c) are significantly different (p < 0.05) from each other.

FIG. 7.

Resveratrol inhibits lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) secretion in BV-2 cells. BV-2 cells were pretreated with resveratrol (0–50 μM) for 1 h and stimulated with LPS (100 ng/mL) for a 4-h incubation period. IL-1β secretion was measured by an IL-1β Quantikine immunoassay. Concentration of IL-1β in supernatants from BV-2 cells stimulated with LPS was ∼ 70.0 pg/mL. Bars represent the mean ± standard error of the mean (SEM) from three independent experiments. Means with different letters (a, b, c, or d) are significantly different (p < 0.05) from each other. Resv, Resveratrol; EtOH, ethanol.