[Show abstract][Hide abstract] ABSTRACT: Mannan-containing products are capable of modulating immune responses in animals. However, different products may have diverse immunomodulation. The experiment was conducted to examine effects of mannan oligosaccharide (Actigen; ACT) on growth performance and serum concentrations of antibodies and inflammatory mediators in weanling pigs (Sus scrofa) experimentally infected with porcine reproductive and respiratory syndrome virus (PRRSV). A total of 32 PRRSV-negative pigs (3 wk old) were randomly assigned from within blocks to 1 of 4 treatments in a 2 by 2 factorial arrangement [2 types of diet: control (0%) and ACT addition (0.04%); and with and without PRRSV] in a randomized complete block design. Pigs were blocked by initial BW within sex. Ancestry was equalized across treatments. Pigs (8/treatment) were kept individually in each pen. After 2 wk of an 8-wk period of feeding the treatments, pigs received an intranasal inoculation of PRRSV or sham medium at 5 wk of age. Infection by PRRSV decreased ADG, ADFI, and G:F throughout the experiment (P < 0.01). Actigen did not affect ADG (P = 0.450), but decreased (P = 0.047) ADFI from 28 to 42 days postinoculation (DPI). During that time, ACT improved G:F in infected pigs but not in sham controls (interaction, P = 0.009). Dietary ACT did not affect viremia in infected pigs (P > 0.05), but increased PRRSV-specific antibody titer at 35 DPI (P = 0.042). Infection with PRRSV induced the febrile responses of pigs from 3 to 10 DPI (P < 0.001) with return to normal at 14 DPI. During the experimental period, the rectal temperature of pigs was found slightly elevated by ACT (P = 0.045). Infected pigs had greater serum concentrations of IL-1β, tumor necrosis factor (TNF)-α, IL-12, interferon (IFN)-γ, IL-10, and haptoglobin (Hp) than sham controls (P < 0.001). These results indicate that PRRSV stimulated secretion of cytokines involved in innate, T-helper 1, and T-regulatory immune responses. Actigen tended to decrease the serum TNF-α concentration regardless of PRRSV (P = 0.058). The ACT × PRRSV interaction was significant for IL-1β (P = 0.016), IL-12 (P = 0.026), and Hp (P = 0.047), suggesting that infected pigs fed ACT had greater serum concentrations of these mediators than those fed the control. The increases in IL-1β and IL-12 may favorably promote innate and T-cell immune functions in infected pigs fed ACT. Feeding ACT may be useful as ACT is related to increased PRRSV antibody titers and G:F in infected pigs at certain times during infection.
[Show abstract][Hide abstract] ABSTRACT: This study explored the hypothesis that mannan oligosaccharide (MOS) acts to reduce systemic inflammation in pigs by evaluating cytokine production of alveolar macrophages (AM) and serum cytokine concentrations. A total of 160 pigs were fed diets containing 0.2 or 0.4% MOS for 2 or 4 wk postweaning compared with control diets without MOS. Dietary MOS did not affect the serum concentration of tumor necrosis factor (TNF)-α and tended (P = 0.081) to increase that of IL-10. These cytokine concentrations also changed over time (P < 0.001). After 2-wk feeding of the control or MOS diets, AM were collected and stimulated ex vivo with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (PLIC) as infection models. The LPS-stimulated AM from MOS-fed pigs (n = 12) secreted less TNF-α (P < 0.001) and more IL-10 (P = 0.026) than those from control-fed pigs (n = 6). However, dietary MOS had less effect on ex vivo TNF-α and IL-10 production by PLIC-stimulated AM (P = 0.091 and P > 0.10, respectively. Further, effects of MOS were examined in 4 in vitro experiments. In Exp. 1 (n = 4 pigs), MOS and mannan-rich fraction (MRF), when added to AM cultures, were able to increase TNF-α production. This direct effect of MOS was not due to endotoxin contamination as verified in Exp. 2 (n = 6 pigs) using polymyxin B, an inhibitor of LPS activation of toll-like receptor 4. Polymyxin B inhibited production of TNF-α by AM after treatment with LPS (P < 0.001), but not after treatment with MOS in the absence of LPS (P > 0.70). In Exp. 3 (n = 6 pigs), when MOS was directly applied in vitro, the pattern of cytokine production by LPS-activated AM was similar to that observed ex vivo, as MOS suppressed LPS-induced TNF-α (P < 0.001) and enhanced LPS-induced IL-10 (P = 0.028). In Exp. 4 (n = 6 pigs), when MRF replaced MOS, AM-produced TNF-α induced by LPS or PLIC was suppressed by MRF (P = 0.015 or P < 0.001, respectively). These data establish that MOS and MRF suppress LPS-induced TNF-α secretions by AM. Generally, the study suggests that MOS may be a potent immunomodulator because it directly activates AM to secrete TNF-α and alters the cytokine responses of bacterial endotoxin-induced AM in both ex vivo and in vitro systems. In particular, feeding MOS to pigs for 2 wk reduces TNF-α and increases IL-10 concentrations after ex vivo treatment of AM with LPS. These immunomodulatory properties of MOS may have important implications for both host defense and avoidance of harmful overstimulation of the immune system.
[Show abstract][Hide abstract] ABSTRACT: This study characterized gene expression in peripheral blood mononuclear cells (PBMC) and bronchoalveolar lavage fluid (BALF) cells from control- or mannan oligosaccharide (MOS)-fed pigs with or without porcine reproductive and respiratory syndrome virus (PRRSV) at d 7 postinfection (PI). Weaned pigs (3 wk old) fed 0 or 0.2% MOS (Bio-Mos) diets were intranasally inoculated with PRRSV or a sterile medium at 5 wk of age. Total RNA (3 pigs/treatment) was extracted from cells. Double-stranded cDNA was amplified, labeled, and further hybridized to the Affymetrix GeneChip Porcine Genome Array consisting of 23,937 probe sets representing 20,201 genes. Microarray data were analyzed in R using packages from the Bioconductor project. Differential gene expression was tested by fitting a mixed linear model equivalent to a 2 × 2 factorial ANOVA using the limma package. Dietary MOS and PRRSV changed the expression of thousands of probe sets in PBMC and BALF cells (P < 0.05). The MOS × PRRSV interaction altered the expression of more nonimmune probe sets in PBMC (977 up, 1,128 down) than in BALF cells (117 up, 78 down). The MOS × PRRSV interaction (P < 0.05) for immune probe sets in PBMC affected genes encoding key inflammatory mediators. In uninfected pigs, gene expression of IL-1α, IL-6, myeloid differentiation factor 88, Toll-like receptor (TLR) 4, major histocompatibility complex (MHC) II, and dead box polypeptide 58 increased in PBMC of MOS-fed pigs (P < 0.05). This suggests that MOS enhances disease resistance in pigs and supports the fact that MOS induced a rapid increase in leukocytes at d 3 and 7 PI. Within infected pigs, however, MOS reduced the expression of IL-1β, IL-6, IL-8, macrophage inflammatory protein (MIP)-1α, MIP-1β, monocyte chemotactic protein (MCP)-1, and TLR4 genes in PBMC (P < 0.05). This finding may explain why fever was ameliorated in infected pigs fed MOS by d 7 PI. The expression of IL-1β, IL-6, MIP-1β, MCP-1, and TLR4 genes was confirmed by quantitative real-time reverse-transcription PCR. In BALF cells of infected pigs, MOS reduced the gene expression of TLR4, MHCII, and molecules associated with the complement system, but increased the gene expression of MHCI. In short, MOS regulated the expression of nonimmune and immune genes in pig leukocytes, perhaps providing benefits by enhancing the immune responses of the pigs to an infection, while preventing overstimulation of the immune system.
[Show abstract][Hide abstract] ABSTRACT: This study was conducted to determine whether the ingestion of mannan oligosaccharide (MOS, Bio-Mos) alters the immune response of nursery pigs challenged with porcine reproductive and respiratory syndrome virus (PRRSV). A total of 64 pigs (3 wk old), free of PRRSV, were used in 2 separate but similar experiments conducted sequentially. Pigs were blocked by initial BW. Sex and ancestry were equalized across treatments. Pigs were randomly assigned from within blocks to 1 of 4 treatments in a 2 × 2 factorial arrangement [2 types of diet: control (0%) and MOS addition (0.2%); 2 levels of PRRSV: with and without]. There were 8 replicate chambers of 2 pigs each. After 2 wk of a 4-wk period of feeding the treatments, pigs were intranasally inoculated with PRRSV or a sterile medium at 5 wk of age. The PRRSV challenge decreased ADG, ADFI, and G:F throughout the experiment (P < 0.001). Feeding MOS improved G:F of the pigs during d 7 to 14 (P=0.041) postinfection (PI). Serum concentrations of tumor necrosis factor (TNF)-α, C-reactive protein, and haptoglobin were increased by PRRSV (P < 0.001). The MOS × PRRSV interaction was significant for TNF-α at d 14 PI (P=0.028), suggesting that infected pigs fed MOS had less TNF-α than those fed the control. Dietary MOS increased serum IL-10 at d 14 PI (P=0.036). Further, MOS-fed pigs had greater numbers of white blood cells (WBC) at d 3 (P=0.048) and 7 PI (P=0.042) and lymphocytes at d 7 PI (P=0.023) than control-fed pigs. In contrast, PRRSV decreased (P < 0.01) WBC numbers until d 14 PI. Dietary MOS appeared (P=0.060) to increase the neutrophils in PRRSV-infected pigs at d 3 PI, but no (P=0.202) MOS × PRRSV interaction was found. Infection with PRRSV increased rectal temperature (RT) of pigs at d 3 PI (P < 0.001) and continued to affect the infected pigs fed the control diet until d 14 PI. The MOS × PRRSV interaction for RT was found at d 7 (P < 0.01) and 10 (P=0.098) PI, indicating that the infected pigs fed MOS had a decreased RT compared with those fed the control. This could explain why feed efficiency was improved by MOS. No effect (P > 0.05) of treatments on viremia or PRRSV-specific antibody was observed. These results suggest that MOS is associated with rapidly increased numbers of WBC at the early stage of infection and alleviates PRRSV-induced effects on G:F and fever. The results also indicate that the reduced intensity of inflammation by MOS may be related to changes in inflammatory mediator levels at the end of the acute phase.
[Show abstract][Hide abstract] ABSTRACT: Methamphetamine (MA) use is associated with activation of microglia and, at high doses, can induce neurotoxicity. Given the changes in the neuroinflammatory environment associated with MA, we investigated whether MA sensitization, a model of stimulant psychosis and an indicator of drug addiction, would interfere with the thermoregulatory and neuroinflammatory response to a subsequent peripheral immune stimulus. C57BL6/J mice were given either 1 mg/kg MA or saline i.p. once a day for 5 days to produce behavioral sensitization. Seventy-two hours following the last MA injection, 100 microg/kg LPS or saline was co-administered with 1 mg/kg MA or saline and blood and brains were collected. Here we report that while co-administration of LPS and MA did not affect the LPS-induced increase in central cytokine mRNA, mice sensitized to MA showed an attenuated central response to LPS. Interestingly, the peripheral response to LPS was not affected by MA sensitization. Plasma cytokines increased similarly in all groups after LPS. Further, c-Fos expression in the nucleus of the solitary tract did not differ between groups, suggesting that the periphery-to-brain immune signal is intact in MA-sensitized mice and that the deficit lies in the central cytokine compartment. We also show that MA sensitization decreased LPS- or acute MA-induced microglial Iba1 expression compared to non-sensitized mice. Taken together, these data show that MA sensitization interferes with the normal central immune response, preventing the CNS from efficiently responding to signals from the peripheral immune system.
[Show abstract][Hide abstract] ABSTRACT: The objective of this experiment was to evaluate the central and peripheral expression of selected pro-inflammatory cytokines and Toll-like receptors (TLRs) in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Twenty-four 8-week-old pigs were inoculated with either sterile medium or PRRSV. Pigs were monitored 14d after inoculation and then euthanized for tissue sample collection. PRRSV was detected in serum, lung and brain tissue of pigs given PRRSV but not in any tissue of pigs given medium. Infection with PRRSV increased serum levels of IL-1beta, IL-6, TNFalpha, and IFNgamma and elicited a mild transient fever and reduced growth performance. Infection by PRRSV also increased mRNA for the pro-inflammatory cytokines as well as mRNA for TLR3, TLR4, and TLR7 in the tracheobronchial lymph nodes. The TLR3, TLR4, TLR7 and most of the pro-inflammatory genes also were up-regulated in discrete brain areas of PRRSV-infected pigs. Collectively, the results indicate that following inoculation, PRRSV is present in the periphery and brain and that infection is associated with a peripheral and central pro-inflammatory response, fever, and reduced growth performance. The findings are interpreted to suggest the innate immune system of the brain is responsive to PRRSV infection.
[Show abstract][Hide abstract] ABSTRACT: The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation in the periphery and brain, but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the present study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3-mo-old) and middle-aged (12-mo-old) wild-type (IL-10(+/+)) and IL-10-deficient (IL-10(-/-)) mice after intraperitoneal injection of lipopolysaccharide (LPS) or saline. No age-related differences were observed; therefore, data from the two ages were pooled and analyzed to determine effects of genotype and treatment. LPS treatment increased IL-1beta, IL-6, and TNFalpha mRNA in all brain areas examined in IL-10(+/+) and IL-10(-/-) mice, but to a greater extent and for a longer time in IL-10(-/-) mice. Plasma IL-1beta and IL-6 were increased similarly in IL-10(+/+) and IL-10(-/-) mice 4 h after LPS but remained elevated longer in IL-10(-/-) mice, whereas TNFalpha was higher in IL-10(-/-) mice throughout after LPS treatment. Motor performance and motor learning in IL-10(+/+) mice were not affected by LPS treatment; however, both were reduced in IL-10(-/-) mice treated with LPS compared with those treated with saline. Furthermore, although LPS reduced the time to fatigue in IL-10(+/+) and IL-10(-/-) mice, the effects were exacerbated in IL-10(-/-) mice. Thus the increased brain and peripheral inflammation induced by LPS in IL-10(-/-) mice was associated with increased coordination deficits and fatigue. These data suggest that IL-10 may inhibit motor deficits and fatigue associated with peripheral infections via its anti-inflammatory effects.
[Show abstract][Hide abstract] ABSTRACT: Peripheral immune stimulation as well as certain types of psychological stress increases brain levels of inflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6 and tumor necrosis factor alpha (TNFalpha). We have demonstrated that aged mice show greater increases in central inflammatory cytokines, as well as greater cognitive deficits, compared to adults in response to peripheral lipopolysaccharide (LPS) administration. Because aged mice are typically more sensitive to systemic stressors such as LPS, and certain psychological stressors induce physiological responses similar to those that follow LPS, we hypothesized that aged mice would be more sensitive to the physiological and cognitive effects of mild stress than adult mice. Here, adult (3-5 months) and aged (22-23 months) male BALB/c mice were trained in the Morris water maze for 5 days. Mice were then exposed to a mild restraint stress of 30 min before being tested in a working memory version of the water maze over a 3-day period. On day 4 mice were stressed and then killed for collection of blood and brain. In a separate group of animals, mice were killed immediately after one, two or three 30 min restraint sessions and blood was collected for peripheral corticosterone and cytokine protein measurement, and brains were dissected for central cytokine mRNA measurement. Stress disrupted spatial working memory in both adult and aged mice but to a much greater extent in the aged mice. In addition, aged mice showed an increase in stress-induced expression of hippocampal IL-1beta mRNA and MHC class II protein compared to non-stressed controls while expression in adult mice was unaffected by stress. These data show that aged mice are more sensitive to both the cognitive and inflammatory effects of mild stress than are adult mice and suggest a possible role for IL-1beta.
[Show abstract][Hide abstract] ABSTRACT: Following surgery, elderly patients often suffer from postoperative cognitive dysfunction (POCD) which can persist long after physical recovery. It is known that surgery-induced tissue damage activates the peripheral innate immune system resulting in the release of inflammatory mediators. Compared to adults, aged animals demonstrate increased neuroinflammation and microglial priming that leads to an exaggerated proinflammatory cytokine response following activation of the peripheral immune system. Therefore, we sought to determine if the immune response to surgical trauma results in increased neuroinflammation and cognitive impairment in aged mice. Adult and aged mice underwent minor abdominal surgery and 24h later hippocampal cytokines were measured and working memory was assessed in a reversal learning version of the Morris water maze. While adult mice showed no signs of neuroinflammation following surgery, aged mice had significantly increased levels of IL-1beta mRNA in the hippocampus. Minor surgery did not result in severe cognitive impairment although aged mice that underwent surgery did tend to perseverate in the old target during reversal testing suggesting reduced cognitive flexibility. Overall these results suggest that minor surgery leads to an exaggerated neuroinflammatory response in aged mice but does not result in significantly impaired performance in the Morris water maze.
[Show abstract][Hide abstract] ABSTRACT: Antioxidants are associated with reduced pro-inflammatory cytokine expression in immune cells and isolated tissues; however, no studies have examined whether short-term vitamin E administration is associated with reduced lipopolysaccharide (LPS)-induced cytokine expression in mouse skeletal and cardiac muscle, in vivo. These experiments tested the hypothesis that vitamin E administration attenuates nuclear factor kappaB (NF-kappaB), IL-6, IL-1beta and tumour necrosis factor alpha (TNFalpha) responses in skeletal and cardiac muscle to an inflammatory challenge induced by systemic LPS. We compared IL-6, IL-1beta and TNFalpha mRNA and protein, activated NF-kappaB and total oxidized proteins in skeletal and cardiac muscle 4 or 24 h after saline or LPS injection in mice receiving vitamin E or placebo for 3 days prior to the insult. Skeletal and cardiac IL-6 mRNA and protein were significantly elevated by LPS in both groups, but responses were significantly lower in vitamin E- compared with placebo-treated mice. In skeletal and cardiac muscle, LPS increased IL-1beta mRNA and protein in placebo- but not vitamin E-treated mice. Lipopolysaccharide-induced levels of cardiac IL-1beta mRNA and protein and skeletal IL-1beta mRNA were lower with vitamin E than placebo. Lipopolysaccharide-induced NF-kappaB activation and increases in total oxidized proteins were attenuated with vitamin E compared with placebo in both tissues. Vitamin E decreased LPS-induced increases in plasma IL-1beta but not IL-6 compared with placebo. The major results provide the first in vivo evidence that short-term vitamin E administration reduces IL-6 and IL-1beta responses to LPS in skeletal and cardiac muscle and prevents LPS-induced increases in NF-kappaB activation and total oxidized proteins.
[Show abstract][Hide abstract] ABSTRACT: Exaggerated proinflammatory cytokine responses can be observed with aging, and reduced levels of the anti-inflammatory cytokine IL-10 may contribute to these responses. IL-10 can reduce IL-6, IL-1beta, and TNF-alpha expression in nonmuscle tissues; however, no studies have examined the combined effects of IL-10 and age on cytokine responses in skeletal and cardiac muscle. These experiments tested the hypothesis that the absence of IL-10, in vivo, is associated with greater IL-6, TNF-alpha, and IL-1beta responses to an inflammatory challenge in skeletal and cardiac muscle and that aging exaggerates these responses. We compared IL-6, IL-1beta, and TNF-alpha mRNA and protein levels in skeletal and cardiac muscle of young (4 mo) and mature (10-11 mo) wild-type (IL-10(+/+)) and IL-10 deficient (IL-10(-/-)) mice following LPS. Skeletal and cardiac IL-6 mRNA and protein were elevated by LPS for IL-10(+/+) and IL-10(-/-) mice with greater responses in the IL-10(-/-) mice (P < 0.01). In skeletal muscle these effects were greater in mature than young mice (P < 0.01). IL-1beta mRNA and protein responses to LPS were greater in cardiac muscle of young but not mature IL-10(-/-) mice compared with IL-10(+/+) (P < 0.01). However, IL-1beta responses were greater in mature than young mice, but only in IL-10(+/+) groups (P < 0.05). The absence of IL-10 was associated with higher TNF-alpha protein levels in cardiac muscle (P < 0.05). The results provide the first in vivo evidence that the absence of IL-10 is associated with a greater IL-6 response to LPS in skeletal and cardiac muscles, and in skeletal muscle aging further exaggerates these responses.
[Show abstract][Hide abstract] ABSTRACT: The number of older adults with HIV-1 disease is increasing but little is known about how age influences behavioral deficits associated with HIV-1 infection. The purpose of this study was to determine in a murine model if aging influenced sickness behavior following central injection of HIV-1 gp120. In initial studies, behavioral deficits induced by acute and repeated intracerebroventricular (ICV) injection of gp120 were greater in aged mice than in adults. Furthermore, repeated ICV injection of gp120 increased hippocampal levels of IL-1 beta and IL-6 mRNA in aged mice but not in adults. To determine if IL-6, which is elevated in aged brain, affects expression of the gp120-binding target, CCR5, microglia (BV-2 cell line) were incubated with increasing concentrations of IL-6. Cell surface expression of CCR5 was increased by IL-6 in a dose-dependent manner. Additionally, IL-6 increased gp120-dependent chemotaxis. These results suggest that aging increases the sensitivity of mice to behavioral deficits caused by ICV gp120, perhaps by increasing expression of CCR5 and augmenting production of cytokines.
Neurobiology of aging 05/2008; 29(4):614-21. DOI:10.1016/j.neurobiolaging.2006.11.002 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age-associated changes in glial reactivity may predispose individuals to exacerbated neuroinflammatory cytokine responses that are permissive to cognitive and behavioral complications. The purpose of this study was to determine if aging is associated with an exaggerated sickness response to central innate immune activation. Our results show that intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) caused a heightened proinflammatory cytokine response (IL-1beta, IL-6, and TNFalpha) in the cerebellum 2h post i.c.v. injection in aged mice compared to adults. This amplified inflammatory profile was consistent with a brain region-dependent increase in reactive glial markers (MHC class II, TLR2 and TLR4). Moreover, LPS caused a prolonged sickness behavior response in aged mice that was paralleled by a protracted expression of brain cytokines in the cerebellum and hippocampus. Finally, central LPS injection caused amplified and prolonged IL-6 levels at the periphery of aged mice. Collectively, these data establish that activation of the central innate immune system leads to exacerbated neuroinflammation and prolonged sickness behavior in aged as compared to adult mice.
Neurobiology of aging 06/2007; 29(11):1744-53. DOI:10.1016/j.neurobiolaging.2007.04.012 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to determine whether providing nursery pigs drinking water supplemented with spray-dried animal plasma (Solutein, American Protein Corporation Inc., Ankeny, IA) would reduce the detrimental impact of porcine reproductive and respiratory syndrome virus (PRRSV) infection. Sixty-four pigs were subjected to 1 of 4 treatment combinations (2 x 2 factorial arrangement) of Solutein [0 or 2.5% (wt/wt) in drinking water] and PRRSV (sterile medium or 5 mL of tissue culture infectious dose of high-virulence strain ATCC VR-2385). Pigs were provided the water treatments during a 1-wk period before inoculation as well as during a 2-wk period after inoculation. Growth performance was determined throughout the study, and several indicators of the immunological response to PRRSV and disease pathology were assessed in blood and tissue samples collected from pigs killed 7 or 14 d after inoculation. Before inoculation, pigs provided water supplemented with Solutein tended to eat less (P = 0.08) but tended to gain more BW (P = 0.13) than pigs provided tap water. Thus, Solutein markedly improved G:F (P < 0.01), after accounting for the DM provided by Solutein. Inoculation with PRRSV reduced ADG and ADFI (P < 0.01) irrespective of water treatment; however, the beneficial effects of Solutein on G:F persisted. Infection with PRRSV also reduced (P < 0.009) villus height and crypt depth in cranial, medial, and caudal segments of the small intestine and increased (P < 0.05) lung and spleen weight, the number of leukocytes in lung lavage fluid, and serum concentrations of interferon-gamma and IL-1beta regardless of water treatment. Collectively, these results indicate that supplementing water with spray-dried animal plasma improved feed efficiency but did not afford nursery pigs protection from the effects of PRRSV on growth and certain hematological traits.
[Show abstract][Hide abstract] ABSTRACT: This study was conducted to determine if alpha-tocopherol facilitates recovery from lipopolysaccharide (LPS)-induced sickness behavior through a NFkappaB-dependent mechanism. In the first study, 3 daily intraperitoneal (i.p.) injections of alpha-tocopherol (20 mg) improved recovery from sickness behavior induced by i.p. injected LPS. Furthermore, alpha-tocopherol pretreatment attenuated LPS-activated NFkappaB and pro-inflammatory cytokine production in brain. In addition, inhibiting NFkappaB activity in the brain specifically by ICV injection of a NFkappaB decoy prior to LPS, significantly accelerated recovery from LPS-induced sickness behavior. Taken together, these data indicate alpha-tocopherol modulates sickness behavior and inflammatory cytokine production in the brain through an NFkappaB-dependent pathway.
Journal of Neuroimmunology 01/2006; 169(1-2):97-105. DOI:10.1016/j.jneuroim.2005.08.003 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Psychomotor performance is decreased in the aged. This study investigated the relationship between brain oxidative stress, interleukin-6 (IL-6) production by brain tissue ex vivo and psychomotor deficits during aging, and the effects of feeding an antioxidant-rich diet on ex vivo brain IL-6 production and motor function in aged mice. Male BALBc mice reared in SPF conditions and ranging in age from 3 to 24 months were studied. There was a precipitous decline in motor function after 12 months of age and an increase in brain lipid peroxidation and IL-6 production by coronal brain slices ex vivo. In another study, 12-month-old mice were fed diets formulated to provide a disparate range of antioxidants. At 18 months of age psychomotor coordination, motor learning, and ex vivo brain IL-6 production were evaluated. Mice fed an antioxidant-rich diet had improved psychomotor coordination compared to mice fed diet adequate or low in antioxidants. When mice were tested on successive days, only those fed adequate and high antioxidants exhibited motor learning. Analysis of IL-6 production by coronal brain slices indicated that as dietary antioxidants increased, IL-6 production decreased. Collectively, these data indicate that antioxidants improve psychomotor performance in aged mice, and suggest antioxidants may be useful for reducing brain IL-6 production, which has been shown to increase in aged mice.