Omega-3 fatty acid ethyl-eicosapentaenoate, but not soybean oil, attenuates memory impairment induced by central IL-1β administration

Proinflammatory cytokine interleukin (IL)-1β can cause cognitive impairment, activate the hypothalamic-pituitary-adrenal axis and impair monoaminergic neurotransmission in the rat. IL-1β has also been shown to increase the concentration of the inflammatory mediator prostaglandin E2 (PGE2) in the blood. Omega (n)-3 fatty acids, such as eicosapentaenoic acid (EPA), which are components of fish oil, have been shown to reduce both the proinflammatory cytokines and the synthesis of PGE2. The purpose of this study was to determine whether dietary supplements of EPA would attenuate the inflammation-induced impairment of spatial memory by centrally administered IL-1β. Rats were fed with a diet of coconut oil (contained a negligible quantity of fatty acids), soybean oil (contained mainly n-6 fatty acids), or a diet of coconut oil enriched with ethyl-EPA (E-EPA). The rats were then injected intracerebroventricularly with IL-1β or saline.The results of this study demonstrated that the IL-1-induced deficit in spatial memory was correlated with an impairment of central noradrenergic and serotonergic (but not dopaminergic) function and an increase in the serum corticosterone concentration. IL-1β also caused an increase in the hippocampal PGE2 concentration. These effects of IL-1 were attenuated by the chronic administration of E-EPA. By contrast, rats fed with the soybean oil diet showed no effect on the changes induced by the IL-1 administration. Proinflammatory cytokine interleukin (IL)-1β can cause cognitive impairment, activate the hypothalamic-pituitary-adrenal axis and impair monoaminergic neurotransmission in the rat. IL-1β has also been shown to increase the concentration of the inflammatory mediator prostaglandin E2 (PGE2) in the blood. Omega (n)-3 fatty acids, such as eicosapentaenoic acid (EPA), which are components of fish oil, have been shown to reduce both the proinflammatory cytokines and the synthesis of PGE2. The purpose of this study was to determine whether dietary supplements of EPA would attenuate the inflammation-induced impairment of spatial memory by centrally administered IL-1β. Rats were fed with a diet of coconut oil (contained a negligible quantity of fatty acids), soybean oil (contained mainly n-6 fatty acids), or a diet of coconut oil enriched with ethyl-EPA (E-EPA). The rats were then injected intracerebroventricularly with IL-1β or saline. The results of this study demonstrated that the IL-1-induced deficit in spatial memory was correlated with an impairment of central noradrenergic and serotonergic (but not dopaminergic) function and an increase in the serum corticosterone concentration. IL-1β also caused an increase in the hippocampal PGE2 concentration. These effects of IL-1 were attenuated by the chronic administration of E-EPA. By contrast, rats fed with the soybean oil diet showed no effect on the changes induced by the IL-1 administration. The immune system and central neurotransmitters form a complex interacting network that has been extensively studied in the last decade (1Elenkov I.J. Wilder R. Chrousos G.P. Vizi E.S. The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system.Pharmacol. Rev. 2000; 52: 595-640PubMed Google Scholar, 2Song C. The interaction between cytokines and neurotransmitters in depression and stress: possible mechanism of antidepressant treatments.Hum. Psychopharmacol. Clin. Exp. 2000; 15: 199-211Crossref PubMed Scopus (30) Google Scholar). Thus, despite the widely held view that the immune system is primarily autoregulated and is concerned with protection against infection, it is now apparent that there is “cross talk” between aspects of the immune, endocrine, and central nervous processes (1Elenkov I.J. Wilder R. Chrousos G.P. Vizi E.S. The sympathetic nerve-an integrative interface between two supersystems: the brain and the immune system.Pharmacol. Rev. 2000; 52: 595-640PubMed Google Scholar, 2Song C. The interaction between cytokines and neurotransmitters in depression and stress: possible mechanism of antidepressant treatments.Hum. Psychopharmacol. Clin. Exp. 2000; 15: 199-211Crossref PubMed Scopus (30) Google Scholar, 3Maier S.F. Watkins L.R. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition.Psychol. Rev. 1998; 105: 83-107Crossref PubMed Scopus (960) Google Scholar). This may be illustrated by the role of the proinflammatory cytokine interleukin (IL)-1β, which is produced by activated macrophages in the periphery and by microglia, astrocytes, and neurons in the brain (4Johnstone M. Gearing A.J. Miller K.M. A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced.J. Neuroimmunol. 1999; 93: 182-193Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 5von Bernhardi R. Ramirez G. Microglia-astrocyte interaction in Alzheimer's disease: friends or foes for the nervous system?.Biol. Res. 2001; 34: 123-128Crossref PubMed Scopus (67) Google Scholar, 6Neumann H. Control of glial immune function by neurons.Glia. 2001; 36: 191-199Crossref PubMed Scopus (253) Google Scholar). Several studies have shown that central or systemic administration of IL-1β can cause cognitive impairment (3Maier S.F. Watkins L.R. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition.Psychol. Rev. 1998; 105: 83-107Crossref PubMed Scopus (960) Google Scholar, 7Oitzl M.S. van Oers H. Schobitz B. de Kloet E.R. Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning.Brain Res. 1993; 613: 160-163Crossref PubMed Scopus (204) Google Scholar, 8Gibertini M. Newton C. Friedman H. Klein T.W. Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta.Brain Behav. Immun. 1995; 9: 113-128Crossref PubMed Scopus (189) Google Scholar), which may be related to its induced brain inflammatory response and the expression of amyloid precursor protein, IL-1 activated hypothalamus-pituitary-adrenal (HPA) axis, and changed neurotransmission (2Song C. The interaction between cytokines and neurotransmitters in depression and stress: possible mechanism of antidepressant treatments.Hum. Psychopharmacol. Clin. Exp. 2000; 15: 199-211Crossref PubMed Scopus (30) Google Scholar, 9Potter H. Wefes I.M. Nilsson L.N. The inflammation-induced pathological chaperones ACT and apo-E are necessary catalysts of Alzheimer amyloid formation.Neurobiol. Aging. 2001; 22: 923-930Crossref PubMed Scopus (68) Google Scholar, 10Dunn A.J. Cytokine activation of the HPA axis.Ann. NY Acad. Sci. 2000; 917: 608-617Crossref PubMed Scopus (260) Google Scholar, 11Hoozemans J.J. Veerhuis R. Janssen I. Rozemuller A.J. Eikelenboom induced expression and prostaglandin E2 by implications for Alzheimer's 2001; 36: PubMed Scopus Google Scholar, H. for the effects of and Behav. Immun. PubMed Scopus Google Scholar). IL-1β the of the of and and in the and of the brain M. Newton C. Friedman H. Klein T.W. 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PubMed Scopus Google Scholar). has been shown that the increase in and the of the central in the which in a in the of are by the of IL-1β A.J. Cytokine activation of the HPA axis.Ann. NY Acad. Sci. 2000; 917: 608-617Crossref PubMed Scopus (260) Google Scholar). or corticosterone can also changes and impair learning and memory M. R. and its in brain of the Res. PubMed Scopus Google Scholar, B. and corticosterone spatial learning in Res. 1999; PubMed Scopus Google Scholar). in prostaglandin E2 and proinflammatory have been with cognitive in with and G. C. of and in with Alzheimer's disease: or the Neuroimmunol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. aspects of inflammatory and immune in Alzheimer's Aging. PubMed Scopus Google Scholar, C. M. M. H. 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IL-1β PGE2 was in the fed with coconut oil or soybean oil The interaction between IL-1 and EPA was also The showed that of EPA attenuated the IL-1-induced increase in PGE2 studies have shown that central administration of IL-1β to rats a or mice memory in the M.S. van Oers H. Schobitz B. de Kloet E.R. Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning.Brain Res. 1993; 613: 160-163Crossref PubMed Scopus (204) Google Scholar, 8Gibertini M. Newton C. Friedman H. Klein T.W. Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta.Brain Behav. Immun. 1995; 9: 113-128Crossref PubMed Scopus (189) Google Scholar). and R. G. I. is in spatial memory and PubMed Scopus Google that IL-1β to the spatial memory of rats in the The study has shown that IL-1β spatial memory in the These results are to by M.S. van Oers H. Schobitz B. de Kloet E.R. Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning.Brain Res. 1993; 613: 160-163Crossref PubMed Scopus (204) Google Scholar), that IL-1 memory The by IL-1β demonstrated that IL-1β memory on the of Several studies have that fatty acid can impair spatial learning and which can be by a diet enriched with fatty M. administration of acid the of in Exp. 2001; PubMed Scopus Google Scholar, with dietary of brain acid 2000; PubMed Scopus Google Scholar). studies have also shown that or fish oil both and spatial memory or of memory in and between of fatty in brain and learning in A PubMed Scopus Google Scholar, I. H. fatty in 2000; Google Scholar, M. H. H. M. learning and memory in the Res. 1995; PubMed Scopus Google Scholar). the of to were two or fatty acid the the effect of EPA on the spatial memory of has been for the as a precursor of not memory in the These results were to the of that an fatty diet for two or for two not memory in of dietary acid and on brain and Behav. PubMed Scopus Google Scholar, I. M. de H. and induced by fatty acid in Res. 2000; Full Text Full Text PDF PubMed Google Scholar). the study demonstrated that EPA attenuated memory impairment induced by IL-1β. was also demonstrated that IL-1-induced memory impairment and EPA effect were not related to changes in or in the concentration of and PGE2 may be in the IL-1 spatial learning and memory EPA and memory was with the of the IL-1β the concentration. Spatial memory in the is learning and 2000; PubMed Scopus Google Scholar, M. M. of spatial memory in rats is with changes in the hippocampal and noradrenergic Res. PubMed Scopus Google Scholar). 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Full Text Full Text PDF PubMed Scopus Google Scholar), the increase in hippocampal PGE2 concentration not with soybean The of effects of soybean oil on the concentration of PGE2 in the brain may be to the of fatty as a of the oil, the in the corticosterone concentration the soybean oil diet be to an increase in caused by the fatty H. R. of soybean oil on response and immune function in or PubMed Scopus Google Scholar). EPA has been shown to reduce concentration of IL-1β by M. H. effects of with and fatty acid Clin. 1993; PubMed Scopus Google Scholar). The of corticosterone by may be related to its effect on as both EPA and PGE2 can the M. and as inflammatory the Scholar, R. and of fatty to 2001; PubMed Scopus Google Scholar, The of fatty in to and function of the brain and Res. 2001; PubMed Scopus Google Scholar). 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PGE2 also an role in activation and of in the of the corticosterone M. and as inflammatory the Scholar). administration of the can attenuate IL-1 effects in the C. for an mechanism in the activation of by PubMed Google Scholar). the attenuated memory deficit and corticosterone concentration for may in the of EPA on the of and the of PGE2. the spatial memory deficit in the study to be related to changes in the noradrenergic and serotonergic system and an increase in corticosterone concentration. the mechanism attenuated the impairment of spatial memory by IL-1β may be in to a of as EPA can and fatty and inflammatory mediator Clin. 2000; PubMed Scopus Google Scholar, effects of dietary on immune system 2000; PubMed Scopus Google Scholar). oil, n-6 fatty acids, no effect on IL-1-induced The for the to the of this study and for and The also and for This was by and by of acid acid Alzheimer's acid acid acid acid interleukin prostaglandin E2

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