Apoptotic Changes in the Aged Brain Are Triggered by Interleukin-1β-induced Activation of p38 and Reversed by Treatment with Eicosapentaenoic Acid

Abstract

Among the several changes that occur in the aged brain is an increase in the concentration of the proinflammatory cytokine interleukin-1β that is coupled with a deterioration in cell function. This study investigated the possibility that treatment with the polyunsaturated fatty acid eicosapentaenoic acid might prevent interleukin-1β-induced deterioration in neuronal function. Assessment of four markers of apoptotic cell death, cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end staining, revealed an age-related increase in each of these measures, and the evidence presented indicates that treatment of aged rats with eicosapentaenoate reversed these changes as well as the accompanying increases in interleukin-1β concentration and p38 activation. The data are consistent with the idea that activation of p38 plays a significant role in inducing the changes described since interleukin-1β-induced activation of cytochrome ctranslocation and caspase-3 activation in cortical tissue in vitro were reversed by the p38 inhibitor SB203580. The age-related increases in interleukin-1β concentration and p38 activation in cortex were mirrored by similar changes in hippocampus. These changes were coupled with an age-related deficit in long term potentiation in perforant path-granule cell synapses, while eicosapentaenoate treatment was associated with reversal of age-related changes in interleukin-1β and p38 and with restoration of long term potentiation. Among the several changes that occur in the aged brain is an increase in the concentration of the proinflammatory cytokine interleukin-1β that is coupled with a deterioration in cell function. This study investigated the possibility that treatment with the polyunsaturated fatty acid eicosapentaenoic acid might prevent interleukin-1β-induced deterioration in neuronal function. Assessment of four markers of apoptotic cell death, cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end staining, revealed an age-related increase in each of these measures, and the evidence presented indicates that treatment of aged rats with eicosapentaenoate reversed these changes as well as the accompanying increases in interleukin-1β concentration and p38 activation. The data are consistent with the idea that activation of p38 plays a significant role in inducing the changes described since interleukin-1β-induced activation of cytochrome ctranslocation and caspase-3 activation in cortical tissue in vitro were reversed by the p38 inhibitor SB203580. The age-related increases in interleukin-1β concentration and p38 activation in cortex were mirrored by similar changes in hippocampus. These changes were coupled with an age-related deficit in long term potentiation in perforant path-granule cell synapses, while eicosapentaenoate treatment was associated with reversal of age-related changes in interleukin-1β and p38 and with restoration of long term potentiation. interleukin-1β poly(ADP-ribose) polymerase terminal dUTP nick-end labeling long term potentiation type I IL-1 receptor IL-1R antagonist eicosapentaenoic acid phosphate-buffered saline 7-amino-4-trifluoromethyl coumarin analysis of variance Increased expression of the proinflammatory cytokine interleukin-1β (IL-1β)1has been linked with neurodegenerative disorders like Down’s syndrome, Alzheimer’s disease, and Parkinson’s disease (1Griffin W.S.T. Stanley L.C. Ling C. White L. MacLeod V. Perrot L.J. White III, C.L. Araoz C. Proc. Natl. Acad. Sci. U. S. 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Rev. 2001; 21: 129-145Crossref PubMed Scopus (247) Google Scholar) has been closely linked with apoptotic cell death. Significantly, an increase in p38 activity has been coupled with apoptotic changes in Alzheimer’s disease (17Zhu X. Rottkamp C.A. Boux H. Takeda A. Perry G. Smith M.A. J. Neuropathol. Exp. Neurol. 2000; 59: 880-888Crossref PubMed Scopus (305) Google Scholar, 18Hensley K. Floyd R.A. Zheng N.Y. Nael R. Robinson K.A. Nguyen X. Pye Q.N. Stewart C.A. Geddes J. Markesbery W.R. Patel E. Johnson G.V. Bing G. J. Neurochem. 1999; 72: 2053-2058Crossref PubMed Scopus (316) Google Scholar). Concomitant increases in IL-1β concentration and p38 activity have been reported in the aged rat brain (19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar, 20Murray C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 21O'Donnell E. Vereker E. Lynch M.A. Eur. J. Neurosci. 2000; 12: 345-352Crossref PubMed Scopus (115) Google Scholar); in hippocampus these changes are correlated with compromised synaptic function and with an age-related impairment in long term potentiation (LTP) (19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar, 20Murray C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 21O'Donnell E. Vereker E. Lynch M.A. Eur. J. Neurosci. 2000; 12: 345-352Crossref PubMed Scopus (115) Google Scholar, 22McGahon B.M. Martin D.S.D. Horrobin D.F. Lynch M.A. Neuroscience. 1999; 94: 305-314Crossref PubMed Scopus (205) Google Scholar), while consistent with the high expression of IL-1β and IL-1RI in hippocampus is the finding that the cytokine depresses LTP in dentate gyrus (8Vereker E. O'Donnell E. Lynch M.A. J. Neurosci. 2000; 20: 6811-6819Crossref PubMed Google Scholar, 19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar, 20Murray C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar,23Cunningham A.J. Murray C.A. O'Neill L.A.J. Lynch M.A. O'Connor J.J. Neurosci. Lett. 1996; 203: 1-4Crossref PubMed Scopus (348) Google Scholar, 24Lynch M.A. Prog. Neurobiol. 1998; 56: 1-19Crossref PubMed Scopus (144) Google Scholar). Significantly, we have recently reported that the age-related increases in IL-1β concentration and c-Jun NH2-terminal kinase activity, as well as the decrease in LTP, are reversed by treatment with the n-3 polyunsaturated fatty acid docosahexaenoic acid (22McGahon B.M. Martin D.S.D. Horrobin D.F. Lynch M.A. Neuroscience. 1999; 94: 305-314Crossref PubMed Scopus (205) Google Scholar). In this study we have attempted to identify the downstream consequences of the coupled age-related increases in IL-1β concentration and p38 activation in neuronal tissue. In particular, we have focused on assessing whether these changes might trigger apoptotic changes in neuronal tissue as it does in other tissues and have analyzed the effect of the ethyl ester of the ω-3 fatty acid eicosapentaenoic acid (EPA) on age-related changes in cortex and hippocampus. The data indicate that dietary manipulation reversed several changes in the aged cortex that are indicative of apoptotic cell death as well as age-related changes in IL-1β concentration, p38 activation, and LTP in hippocampus. Groups of young and aged male Wistar rats (300–350 g), maintained at an ambient temperature of 22–23 °C under a 12-h light-dark schedule, were subdivided into those that were fed on a diet enriched in eicosapentaenoic acid (ethyl eicosapentaenoate, 10 mg/rat/day for 3 weeks and 20 mg/rat/day for 5 weeks; Laxdale Research Ltd.) or standard laboratory chow for 8 weeks. Daily food intake was assessed for 2 weeks prior to commencement of the treatment: mean values (±S.E.) were 21.25 ± 1.4 and 18.55 ± 0.6 g/day for 4- and 22-month-old rats, respectively. At this time the mean body weights of young rats assigned to control and experimental groups were 265.6 ± 9.1 and 250.2 ± 11.7 g, respectively; corresponding values in aged rats were 483.6 ± 9.8 and 481.2 ± 7.9 g, respectively. Diet was prepared each and rats were of food intake in groups the treatment and at the of this time mean body weights of young rats assigned to control and experimental groups were ± and ± g, respectively; corresponding values in aged rats were ± and ± g, respectively. At this time rats were and were maintained under for the of this At the of the LTP was as described (19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar). were by of and were in the of the dentate gyrus and to and perforant to and were at for 10 and of for were by and the hippocampus and cortex were into and in of 10 (22McGahon B.M. Martin D.S.D. Horrobin D.F. Lynch M.A. Neuroscience. 1999; 94: 305-314Crossref PubMed Scopus (205) Google Scholar). were in and as described IL-1β concentration was analyzed in prepared cortex and hippocampus by concentration in phosphate-buffered saline IL-1β were at several with for at temperature with of and and IL-1β in or in 2 were and for 2 at concentration, in and IL-1β was and for 2 at were in was and for 20 at of and was and at temperature in the for which time the was of was at and values were for protein 72: PubMed Scopus Google Scholar) and as of of p38 was analyzed in of prepared hippocampus and and expression of were analyzed in cortical tissue. p38 activity was assessed in prepared and cortical tissue that was for 20 in the or of IL-1β while cytochrome ctranslocation was assessed in vitro of of cortex with IL-1β in the or of or analysis of p38 in and for was to for protein concentration, and were to 10 of for 5 and In the of cytochrome were prepared by of cortex in 10 5 2 2 for 20 on and for 10 at The was in to a concentration of for 3 and In were by of for for and with the primary and In the of in phosphate-buffered and were In the of we with an the corresponding to of poly(ADP-ribose) polymerase of human and were and cytochrome a protein corresponding to of was In to of were for analysis of and in other were with an to these treatment In were and of protein was by analysis Ltd.) and Ltd.) for and respectively. of cortical tissue prepared young and aged rats were in 5 5 5 2 10 10 on for 20 analyzed for protein concentration, and to for protein In prepared control young rats were for at °C in the or of IL-1β to which or was these were as described were to 2 of caspase-3 5 to a and for at was assessed and activity was with to a standard of concentration was cortical neurons A. M. Murray M. Campbell V. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) was on of of were for for a of at °C for and °C for 2 was at °C for 10 was the caspase-3 of and of The were analyzed by on and of was as a standard to the expression of caspase-3 were at °C for in 5 2 10 at and were and a were for in in in for and in in for were in in to with p38 or and at were and in the for 2 in and or to labeling with p38 and respectively. a were 2 in in and was analyzed the in which the were by at and and at and which and respectively. were analyzed at under with the at The were analyzed the and the was to decrease In this are and are In a of groups of aged and young rats were and were in in an and to for analysis of p38 as described cell death was assessed the were and in as described In cortical neurons were prepared rats as described A. M. Murray M. Campbell V. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) and maintained in for in the or of IL-1β for was at by with terminal for at were in and in and were as a of the cell IL-1β concentration and p38 activity were both in cortical tissue prepared aged rats fed on the control diet with young rats a these age-related changes that the values in tissue prepared rats were control In vitro analysis revealed that IL-1β p38 activity in cortical tissue In parallel with this we that cytochrome c was in cortical tissue prepared aged rats fed on the control diet with tissue prepared of young rats the age-related changes in cytochrome ctranslocation and IL-1β is by the finding that was by IL-1β and that this on IL-1RI activation since the was by that the was by that the effect was by activation of age-related increase in is by and by was in cortical tissue prepared aged rats fed on the control diet with young rats fed on control diet 3 with this was in tissue prepared aged rats fed on the diet of cortical tissue in the of IL-1β cytochrome c this effect was by and by cytochrome ctranslocation in each downstream of cytochrome c is activation of we analyzed activity in tissue prepared aged and young rats fed on the control or experimental that was a significant age-related increase in caspase-3 the mean in cortical tissue prepared aged rats fed on the control diet was with the in tissue prepared young rats this In an to whether the in caspase-3 activation was coupled with the increases in IL-1β concentration and p38 activation, a of in vitro were that revealed that IL-1β caspase-3 activity in cortical tissue this effect was by that the of IL-1β was on receptor and by that the of IL-1β activation of prepared cortex of young and aged rats fed on both were for p38 and and was assessed cell in young rats in which was evidence of of p38 and In several prepared aged rats fed on the control diet for an is shown in while prepared aged rats for was for and we evidence of These findings the idea that caspase-3 activation is closely coupled with p38 activation. In to the effect of IL-1β on caspase-3 activity, we that IL-1β caspase-3 in cortical In an to these which that was significant evidence of cell death in the aged we investigated of by assessing expression of the of the in a and by analysis of the mean data that was a significant decrease in expression of in cortical tissue prepared aged rats fed on the control diet with young rats that this effect was reversed in tissue prepared aged rats with These data were by changes in a of for in aged rats fed on the control diet with young rats fed on diet The of in aged rats fed on the diet was similar to that in tissue prepared young that of cortical neurons to IL-1β for the of for increase in with is by and by the of that for was in cortex of aged rats fed on the control diet with that in young rats fed on diet dietary manipulation with reversed this of cortical neurons in the of IL-1β the of for In an to the synaptic changes that might occur as a of cell death, we to analysis of changes in hippocampus and assessed and changes in IL-1β concentration and p38 activation. in parallel with the age-related findings in cortical IL-1β concentration was in tissue prepared aged rats fed on the control diet with young rats fed on diet was evidence of a similar age-related increase in aged rats fed on the of p38 activation revealed a similar was a significant age-related increase in p38 activity aged rats fed on the control diet young which was in tissue prepared aged rats fed on the IL-1β concentration and p38 activation is by the finding that IL-1β p38 activity in hippocampus in vitro In a of in which dietary manipulation was of tissue were prepared young and aged that was a increase in p38 in hippocampus of aged with young are in of LTP in dentate gyrus was in the rats in which were that LTP was in both groups of young rats was in aged rats fed on the control diet in the of rats the mean changes in in the 2 and in the 5 of the with the mean in the 5 prior to the were ± and ± respectively. In the corresponding values in aged rats fed on the diet were ± and ± respectively. These values were similar to those in young rats fed on the control ± and ± and ± and ± that treatment the of aged rats to to evidence that treatment with neuronal cell death in aged rats and that of the age-related coupled increases in IL-1β concentration and p38 activity is the to the of that leads to The age-related increase in IL-1β concentration in cortical and which findings (19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar, 20Murray C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 21O'Donnell E. Vereker E. Lynch M.A. Eur. J. Neurosci. 2000; 12: 345-352Crossref PubMed Scopus (115) Google Scholar), is coupled with The that IL-1β cell death is by the finding that IL-1β in cortical a of data experimental with Significantly, treatment with which has been shown to have H. Y. H. Y. H. H. T. 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Significantly, this increase was in cortical tissue prepared aged of the which is by cytochrome c the to the A. 1999; PubMed Scopus Google Scholar), is a in apoptotic cell death. has been shown that the that to these is A. 1999; PubMed Scopus Google Scholar); it is that which we have shown to IL-1β concentration in other (19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar, 20Murray C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 21O'Donnell E. Vereker E. Lynch M.A. Eur. J. Neurosci. 2000; 12: 345-352Crossref PubMed Scopus (115) Google Scholar) and in the is for the age-related increase in cytochrome c a of by with and by activation of and other that in cell death J.C. Science. 1998; PubMed Google Scholar). The of the role of cytochrome ctranslocation in this was by the that of active cytochrome c into to S. 1998; PubMed Scopus Google Scholar). The which parallel changes in and are consistent with the view that caspase-3 activation is by E. Science. 1997; 275: PubMed Scopus Google Scholar, J. A.M. X. Science. 1997; 275: PubMed Scopus Google Scholar). data indicate that caspase-3 as well as activity, was by IL-1β in vitro that caspase-3 activation was on of IL-1β with IL-1RI and the activation of The that caspase-3 with p38 was a of a these This finding is similar to data reported in a study that that activity and and cortical neurons cell death S. S. Y. M. Patel Z. R.J. J. Biol. 2000; PubMed Scopus Google Scholar). reversed the age-related increases in p38 activation, cytochrome c translocation, and caspase-3 activity, and we view this as evidence of a the downstream for caspase-3 is the and the findings indicate in parallel with the of and diet on caspase-3 activation, was in aged rats fed on the the have reported that of was in cortex of rats, and this was by changes in of that were indicative of cell death C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). of has been to a of J.C. R. Neurobiol. 1996; PubMed Scopus Google Scholar, M.A. R.A. 2001; 30: PubMed Scopus Google Scholar). Significantly, we that these lipopolysaccharide-induced changes were by inhibition a role for IL-1β in the of to cell death (8Vereker E. O'Donnell E. Lynch M.A. J. Neurosci. 2000; 20: 6811-6819Crossref PubMed Google Scholar). In the study the age-related in was coupled with evidence of cell evidence of both changes was in tissue prepared aged data indicate that the age-related increases in IL-1β concentration and p38 activation in cortical tissue were in the these findings (19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar, 20Murray C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). we that changes were in hippocampus of aged rats that were fed on the LTP in perforant path-granule cell was with data several (19Murray C.A. Lynch M.A. J. Neurosci. 1998; 18: 2974-2981Crossref PubMed Google Scholar, 20Murray C.A. Lynch M.A. J. Biol. Chem. 1998; 273: 12161-12168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 21O'Donnell E. Vereker E. Lynch M.A. Eur. J. Neurosci. 2000; 12: 345-352Crossref PubMed Scopus (115) Google Scholar, 22McGahon B.M. Martin D.S.D. Horrobin D.F. Lynch M.A. Neuroscience. 1999; 94: 305-314Crossref PubMed Scopus (205) Google Scholar, C.A. J. PubMed Scopus Google Scholar); this age-related impairment in LTP was in aged rats fed on the The the IL-1β concentration and p38 activation and the expression of LTP with the that the inhibition of LTP was by p38 inhibition evidence of a these The of polyunsaturated fatty into neuronal tissue is has been shown that fatty the and the of is to evidence indicates that is by a J. Neurosci. 2001; PubMed Scopus Google Scholar). The of the of the decrease in polyunsaturated fatty in aged rats to it that fatty acid into brain tissue is with L. M. G. A. PubMed Scopus Google Scholar). is that is coupled with a significant increase in IL-1β concentration in neuronal tissue that is to activation of that p38 to of cytochrome of these changes is an increase in caspase-3 caspase-3 on in changes in occur since is compromised as a of this The evidence presented to a role for IL-1β in the that to an increase in cell death in the aged brain and identify activation of p38 as a is several age-related the primary of to the age-related increase in IL-1β