title: Apoptotic changes in the aged brain are triggered by interleukin-1beta-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-1beta 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-1beta-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-1beta 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-1beta-induced activation of cytochrome c translocation and caspase-3 activation in cortical tissue in vitro were reversed by the p38 inhibitor SB203580. The age-related increases in interleukin-1beta 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-1beta and p38 and with restoration of long term potentiation.
authors.affiliation: Department of Physiology, Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Darren S D
authors.initials: DS
authors.lastname: Martin
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lonergan
authors.forename: Barry
authors.initials: B
authors.lastname: Boland
authors.forename: Marie P
authors.initials: MP
authors.lastname: Fogarty
authors.forename: Marcella
authors.initials: M
authors.lastname: Brady
authors.forename: David F
authors.initials: DF
authors.lastname: Horrobin
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Campbell
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001095:Arachidonic Acids / Q000494:pharmacology*; D001921:Brain / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007375:Interleukin-1 / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D001095:Arachidonic Acids; D007375:Interleukin-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases