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-1␤ 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-1␤-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-1␤ 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-1␤-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-1␤ 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-1␤ and p38 and with restoration of long term potentiation. Increased expression of the proinflammatory cytokine interleukin-1␤ (IL-1␤)1 has been linked with neurodegenerative disorders like Down's syndrome, Alzheimer's disease, and Parkinson's disease (1, 2). Consistent with the view that IL-1␤ plays a role in deterioration of cell function are the findings that IL-1␤ expression is increased, in parallel with cell damage, in experimental models of ischemia (3), excitotoxicity (4), and traumatic lesions (5). Indeed, IL-1␤ has been shown to trigger cell death in primary cultures of human fetal neurons (6) and inhibition of caspase-1, which leads to formation of active IL-1␤, and blocks lipopolysaccharide-induced changes in cell morphology, which are consistent with cell death (7).IL-1␤ has been shown to stimulate the mitogen-activated protein kinases p38 and c-Jun NH 2 -terminal kinase (8, 9), and activation of both c-Jun NH 2 -terminal kinase (10, 11) and p38 (10, 12-16) has been closely linked with apoptotic cell death. Significantly, an increase in p38 activity has been coupled with apoptotic changes in Alzheimer's disease (17, 18). Concomitant increases in IL-1␤ concentration and p38 activity have been reported in the aged rat brain (19 -21); in hippocampus these changes are correlated with compromised synaptic function and with an age-related impairment in long term potentiation (LTP) (19 -22), while consistent with the high expression of IL-1␤ and IL-1RI in hippocampus is the finding that the cytokine depresses LTP in dentate gyrus (8,19,20,23,24). Significantly, we have ...

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