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.
Highlights
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]
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]
IL-1 concentration and p38 activity were both significantly increased in cortical tissue prepared from aged rats fed on the control diet compared with young rats (p Ͻ 0.05, ANOVA; Fig. 1, a and b), but eicosapentaenoic acid (EPA) suppressed these age-related changes so that the values in tissue prepared from EPA-treated rats were not significantly different from control values
Summary
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].
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