Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain.
Increased expression of proinflammatory cytokines, like interleukin-1 beta (IL-1 beta), is a feature of the aged brain and it is generally accepted that the primary cell source of these cytokines is activated microglia. In hippocampus of aged rats, the increase in IL-1 beta is accompanied by microglial activation and impaired long-term potentiation (LTP). Peroxisome proliferator-activated receptors (PPARs) possess anti-inflammatory properties that target microglia. In this study the PPAR gamma agonist, rosiglitazone, was orally administered to young and aged rats, and we report that the age-related increases in NO and IL-1 beta production were attenuated in hippocampus of rosiglitazone-treated aged rats and that this was associated with a restoration of LTP. In addition, treatment with rosiglitazone increased interleukin-4 (IL-4) mRNA and reversed the age-related decrease in hippocampal IL-4 concentration. Significantly, while rosiglitazone attenuated the LPS-induced increase in MHCII and IL-1 beta concentration in glia prepared from wildtype mice, it failed to exert an effect in glia prepared from IL-4(-/-) mice, thereby suggesting that the anti-inflammatory actions of rosiglitazone are mediated by its ability to increase IL-4 expression.
Loane
David J
DJ
Trinity College Institute for Neuroscience and Physiology Department, Trinity College, Dublin 2, Ireland.
Deighan
Brian F
BF
Clarke
Rachael M
RM
Griffin
Rebecca J
RJ
Lynch
Aileen M
AM
Lynch
Marina A
MA
D000375:Aging; D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*
D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015847:Interleukin-4; D009569:Nitric Oxide