The influence of brain inflammation upon neuronal adenosine A2B receptors.
Alzheimer's disease (AD) is associated with glial activation and increased levels of pro-inflammatory cytokines. Epidemiological results suggest that anti-inflammatory therapies can slow the onset of AD. Adenosine, acting at type-2 receptors, is an effective endogenous anti-inflammatory agent that can modulate inflammation both in the periphery and the brain. We investigated changes in the expression of adenosine type-2B (A2B) receptors and a related intracellular second messenger during chronic brain inflammation and following treatment with the non-steroidal anti-inflammatory drug flurbiprofen and its nitric oxide (NO)-donating derivative, HCT1026. Chronic infusion of lipopolysaccharide (LPS) into the 4th ventricle of young rats induced brain inflammation that was associated with microglial activation and reduced neuronal immunoreactivity for adenosine A2B receptors in the cortex. Daily administration of HCT1026, but not flurbiprofen, reduced microglial activation, prevented the down-regulation of A2B receptors and elevated tissue levels of cAMP. The results suggest that a therapy using an NO-releasing NSAID might significantly attenuate the processes that drive the pathology associated with AD and that this process may involve the activation of adenosine A2B receptors.
Rosi
Susanna
S
Arizona Research Laboratories, Division of Neural Systems, Memory & Aging, University of Arizona, Tucson 85724, USA.
McGann
Kristin
K
Hauss-Wegrzyniak
Beatrice
B
Wenk
Gary L
GL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000494:pharmacology; D007150:Immunohistochemistry; D008070:Lipopolysaccharides; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; C095631:nitroflurbiprofen; D005480:Flurbiprofen