The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo.
Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and non-steroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this work was to study in vivo whether attenuation of brain inflammatory response to excitotoxic insult by the selective cyclooxygenase-2 inhibitor, rofecoxib, may prevent neurodegeneration, as a contribution to a better understanding of the role inflammation plays in the pathology of Alzheimer's disease. We investigated, by immunohistochemical methods, glia reaction, the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway with an antibody selective for the phosphorylated form of the enzyme and the number of choline acetyltransferase-positive neurons and, by in vivo microdialysis, cortical extracellular levels of acetylcholine following the injection of quisqualic acid into the right nucleus basalis of adult rats. Seven days after injection, a marked reduction in the number of choline acetyltransferase-positive neurons was found, along with an intense glia reaction, selective activation of p38MAPK at the injection site and a significant decrease in the extracellular levels of acetylcholine in the cortex ipsilateral to the injection site. The loss of cholinergic neurons persisted for at least up to 28 days. Rofecoxib (3 mg/kg/day, starting 1 h prior to injection of quisqualic acid) treatment for 7 days significantly attenuated glia activation and prevented the loss of choline acetyltransferase-positive cells and a decrease in cortical acetylcholine release. The prevention of cholinergic cell loss by rofecoxib occurred concomitantly with the inhibition of p38MAPK phosphorylation. Our findings suggest an important role of brain inflammatory reaction in cholinergic degeneration and demonstrate a neuroprotective effect of rofecoxib, presumably mediated through the inhibition of p38MAPK phosphorylation.
Scali
C
C
Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
Giovannini
M G
MG
Prosperi
C
C
Bellucci
A
A
Pepeu
G
G
Casamenti
F
F
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000201:enzymology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004660:Encephalitis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D005911:Gliosis / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D016318:Quisqualic Acid / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones; D048051:p38 Mitogen-Activated Protein Kinases
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D018696:Neuroprotective Agents; D009498:Neurotoxins; D013450:Sulfones; C116926:rofecoxib; D016318:Quisqualic Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D002795:Choline O-Acetyltransferase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases