Cyclooxygenase and Prostaglandins
Another main objective of Dr. Doré’s research is to understand the actions of cyclooxygenase and its metabolites. Inflammation and its consequences are suggested to play an important role in the loss of normal neuronal functions associated with aging and Alzheimer disease. Cyclooxygenase (COX) is the rate-limiting enzyme for the production of the prostaglandins (PGs) through metabolism of the arachidonic acid. COX-1 is constitutively expressed in most neuronal cells and has been suggested to respond to normal cellular functions. On the other hand, COX-2 expression and PG production increase markedly in neurons following a variety of brain insults, including hypoxia, inflammation, and excitotoxicity. Studies in rodent ischemic and excitotoxic models show that COX-2 enzymatic activity promotes neuronal injury and the administration of specific inhibitors reduces neuronal damage.
Epidemiologic studies have suggested a reduction in the incidence of AD in patients who were taking anti-inflammatory drugs, and numerous studies have reported the induction of COX-2 in AD brains. Clinical trials using selective COX-2 inhibitors have been designed, although the results reported so far have not satisfied the high expectations. Dr. Doré and his collaborators have recently tested transgenic mice overexpressing COX-2 selectively in neurons and observed an increased infarct size in these transgenic mice; however, they were not able to show significant reduction after administration of a specific COX-2 inhibitor. Their results in primary neuronal cultures indicate that biological actions of the COX inhibitors and the PGs often follow a very narrow bell-shaped curve.
All together, Dr. Doré’s research team believes that a better understanding of the PG receptors is of utmost importance and could explain several of the discrepancies and failures previously reported. The mechanism by which PGs promote neuronal injury in excitotoxic conditions has not yet been defined. Some PGs have been reported to promote injury, while others have been reported to be cytoprotective. PGs are diffusible signaling lipids whose effects are mediated through a diverse class of G-protein-coupled receptors that can have opposing effects on cAMP, IP turnover, and Ca2+ levels. Using in vivo studies, as well as in vitro culture techniques, Dr. Doré’s aim is to define the role of the respective PG receptors in regulating excitotoxic damage. The overall goal is to develop more selective action that would specifically relieve inflammation while minimizing the distressing side effects that are possible with chronic use of the present available drugs (either over-the-counter or prescribed).
- Doré Set al., Neuronal overexpression of cyclooxygenases-2 increases cerebral infarction. Annals of Neurology 54:155 62, 2003.
- DiBattista JA, Doré S, Morin N, He Y, Martel-Pelletier J, Pelletier JP. Prostaglandin E2 stimulates insulin-like growth factor binding protein-4 expression and synthesis in cultured human articular chondrocytes. Possible mediation by Ca2+-calmodulin regulated processes. J Cell Biochem 65:408-19, 1997.
- DiBattista JA, Doré S, Morin N, Abribat T. Prostaglandin E2 up-regulates insulin-like growth factor binding protein-3 expression and synthesis in human articular chondrocytes by a cAMP-independent pathway: Role of calcium and protein kinase A and C. J Cell Biochem 63:320-33, 1996.