17 April 2002. Cyclooxygenase (COX), the rate-limiting enzyme in prostaglandin synthesis, is well known for its role in inflammation, but less well known for its role in neurodegeneration and cell death. However, in the late nineties it was found that neurons from transgenic mice expressing the human COX-2 isoform were more susceptible to glutamate-induced cell damage, implicating COX-2 in the process of "excitotoxicity." Just how COX-2 may mediate such effects, however, has remained a mystery.
In tomorrow's Journal of Pharmacology and Experimental Therapy, work from the lab of Giulio Pasinetti at the Mount Sinai School of Medicine, New York, indicates that COX-2 may be involved in deregulating the cell cycle. (Cox-2 is being widely studied in various human cancer cell types.) Mirjani et al. used transgenic mice expressing human COX-2 and probed expression levels of more than 8,000 mRNAs in the mice's brains with a DNA microarray. They found that in addition to elevated prostaglandin E2, these animals had reduced levels of p18ink4, an inhibitor of the cell cycle kinase (CDK) 4,6. In contrast, when the same animals were fed a diet containing the COX-2 inhibitor nimesulide, p18ink4 levels remained normal. Moreover, cultured neurons from the transgenic mice were more susceptible to glutamate-induced apoptotic damage, but this effect could be reversed by the CDK inhibitor flavoperidol. COX-2 may therefore work by relieving inhibition of CDKs, the authors suggest.
CDK 4,6 has been implicated in the phosphorylation of the retinoblastoma tumor suppressor protein (Rb). Indeed, the researchers found an increase in Rb phosphorylation in COX-2 transgenic neurons, which could be reversed by administration of nimesulide. The authors contend that excitotoxicity may be a result of apoptosis, kick-started by re-activation of the cell cycle in these post-mitotic cells. This would provide a rationale for the hypothesis that attempts by neurons to re-enter the cell cycle may be a contributing factor to Alzheimer's disease (Raina et al, 2000; Husseman et al., 2000). Given that elevated levels of COX-2 were found in Alzheimer's patients, this enzyme may be a drug target, the authors write.-Tom Fagan.
Reference:Mirjany M, Ho L, Pasinetti GM. Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity. J. Pharm. Exp. Therap. May 2002;(301):1-7. Abstract