96. Anti-depressants and kynurenine pathway inhibition: A therapeutic strategy for neuroprotection in vitro?

Abstract

The kynurenine pathway (KP) is the main pathway by which tryptophan is metabolized. Its rate limiting enzyme indolamine 2, 3-dioxygenase (IDO) catalyses the production of kynurenine, which in turn is metabolised by either kynurenine 3-hydroxylase (KMO) which leads to the production of quinolinic acid (neurotoxic), or by kynurenine aminotransferase (KAT II) which yields kynurenic acid (neuroprotective). These enzymes are localised in microglia and astrocytes respectively. The present studies demonstrated that IFN- γ induces expression of IDO, KMO and kynase along with the production of neurotoxic molecules from BV-2 microglia. This was determined using a cell culture system whereby microglia were activated with IFN- γ and this conditioned medium was then placed on primary cortical neurons. Inhibition of the kynurenine pathway with 1-(D)-methyl-tryptophan (IDO inhibitor) and Ro 61-8048 (KMO inhibitor) completely attenuated this microglial-mediated neurotoxicity, as did the NMDA antagonist MK-801. Furthermore the anti-depressant fluoxetine partially attenuated this neurotoxicity and IFN- γ induced increases in IDO and kynase mRNA expression. Inhibition of classical neurotoxic factors released from microglia i.e. iNOS and the enzyme NADPH oxidase had no effect on this microglial mediated neurotoxicity, and neither did the anti-inflammatory agent dexamethasone. These results propose IFN- γ activated microglia induce neurotoxicity by activating the KP, and this can be attenuated using fluoxetine, suggesting a possible role for anti-depressants in ameliorating neuronal damage and in influencing the KP balance.