Research Project
10303877
Project Summary Aging is metabolism modifiable Post-stroke depression (PSD) affects over 40% of patients and negatively influences their recovery. The kynurenine pathway (KP) is the main catabolic pathway of tryptophan, the precursor of serotonin, and has been independently implicated in both depression and stroke. The KP has never been evaluated in the context of PSD, and is a very promising pathway for development of therapeutic targets. In our preliminary studies, we have found that aged mice, but not young mice, develop a significant PSD phenotype. Moreover, compared to the young brain, the brain levels of a key enzyme in the KP, kynurenine 3-monooxygenase (KMO), are higher in the aged brain at baseline, and increase after stroke. Our main hypothesis is that inhibiting KMO activity will prevent and/or minimize the development of PSD in aged animals, and that this will produce a more robust effect in aged females. To address our first aim, i.e. determine whether the post-stroke increase in KMO expression and KP metabolites varies according to sex, we will measure KMO expression and KP metabolites in the brain and plasma of aged mice subjected to reversible middle cerebral arterial occlusion (MCAO). In aim 2, i.e. to determine whether KMO inhibition prevents PSD, reduces inflammation, and improves recovery, aged animals from both sexes will be subjected to stroke or sham surgery, and half of the animals will be treated with Ro 61- 8048, a KMO inhibitor, and the other half with vehicle. A series of behavioral tests will be performed to evaluate neurological recovery and PSD phenotypes. We will then use KMO knockout mice to further validate our hypothesis, assessing how deletion of KMO will alter infarct size, PSD phenotypes and recovery in both aged males associated with in multiple biological systems, including altered and increased brain and systemic inflammation, also known as `inflammaging'. Aging is a non- risk factor for many neurological diseases, including stroke. significant changes serotonin and females. The results obtained in this project will determine contribute the mechanisms by which aging and KP to the pathogenesis of PSD. Furthermore, this contribution is expected to have high translational potential, constituting the theoretical framework for developing future trials in humans.
