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.