Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment. However, ADT has adverse effects, including cognitive impairment that compromises quality of life for survivors, and increases the risk of dementia. Neuroimaging studies have shown structural and functional deficits in hippocampus (Hipp), which mediates spatial cognition, and medial prefrontal cortex (mPFC), which mediates executive function, both of which are compromised after ADT. In previous studies using physically castrated rats as a model of ADT, we replicated visuospatial and executive deficits seen in ADT patients. Further, we showed that vortioxetine, a novel antidepressant that improves cognitive impairment in depression, mitigated the effects of ADT. To identify mechanisms underlying effects of ADT and vortioxetine independent of confounding influences of cancer itself, we conducted our prior studies in healthy cancer-free Sprague-Dawley rats. However, cancer can affect the brain indirectly, e.g., by neuroinflammation. Thus, to make this work more translationally relevant, we will now introduce cancer pathophysiology, using a rat prostate cancer model most suitable for these studies. Dunning R-3327-G rat prostate cancer cells will be implanted into the flank of Copenhagen rats, with which the Dunning cells are syngeneic. This will allow us to induce cancer and maintain the rats for a sufficient time to study mechanisms underlying effects of both ADT and novel therapeutic interventions on cognition, and on neural structure and function in the mPFC and Hipp. We will monitor tumor progression to ensure that such interventions do not promote cancer growth or interfere with anti-cancer efficacy of ADT. These goals will be accomplished in 3 specific aims: Aim 1 will assess effects of prostate cancer alone on cognition, IL-6 neuroinflammation, and neuronal circuit function and structure in the mPFC and Hipp. We focus on IL-6 because of the prominent role of this inflammatory mediator in prostate cancer pathophysiology, and in compromising neural function and cognition via oxidative stress. Aim 2 will test effects of ADT by chemical castration with degarelix on cognition, IL-6 neuroinflammation, neural circuit function, neuronal structure in mPFC and Hipp, and prostate tumor progression. We will test the role of JAK2, the primary mediator of IL-6 activity, in ADT-induced cognitive impairment by knocking down JAK2 in mPFC and Hipp. In Aim 3, we will test the therapeutic potential of 3 drug candidates: a) first, we will dissect the pharmacological mechanism(s) responsible for vortioxetine's effect, by testing the antidepressant citalopram , a serotonin reuptake inhibitor that lacks other receptor activity, and ondansetron, a 5-HT3 receptor antagonist that lacks reuptake blockade. Both are translation-ready. We will then test a new neuroprotective drug, P7C3-A20 that enhances NAO+ levels, preventing oxidative stress such as that produced by IL-6-stimulated JAK2 signaling. In sum, this project will elucidate mechanisms by which ADT impairs cognition, identify potential therapeutic targets, and establish the Copenhagen rat model as a platform to study potential treatments for the cognitive impairment that challenges quality of life for prostate cancer survivors.

Androgen deprivation therapy (ADT) for prostate cancer induces cognitive impairment that negatively impacts the quality of life for prostate cancer survivors, for which there is currently no treatment. We will study the neural mechanisms underlying this cognitive impairment to identify potential treatment targets using a rat model of prostate cancer in which ADT is produced by chemical castration. We will then test the utility of novel therapeutic candidates for treating cognitive impairment after ADT without interfering with the anti-cancer efficacy of ADT. The overall goal is to improve the quality of life for prostate cancer survivors and their families.