Abstract 5750: The antidepressant vortioxetine reverses cognitive deficits associated with androgen deprivation therapy for the treatment of prostate cancer in healthy rats

Abstract

First-line treatment for prostate cancer includes androgen deprivation therapy (ADT). However, this intervention can induce severe cognitive impairments in more than half of patients and increases the likelihood of dementia or Alzheimer's disease. Long-term occurrence of these impairments can significantly reduce quality of life for cancer survivors and ultimately impacts their families and caregivers. Thus, it is important to improve the cognitive side effects of ADT, as 45% of prostate cancer patients will undergo ADT, and the five-year relative survival rate is greater than 99%. The clinical literature indicates that ADT-induced impairments typically occur in the cognitive domains of spatial memory and executive function, which are associated with function of the hippocampus (Hipp) and medial prefrontal cortex (mPFC), respectively. The cognitive symptoms that develop can also increase in severity with duration of treatment, suggesting that it may be possible to slow or reverse the impairment. To address the mechanisms underlying these effects, we used the Attentional Set-shifting Test (AST) and the Novel Object Location (NOL) Test to assess cognitive function after surgical castration as a rodent model of ADT. ADT induced impairments in cognitive flexibility on the AST (p<0.001, n=10-12) and visuospatial memory on the NOL task (p<0.05, n=8-11) in male Sprague Dawley rats. These deficits were reversed by chronic administration of a multimodal antidepressant drug, vortioxetine (28 mg/kg/day for 2 weeks). Vortioxetine is FDA-approved for the treatment of Major Depressive Disorder, and it has been shown to improve cognitive impairment associated with depression. Our data indicate that vortioxetine may also represent a novel therapeutic approach to alleviate ADT-induced cognitive impairments. To increase the translational relevance our rodent model of ADT, we are investigating potential cognitive impairments induced by chemical castration with degarelix, a gonadotropin releasing hormone antagonist. Experiments are underway to test the hypothesis that vortioxetine will also reverse cognitive impairments induced by androgen depletion with degarelix. The results of this study will be compared to those obtained with surgical castration. In sum, these studies aim to identify possible therapeutic interventions by which cognitive impairment induced by ADT as a treatment for prostate cancer can be reversed or prevented. This research was funded by the Cancer Prevention & Research Institute of Texas grant RP180055, and by NIH grant R01 CA224672. Citation Format: Alexandra M. Vaiana, Jonathan Gelfond, Teresa Johnson-Pais, Robin Leach, Michael Liss, Anna Sullivan, Ian Thompson, David A. Morilak. The antidepressant vortioxetine reverses cognitive deficits associated with androgen deprivation therapy for the treatment of prostate cancer in healthy rats [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5750.

Vortioxetine Reverses Impairment of Visuospatial Memory and Cognitive Flexibility Induced by Degarelix as a Model of Androgen Deprivation Therapy in Rats

“…Cognition is dependent on functional plasticity, including in the circuitry between the mPFC and hippocampus. In our previous study, we found that vortioxetine reversed the attenuated responsivity induced in mPFC- and hippocampus-related circuitry after surgical castration in young rats [15]. The fact that vortioxetine was also effective in reversing ADT-induced changes in evoked local field potentials of middle-aged rats is important to informing the potential utility of vortioxetine to improve cognition impaired by ADT in prostate cancer patients.…”

“…In our previous studies, we reported results using young adult male Sprague-Dawley rats [14, 15]. Surgical castration was used to isolate the cognitive effects of testosterone depletion from potentially confounding pharmacological effects of drugs used for chemical castration.…”

“…Adapted from Barker and Warburton [22], the NOL test was performed 24 h after habituation, as previously described [15]. Testing occurred in the same arena as the OFT.…”

“…The AST was performed as described previously [15, 23]. One half of a Honey Nut Cheerio (General Mills, Minneapolis, MN) was used as reward.…”

“…We have previously shown that surgical castration induced cognitive set-shifting deficits in young adult rats [14, 15]. Further, we have shown previously that the multimodal antidepressant vortioxetine reversed these impairments.…”