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.
Androgen deprivation therapy (ADT) is a frontline treatment for prostate cancer but induces profound cognitive impairment in more than half of patients. This significantly reduces quality of life for cancer survivors and their families. Deficits occur in cognitive domains associated with function of the hippocampus (Hipp) and medial prefrontal cortex (mPFC) and increase in severity with duration of treatment. Therefore, it may be possible to slow or reverse the impairment. In preclinical studies, we reported that vortioxetine, a novel multi-modal antidepressant that has been shown to improve cognitive impairment in depressed patients, may reverse the ADT-induced impairment. Our lab established a rodent model of ADT in which surgically castrated rats display deficits in cognitive flexibility and visuospatial recognition, measures of prefrontal executive function and hippocampal spatial learning, respectively. We also found that castration reduces response of the mPFC to activation of the afferent pathway from the vHipp in anesthetized animals. Chronic dietary vortioxetine (28mg/kg/day) normalized response in this pathway and reversed the cognitive impairments associated with both the mPFC and Hipp. In a microarray study (Agilent Technologies, Inc.) of tissue collected from the mPFC, dorsal-, and ventral-Hipp, we found that castration altered over 1,000 genes in each of these regions (adjusted p <0.05). Vortioxetine did not have a significant main effect on individual genes, but pathway analysis revealed significant changes in processes involved in synaptic plasticity, such as synapse formation, axonogenesis, and MAPK signaling. In the present study, qPCR and western blot analyses were used to investigate potential ADT- and vortioxetine-induced changes in candidate factors. Factors were identified in the top-hit pathways from the vortioxetine x castration microarray analysis and confirmed by qPCR. These included plasticity-related proteins such as Arc, Akt, CREB, mGlur1, and PSD95, among others. Changes in expression and phosphorylation were further determined using western blots. Early results indicate that vortioxetine selectively reversed the reduced expression induced by castration for some, but not all, of these proteins, including CREB and mGlur1 (p<0.05). Experiments are underway to identify potential alterations in protein phosphorylation, as changes in activation rather than expression may also be important to the beneficial effects of vortioxetine. These results suggest that vortioxetine may reverse deficits in executive function and visuospatial recognition after ADT by modulating structural and functional plasticity in mPFC and Hipp. Citation Format: Alexandra M. Vaiana, Roman Fernandez, Jonathan Gelfond, Teresa L. Johnson-Pais, Robin Leach, Chethan Ramamurthy, Ian Thompson, David A. Morilak. Plasticity-related signaling pathways in the medial prefrontal cortex and hippocampus as potential targets of the antidepressant vortioxetine in reversing cognitive impairments after androgen deprivation therapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2560.
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