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.