Alexandra M Sharp1,2, Suphada Lertphinyowong1,2, Samantha S Yee1, Denisse Paredes1,2, Jonathan Gelfond3, Teresa L Johnson-Pais4,5, Robin J Leach4,5,6, Michael Liss4,5,7, April L Risinger1,5, Anna C Sullivan2,8,9, Ian M Thompson4,10, David A Morilak11,12,13,14. 1. Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 2. Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 3. Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 4. Department of Urology, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 5. Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 6. Department of Cell Systems & Anatomy, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 7. South Texas Veterans Health Care Service, San Antonio, TX, 78229, USA. 8. Department of Neurology, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 9. Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, 78229, USA. 10. CHRISTUS Santa Rosa Hospital, San Antonio, TX, 78229, USA. 11. Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, 78229, USA. morilak@uthscsa.edu. 12. Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, 78229, USA. morilak@uthscsa.edu. 13. Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA. morilak@uthscsa.edu. 14. South Texas Veterans Health Care Service, San Antonio, TX, 78229, USA. morilak@uthscsa.edu.
Abstract
RATIONALE: Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer, but induces profound cognitive impairment. Little research has addressed mechanisms underlying these deficits or potential treatments. This is an unmet need to improve quality of life for prostate cancer survivors. OBJECTIVES: We investigated mechanisms of cognitive impairment after ADT in rats and potential utility of the multimodal serotonin-targeting drug, vortioxetine, to improve the impairment, as vortioxetine has specific efficacy against cognitive impairment in depression. METHODS: Male Sprague-Dawley rats were surgically castrated. Vortioxetine (28 mg/kg/day) was administered in the diet. The attentional set-shifting test was used to assess medial prefrontal cortex (mPFC) executive function. Afferent-evoked field potentials were recorded in the mPFC of anesthetized rats after stimulating the ventral hippocampus (vHipp) or medial dorsal thalamus (MDT). Gene expression changes were assessed by microarray. Effects of vortioxetine on growth of prostate cancer cells were assessed in vitro. RESULTS: ADT impaired cognitive set shifting and attenuated responses evoked in the mPFC by the vHipp afferent, but not the MDT. Both the cognitive impairment and attenuated vHipp-evoked responses were reversed by chronic vortioxetine treatment. Preliminary investigation of gene expression in the mPFC indicates that factors involved in neuronal plasticity and synaptic transmission were down-regulated by castration and up-regulated by vortioxetine in castrated animals. Vortioxetine neither altered the growth of prostate cancer cells in vitro nor interfered with the antiproliferative effects of the androgen antagonist, enzalutamide. CONCLUSIONS: These results suggest that vortioxetine may be useful in mitigating cognitive impairment associated with ADT for prostate cancer.
RATIONALE: Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer, but induces profound cognitive impairment. Little research has addressed mechanisms underlying these deficits or potential treatments. This is an unmet need to improve quality of life for prostate cancer survivors. OBJECTIVES: We investigated mechanisms of cognitive impairment after ADT in rats and potential utility of the multimodal serotonin-targeting drug, vortioxetine, to improve the impairment, as vortioxetine has specific efficacy against cognitive impairment in depression. METHODS: Male Sprague-Dawley rats were surgically castrated. Vortioxetine (28 mg/kg/day) was administered in the diet. The attentional set-shifting test was used to assess medial prefrontal cortex (mPFC) executive function. Afferent-evoked field potentials were recorded in the mPFC of anesthetized rats after stimulating the ventral hippocampus (vHipp) or medial dorsal thalamus (MDT). Gene expression changes were assessed by microarray. Effects of vortioxetine on growth of prostate cancer cells were assessed in vitro. RESULTS: ADT impaired cognitive set shifting and attenuated responses evoked in the mPFC by the vHipp afferent, but not the MDT. Both the cognitive impairment and attenuated vHipp-evoked responses were reversed by chronic vortioxetine treatment. Preliminary investigation of gene expression in the mPFC indicates that factors involved in neuronal plasticity and synaptic transmission were down-regulated by castration and up-regulated by vortioxetine in castrated animals. Vortioxetine neither altered the growth of prostate cancer cells in vitro nor interfered with the antiproliferative effects of the androgen antagonist, enzalutamide. CONCLUSIONS: These results suggest that vortioxetine may be useful in mitigating cognitive impairment associated with ADT for prostate cancer.
Authors: Corina O Bondi; Gustavo Rodriguez; Georgianna G Gould; Alan Frazer; David A Morilak Journal: Neuropsychopharmacology Date: 2007-04-04 Impact factor: 7.853
Authors: Wayne R Hawley; Elin M Grissom; Ryan C Martin; Miklos B Halmos; Corrine L S Bart; Gary P Dohanich Journal: Horm Behav Date: 2013-02-26 Impact factor: 3.587