Vaiana Alexandra M, Asher Amber M, Tapia Karla, Morilak David A
Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas, USA.
Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, Texas, USA.
Neuroendocrinology. 2024;114(3):279-290. doi: 10.1159/000535365. Epub 2023 Dec 16.
Androgen deprivation therapy (ADT) is a mainstay treatment for prostate cancer, but many patients experience cognitive impairment in domains mediated by the medial prefrontal cortex (mPFC) and hippocampus. Prostate cancer typically occurs in older patients (>65 years). As age is often accompanied by cognitive decline, it may impact the efficacy of any treatment aimed at restoring cognitive impairment induced by ADT. Vortioxetine, a multimodal antidepressant that improves cognition in depression, has been shown to be efficacious in elderly patients. Therefore, vortioxetine may improve cognition in older patients who experience cognitive decline after ADT.
Young (3 months) and middle-aged (13 months) rats were used to investigate the influence of age on treating ADT-induced cognitive decline. As our previous studies used surgical castration, we tested if vortioxetine would reverse cognitive deficits associated with more translationally relevant chemical castration using degarelix. Vortioxetine was given in the diet for 21 days. Animals underwent behavioral testing to assess visuospatial memory mediated by the hippocampus and cognitive flexibility mediated by the mPFC. We also investigated changes in afferent-evoked responses in these regions in middle-aged rats.
Degarelix induced impairments in both visuospatial memory and cognitive flexibility that were reversed by vortioxetine. Vortioxetine also rescued afferent-evoked responses in the mPFC and hippocampus. However, modest age-related reductions in baseline visuospatial memory limited our ability to detect further decreases induced by degarelix in middle-aged rats due to a floor effect.
These results suggest that vortioxetine may be a treatment option for older prostate cancer patients who experience cognitive decline after ADT.
雄激素剥夺疗法（ADT）是前列腺癌的主要治疗方法，但许多患者在内侧前额叶皮质（mPFC）和海马体介导的认知领域出现认知障碍。前列腺癌通常发生在老年患者（>65岁）中。由于年龄常伴有认知能力下降，这可能会影响旨在恢复ADT诱导的认知障碍的任何治疗的疗效。伏硫西汀是一种多模式抗抑郁药，可改善抑郁症患者的认知，已被证明在老年患者中有效。因此，伏硫西汀可能改善ADT后出现认知下降的老年患者的认知。
使用年轻（3个月）和中年（13个月）大鼠研究年龄对治疗ADT诱导的认知下降的影响。由于我们之前的研究使用了手术去势，我们测试了伏硫西汀是否能逆转与更具转化相关性的使用地加瑞克进行化学去势相关的认知缺陷。伏硫西汀在饮食中给予21天。动物接受行为测试，以评估海马体介导的视觉空间记忆和mPFC介导的认知灵活性。我们还研究了中年大鼠这些区域传入诱发反应的变化。
地加瑞克导致视觉空间记忆和认知灵活性受损，伏硫西汀可逆转这些损伤。伏硫西汀还挽救了mPFC和海马体中的传入诱发反应。然而，与年龄相关的基线视觉空间记忆适度下降限制了我们检测中年大鼠中地加瑞克由于地板效应引起的进一步下降的能力。
这些结果表明，伏硫西汀可能是ADT后出现认知下降的老年前列腺癌患者的一种治疗选择。
