Effects of vortioxetine on cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment

Androgen deprivation therapy (ADT) is a foundational treatment for advanced prostate cancer, but more than half of patients treated with ADT experience debilitating cognitive impairments in domains known to be mediated by the hippocampus and prefrontal cortex. Unfortunately, there are few treatments to prevent or reverse these changes from occuring, thus severely decreasing quality of life in patients. To begin studying these deficits, surgically castrated rats were used to model cognitive impairments associated with the spatial learning and executive function, then chronically treated with the multimodal antidepressant, vortioxetine, as in intervention to reverse these impairments. Vortioxetine effectively rescued cognitive deficits in after surgical castration, and increased resposivity in in vivo evoked local field potentials within the Schaeffer Collateral-CA1 pathway and the ventral hippocampus-mPFC pathway. Surgical castration also induced significant changes in gene expression within the mPFC and the dorsal hippcampus, whereas vortioxetine had little effect. Pathway analysis revealed that androgen depletion altered pathways related to synaptic plasticity. These results suggest that these two regions may be vulnerable to ADT, contributing to cognitive impairment in prostate cancer patients. Further, vortioxetine may be a candidate to improve cognition in patients that experience cognitive decline after androgen deprivation therapy for prostate cancer and may do so by restoring molecular and circuit level plasticity-related mechanisms compromised by ADT. Whole genome microarray in tissue collected from the dorsal hippocampus (dHipp) or medial prefrontal cortex (mPFC) of surgically castrated rats after chronic dietary drug treatment with the antidepressant vortioxetine (40 mg/kg/day at free-feeding or 28 mg/kg/day at food restriction for 17 days), compared to sham controls and animals receiving control diet (n=2-6/group, 4 groups total x two brain regions)

雄激素剥夺疗法（Androgen deprivation therapy, ADT）是晚期前列腺癌的基础治疗方案，但超过半数接受ADT治疗的患者会出现由海马体与前额叶皮层介导的认知领域损伤，且症状严重影响生活质量。遗憾的是，目前尚无有效手段可预防或逆转此类认知改变，这极大降低了患者的生存质量。为研究此类认知缺陷，本研究采用手术去势大鼠构建与空间学习、执行功能相关的认知障碍模型，并以多模式抗抑郁药沃替西汀（vortioxetine）进行长期给药干预，以期逆转此类认知损伤。结果显示，沃替西汀可有效改善手术去势大鼠的认知缺陷，并提升施弗侧支-CA1通路及腹侧海马-内侧前额叶皮层通路的在体诱发电位响应性。手术去势还可诱导内侧前额叶皮层与背侧海马出现显著的基因表达变化，而沃替西汀对此类基因表达改变的影响较小。通路分析表明，雄激素剥夺会改变与突触可塑性相关的信号通路。上述结果提示，这两个脑区可能对ADT存在易感性，进而导致前列腺癌患者出现认知障碍。此外，沃替西汀或可作为改善前列腺癌患者ADT后认知衰退的潜在候选药物，其作用机制可能是修复ADT所损伤的分子与环路层面的突触可塑性相关机制。本研究对接受17天沃替西汀长期饮食给药（自由进食组每日给药40mg/kg，食物限制组每日给药28mg/kg）的手术去势大鼠的背侧海马（dHipp）及内侧前额叶皮层（mPFC）组织开展全基因组芯片检测，并以假手术对照组及普通饮食给药组作为对照（每组样本量n=2-6，共4组，涵盖2个脑区）。