Therapy-induced cognitive impairment in a rat model of prostate cancer

雄激素剥夺疗法(ADT)是前列腺癌治疗的主要手段。然而，ADT有不利的 影响，包括影响幸存者生活质量的认知障碍，并增加 痴呆症。神经成像研究显示，海马区(HIPP)存在结构和功能缺陷， 调节空间认知，以及调节执行功能的内侧前额叶皮质(MPFC)，两者都 它们在ADT之后会受到损害。在之前的研究中，我们使用物理去势的大鼠作为ADT的模型，我们 ADT患者出现重复的视觉空间和执行缺陷。此外，我们还展示了伏替西汀，一种新的 抗抑郁药可改善抑郁症患者的认知障碍，减轻ADT的影响。要确定 ADT和伏替西汀的潜在作用机制独立于癌症本身的混杂影响， 我们之前的研究是在健康的无癌Spraogue-Dawley大鼠身上进行的。然而，癌症会影响 大脑间接的，例如，通过神经炎。因此，为了使这项工作更具翻译相关性，我们现在将 介绍癌症病理生理学，使用最适合这些研究的大鼠前列腺癌模型。催款 将R-3327-G大鼠前列腺癌细胞移植到哥本哈根大鼠的侧腹，用Dunning 细胞是同基因的。这将使我们能够诱发癌症，并使大鼠有足够的时间进行研究 ADT和新的治疗干预措施对认知和神经的潜在作用机制 MPFC和HIPP的结构和功能。我们将监测肿瘤的进展，以确保这种干预措施 不促进肿瘤生长或干扰ADT的抗癌效果。这些目标将在#年实现。 3个具体目标：目标1将评估单独前列腺癌对认知、IL-6神经炎症和 MPFC和HIPP中神经元回路的功能和结构。我们关注IL-6是因为IL-6的重要作用 这种炎性介质在前列腺癌的病理生理和神经功能损害中的作用 通过氧化应激进行认知。目的2通过化学去势来测试ADT对认知功能的影响。 IL-6神经炎症、神经回路功能、mPFC和HIPP的神经元结构与前列腺癌 进步。我们将测试JAK2在ADT诱导的认知过程中的作用，JAK2是IL-6活性的主要中介 在mPFC和HIPP中通过击倒JAK2造成的损伤。在目标3中，我们将测试3种药物的治疗潜力 候选人：A)首先，我们将剖析(S)伏替西汀作用的药理机制，通过 测试抗抑郁剂西酞普兰，一种缺乏其他受体活性的5-羟色胺再摄取抑制剂，以及 恩丹西酮，一种5-HT3受体拮抗剂，缺乏再摄取阻断。两者都已准备好翻译。到时候我们会的 测试一种新的神经保护药物P7C3-A20，它可以提高NAO+水平，防止氧化应激等 由IL-6刺激的JAK2信号产生。总而言之，这个项目将阐明ADT损害的机制 认知，确定潜在的治疗靶点，建立哥本哈根大鼠模型作为研究的平台 对前列腺癌幸存者生活质量构成挑战的认知障碍的可能治疗方法。

Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment. However, ADT has adverse effects, including cognitive impairment that compromises quality of life for survivors, and increases the risk of dementia. Neuroimaging studies have shown structural and functional deficits in hippocampus (Hipp), which mediates spatial cognition, and medial prefrontal cortex (mPFC), which mediates executive function, both of which are compromised after ADT. In previous studies using physically castrated rats as a model of ADT, we replicated visuospatial and executive deficits seen in ADT patients. Further, we showed that vortioxetine, a novel antidepressant that improves cognitive impairment in depression, mitigated the effects of ADT. To identify mechanisms underlying effects of ADT and vortioxetine independent of confounding influences of cancer itself, we conducted our prior studies in healthy cancer-free Sprague-Dawley rats. However, cancer can affect the brain indirectly, e.g., by neuroinflammation. Thus, to make this work more translationally relevant, we will now introduce cancer pathophysiology, using a rat prostate cancer model most suitable for these studies. Dunning R-3327-G rat prostate cancer cells will be implanted into the flank of Copenhagen rats, with which the Dunning cells are syngeneic. This will allow us to induce cancer and maintain the rats for a sufficient time to study mechanisms underlying effects of both ADT and novel therapeutic interventions on cognition, and on neural structure and function in the mPFC and Hipp. We will monitor tumor progression to ensure that such interventions do not promote cancer growth or interfere with anti-cancer efficacy of ADT. These goals will be accomplished in 3 specific aims: Aim 1 will assess effects of prostate cancer alone on cognition, IL-6 neuroinflammation, and neuronal circuit function and structure in the mPFC and Hipp. We focus on IL-6 because of the prominent role of this inflammatory mediator in prostate cancer pathophysiology, and in compromising neural function and cognition via oxidative stress. Aim 2 will test effects of ADT by chemical castration with degarelix on cognition, IL-6 neuroinflammation, neural circuit function, neuronal structure in mPFC and Hipp, and prostate tumor progression. We will test the role of JAK2, the primary mediator of IL-6 activity, in ADT-induced cognitive impairment by knocking down JAK2 in mPFC and Hipp. In Aim 3, we will test the therapeutic potential of 3 drug candidates: a) first, we will dissect the pharmacological mechanism(s) responsible for vortioxetine's effect, by testing the antidepressant citalopram , a serotonin reuptake inhibitor that lacks other receptor activity, and ondansetron, a 5-HT3 receptor antagonist that lacks reuptake blockade. Both are translation-ready. We will then test a new neuroprotective drug, P7C3-A20 that enhances NAO+ levels, preventing oxidative stress such as that produced by IL-6-stimulated JAK2 signaling. In sum, this project will elucidate mechanisms by which ADT impairs cognition, identify potential therapeutic targets, and establish the Copenhagen rat model as a platform to study potential treatments for the cognitive impairment that challenges quality of life for prostate cancer survivors.