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

前列腺癌大鼠模型中治疗引起的认知障碍

• 批准号: 10766874
• 负责人: David A Morilak
• 金额: $ 41.15万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10766874
• 关键词: Address; Adverse effects; Affect; Androgens; Antidepressive Agents; Attention; Autoimmune; Brain; Brain Neoplasms; Cancer Patient; Castrate sensitive prostate cancer; Castration; Cells; Chemicals; Citalopram; Cognition; Cognitive; Endocrine; Family; Functional disorder; Goals; Growth; Hippocampus; Impaired cognition; Impairment; Implant; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Intervention; JAK2 gene; Label; Location; Malignant Neoplasms; Malignant neoplasm of prostate; Medial; Mediating; Mediator; Memory impairment; Mental Depression; Metabolic Brain Diseases; Metastatic malignant neoplasm to brain; Modeling; Monitor; Neurons; Neurophysiology - biologic function; Neuroprotective Agents; Nicotinamide adenine dinucleotide; Ondansetron; Oxidative Stress; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Physical therapy; Prefrontal Cortex; Process; Prostate Cancer therapy; Prostatic Neoplasms; Quality of life; Rattus; Reporting; Research; Role; Selective Serotonin Reuptake Inhibitor; Serotonin Receptors 5-HT-3; Signal Transduction; Sprague-Dawley Rats; Structure; Survivors; Testing; Therapeutic Effect; Time; Translations; Visuospatial; Work; androgen deprivation therapy; antagonist; anti-cancer; brain tissue; carcinogenesis; cognitive change; cognitive performance; dementia risk; drug candidate; enzalutamide; executive function; improved; knock-down; male; neural; neural circuit; neuroimaging; neuroinflammation; neuromechanism; neuronal circuitry; neurovascular; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; prevent; prostate cancer cell; prostate cancer model; prostate cancer survivors; receptor; response; reuptake; therapeutic candidate; therapeutic evaluation; therapeutic target; tumor progression

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.

雄激素剥夺疗法（ADT）是前列腺癌治疗的主要手段。然而，ADT具有不利的 影响，包括损害幸存者生活质量的认知障碍，并增加 痴呆神经影像学研究显示海马体（Hipp）的结构和功能缺陷， 调节空间认知，以及调节执行功能的内侧前额叶皮层（mPFC）， 在ADT之后受损。在以前的研究中，我们使用物理去势大鼠作为ADT模型， 在ADT患者中观察到重复的视觉空间和执行缺陷。此外，我们发现沃替西汀， 抗抑郁药，改善抑郁症的认知障碍，减轻ADT的影响。以识别 ADT和沃替西汀的作用机制独立于癌症本身的混杂影响， 我们在健康的无癌Sprague-Dawley大鼠中进行了先前的研究。然而，癌症可以影响 大脑间接地，例如，神经炎症。因此，为了使这项工作更有意义，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。邓宁 将R-3327-G大鼠前列腺癌细胞植入哥本哈根大鼠的侧腹， 细胞是同源的。这将使我们能够诱发癌症并维持大鼠足够的时间进行研究 ADT和新型治疗干预对认知和神经功能的影响机制 mPFC和Hipp的结构和功能。我们将监测肿瘤进展，以确保这种干预措施 不会促进癌症生长或干扰ADT的抗癌功效。这些目标将在 3个具体目标：目标1将评估单独的前列腺癌对认知、IL-6神经炎症和 mPFC和Hipp中的神经元回路功能和结构。我们关注IL-6是因为它在 这种炎症介质在前列腺癌的病理生理学，并在损害神经功能， 通过氧化应激的认知。目的2将通过化学去势与去甲肾上腺素测试ADT对认知的影响， IL-6神经炎症、神经回路功能、mPFC和Hipp中的神经元结构和前列腺肿瘤 进展我们将测试JAK 2（IL-6活性的主要介质）在ADT诱导的认知功能障碍中的作用。 通过敲低mPFC和Hipp中的JAK 2来损害。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，我们将剖析沃替西汀作用的药理学机制， 测试抗抑郁药西酞普兰，一种缺乏其他受体活性的血清素再摄取抑制剂， 昂丹司琼，一种缺乏再摄取阻断的5-HT 3受体拮抗剂。两人都准备好了。然后我们将 测试一种新的神经保护药物P7 C3-A20，它可以提高NAO+水平，防止氧化应激， 由IL-6刺激的JAK 2信号产生。总之，本项目将阐明ADT损害 认知，确定潜在的治疗靶点，并建立哥本哈根大鼠模型作为研究平台 潜在的治疗认知障碍，挑战前列腺癌幸存者的生活质量。