A3AR agonists as a novel approach to mitigate chemotherapy induced neurotoxicity

A3AR 激动剂作为减轻化疗引起的神经毒性的新方法

• 批准号: 10460227
• 负责人: DANIELA SALVEMINI
• 金额: $ 52.98万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460227
• 关键词: Address; Adenosine; Adenosine A3 Receptor; Adenosine Kinase; Adult; Affect; Agonist; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Attenuated; Automobile Driving; Behavioral Assay; Biological Assay; Brain; Cisplatin; Clinic; Clinical Trials; Data; Development; Diagnosis; Dose; Doxorubicin; Enzymes; Event; FDA approved; Hippocampus (Brain); Homeostasis; Impaired cognition; Inflammasome; Inflammatory; Interdisciplinary Study; Interleukin-1; Interleukin-10; Knockout Mice; Lead; Link; Malignant Neoplasms; Mediator of activation protein; Medical; Metabolic; Metabolism; Molecular; Morphology; Motor Activity; Neurocognitive; Neuroglia; Neurons; Oral; Parahippocampal Gyrus; Patients; Pharmacology; Prefrontal Cortex; Preventive; Process; Public Health; Purine Nucleosides; Purinergic P1 Receptors; Receptor Signaling; Regulation; Research; Role; Safety; Serious Adverse Event; Signal Pathway; Signal Transduction; Specificity; Stress; Testing; Therapeutic; Therapeutic Intervention; Translations; Treatment Protocols; Vertebral column; adenosine receptor activation; adverse drug reaction; antagonist; anti-cancer; base; chemobrain; chemotherapy; clinical translation; cognitive function; curative treatments; cytokine; density; dentate gyrus; extracellular; genetic approach; gray matter; insight; kinase inhibitor; metabolomics; mitochondrial dysfunction; mouse model; neuroinflammation; neuron loss; neurotoxicity; new therapeutic target; novel strategies; novel therapeutic intervention; preservation; prevent; preventive intervention; protective effect; receptor; response; subventricular zone; time use; tumor; white matter

Cognitive impairment (chemobrain) is a common neurotoxicity associated with chemotherapy treatment that is estimated to affect >50% of patients.1 However, little is known about the mechanisms underlying CICI, and there have been no FDA-approved preventive or curative interventions. It is therefore imperative that we understand the underlying causes of this serious adverse drug reaction and identify novel therapeutic approaches with the potential for rapid translation to the clinic. Our preliminary data identify a key mechanism driving CICI based on CNS alterations of adenosine-dependent metabolic regulation and a novel target for therapeutic intervention - the A3 adenosine receptor (AR) subtype (A3AR). Therefore, our proposal directly responds to PAR-16-275: Serious Adverse Drug Reaction Research. Extracellular adenosine and its signaling at ARs are regulated by ectonucleotidases and adenosine kinase (ADK). Our preliminary results in mouse models of chemotherapy (cisplatin and doxorubicin)-induced cognitive impairment (CICI) reveal that chemotherapy altered the expression of these enzymes in centers of cognitive function, including the prefrontal cortex (PFC) and hippocampus, and produced morphological abnormalities in the brain (e.g., in white matter organization, dendritic arborization and spine density). Mechanistically, we found that chemotherapy led to mitochondrial dysfunction, oxidative and nitrative stress (nitroxidative stress) and neuroinflammation in CNS. Pilot data suggest that chemotherapy engaged the NLRP3 inflammasome, which is critical in IL1β formation.2 Noteworthy, supplementing adenosine signaling with highly selective, A3AR agonists significantly attenuated CICI without any loss in locomotor activity. This is highly exciting since A3AR agonists are already in advanced clinical trials as anticancer agents with a good safety profile. The mechanisms underpinning the beneficial effects of A3AR agonists are not known. We hypothesize that: chemotherapy disrupts adenosine homeostasis leading to mitochondrial dysfunction and NLRP3- driven neuroinflammation that culminate in cognitive impairment; supplementing adenosine signaling with selective A3AR agonists provides an effective approach for the management of CICI. This proposal uses a multidisciplinary research plan to explore the applicability of A3AR agonists in CICI while investigating underlying protective mechanism(s). Two Specific Aims will test our hypothesis. In Aim 1, we will test the hypothesis that chemotherapy causes the dysregulation of adenosine metabolism and loss of adenosine signaling at A3AR leading to CICI. In Aim 2, we will investigate the mode of action underlying the beneficial effects of A3AR agonists in preserving cognitive function. Our results are anticipated to provide new molecular insights that will advance our understanding of how CICI develops by establishing the specific role of the adenosine-A3AR axis. These studies are predicted to lead to expedited “proof of concept” studies opening the door to a new translational effort in the treatment of CICI to fulfill this highly unmet medical need.

认知障碍（化疗脑）是与化疗相关的常见神经毒性 据估计，这会影响超过 50% 的患者。1 然而，人们对 CICI 的潜在机制知之甚少， 目前尚无 FDA 批准的预防或治疗干预措施。因此，我们当务之急是 了解这种严重药物不良反应的根本原因并确定新的治疗方法 具有快速转化为临床潜力的方法。我们的初步数据确定了一个关键机制 基于中枢神经系统腺苷依赖性代谢调节的改变和新靶点驱动 CICI 治疗干预 - A3 腺苷受体 (AR) 亚型 (A3AR)。因此，我们的建议直接 响应 PAR-16-275：严重药物不良反应研究。 胞外腺苷及其在 AR 上的信号传导受核酸外切酶和腺苷激酶的调节 （ADK）。我们在化疗（顺铂和阿霉素）诱导认知的小鼠模型中的初步结果 损伤（CICI）表明化疗改变了认知中心这些酶的表达 功能，包括前额皮质（PFC）和海马体，并产生形态异常 大脑（例如，白质组织、树突分枝和脊柱密度）。从机械上来说，我们 发现化疗导致线粒体功能障碍、氧化和硝化应激（硝基氧化应激） 和中枢神经系统的神经炎症。试验数据表明化疗参与了 NLRP3 炎性体， 这对于 IL1β 的形成至关重要。2 值得注意的是，用高选择性 A3AR 补充腺苷信号传导 激动剂显着减弱 CICI，但运动活性没有任何损失。自从 A3AR 以来，这非常令人兴奋 激动剂作为具有良好安全性的抗癌药物已进入高级临床试验。 A3AR 激动剂有益作用的机制尚不清楚。我们假设 认为：化疗破坏腺苷稳态，导致线粒体功能障碍和 NLRP3- 驱动神经炎症，最终导致认知障碍；补充腺苷信号传导 选择性 A3AR 激动剂为 CICI 的治疗提供了有效的方法。这个提议 在调查的同时，采用多学科研究计划探索 A3AR 激动剂在 CICI 中的适用性 潜在的保护机制。两个具体目标将检验我们的假设。在目标 1 中，我们将测试 假设化疗导致腺苷代谢失调和腺苷损失 A3AR 处的信号传导至 CICI。在目标 2 中，我们将研究有益的行动模式 A3AR 激动剂在保护认知功能中的作用。我们的结果预计将提供新的分子 通过确立 CICI 的具体角色，我们将加深对 CICI 如何发展的理解。 腺苷-A3AR 轴。预计这些研究将导致加速“概念验证”研究，从而开启 CICI 治疗的新转化努力的大门，以满足这一高度未满足的医疗需求。

项目成果

Editorial: Small molecules and biologics for future purinergic therapeutics.

社论：未来嘌呤能疗法的小分子和生物制剂。

• DOI: 10.1007/s11302-023-09964-9
• 发表时间: 2023
• 期刊: Purinergic signalling
• 影响因子: 3.5
• 作者: Jacobson,KennethA;Salvemini,Daniela
• 通讯作者: Salvemini,Daniela

Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment.

中枢神经系统中的鞘氨氨酸-1-磷酸受体1激活驱动顺铂诱导的认知障碍。

• DOI: 10.1172/jci157738
• 发表时间: 2022-09-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Squillace, Silvia;Niehoff, Michael L.;Doyle, Timothy M.;Green, Michael;Esposito, Emanuela;Cuzzocrea, Salvatore;Arnatt, Christopher K.;Spiegel, Sarah;Farr, Susan A.;Salvemini, Daniela
• 通讯作者: Salvemini, Daniela

Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions.

• DOI: 10.1016/j.tips.2022.05.004
• 发表时间: 2022-09
• 期刊: TRENDS IN PHARMACOLOGICAL SCIENCES
• 影响因子: 13.8
• 作者: Squillace, Silvia;Salvemini, Daniela
• 通讯作者: Salvemini, Daniela