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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

基本信息

批准号：
10225344
负责人：
Robert Dantzer
金额：
$ 56.54万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225344
关键词：
Address Adenosine Adenosine A3 Receptor Adenosine Kinase Adult Affect Agonist Animals Anti-Inflammatory Agents Antineoplastic Agents Attenuated Automobile Driving Behavioral Assay Bioavailable 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 Structure Testing Therapeutic Therapeutic Intervention Translations Treatment Protocols Vertebral column adenosine receptor activation adverse drug reaction 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

项目摘要

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.

认知损伤（化学脑）是一种常见的与化疗相关的神经毒性