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 NLRP3driven 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.