# A3AR agonists as a novel approach to mitigate chemotherapy induced neurotoxicity

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2021 · $565,356

## Abstract

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...

## Key facts

- **NIH application ID:** 10225344
- **Project number:** 5R01CA230512-04
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Robert Dantzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $565,356
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225344

## Citation

> US National Institutes of Health, RePORTER application 10225344, A3AR agonists as a novel approach to mitigate chemotherapy induced neurotoxicity (5R01CA230512-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10225344. Licensed CC0.

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