Targeting A3 Adenosine Receptor (A3AR) Attenuates Paclitaxel-induced Cognitive Impairment

Abstract

<b>Abstract ID 20618</b> <b>Poster Board 400</b> Paclitaxel, standard-of-care first-line chemotherapy for epithelial ovarian cancer and triple negative breast cancer, was shown to impair learning and memory functions in &gt;50% of cancer survivors. Underpinning mechanisms of this major neurotoxicity are still mostly unknown, and there are no FDA-approved interventions. We developed a mouse model of paclitaxel-induced cognitive impairment whose cumulative dose is comparable to the total dose per cycle used in breast cancer patients. Paclitaxel-treated mice showed significant cognitive impairment in different hippocampal tests (T-maze, Novel Object Place Recognition test, NOPRT). Learning and memory functions were improved by co-administration of the selective A3 adenosine receptor (A3AR) agonist, MRS5980, without adversely affecting anxiety-like behavior and locomotor activity. Noteworthy, A3AR agonists possess anticancer activity and enhance the antitumor effects of paclitaxel. Moreover, we previously shown that targeting A3AR successfully improved neurocognitive functions after cisplatin, another widely used chemotherapeutic. Our previous studies in chemotherapy-induced peripheral neuropathy showed that Paclitaxel treatment caused a strong neuroinflammation in the central nervous system through the dysregulation of adenosine signaling. Adenosine kinase (ADK) is a key regulator of the adenosine signaling at its receptors. Here we demonstrated that the ADK inhibitor, ABT-702, attenuated paclitaxel-induced cognitive dysfunctions in mice. Mechanistically, these data suggest that paclitaxel-induced ADK dysregulation leads to a reduction of adenosine signaling at the A3AR and it is functionally linked to the development of cognitive dysfunctions. Collectively, the A3AR is emerging as an exciting novel approach in the treatment of a major chemotherapy-induced neurotoxicity. <b>Keywords:</b> Chemotherapy-induced cognitive impairment; A3 Adenosine receptor (A3AR); hippocampus; Paclitaxel; MRS5980. <b>Fundings:</b> This study was funded by the National Institutes of Health Grant RO1CA230512 (NIH) to Daniela Salvemini. Daniela Salvemini is a co-founder of BioIntervene Inc. All other authors claim no conflicts of interest.