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Targeting S1PR1 in the Central Nervous System Attenuates Chemotherapy-Induced Cognitive Impairment
Silvia Squillace1,2, Michael L. Niehoff2,3, Timothy M. Doyle1,2, Michael Green2,4, Emanuela Esposito5, Salvatore Cuzzocrea5, Christopher K. Arnatt2,4, Sarah Spiegel6, Susan A. Farr2,3, and Daniela Salvemini1,21Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
2The Institute for Translational Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
3Department of Internal Medicine-Geriatrics, Saint Louis School of Medicine, St. Louis, Missouri, USA.
4Department of Chemistry, Saint Louis University, St. Louis, Missouri, USA.
5Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy.
6Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, and the Massey Cancer Center, Richmond, Virginia, USA.
Background: Chemotherapy-induced cognitive impairment (CICI) affects more than 50% of patients during or after completion of chemotherapy. Patients report subtle to moderate deficits in processing speed, memory, executive functioning, and attention that persist for several months. Mitochondrial dysfunction and neuroinflammation in the central nervous system (CNS) are thought to drive CICI. However, the molecular mechanisms underlying this major neurotoxicity are still mostly elusive, and there are no FDA-approved interventions. Cisplatin and paclitaxel are chemotherapeutics widely used for the treatment of several types of cancer (e.g., breast, colon, ovarian and non-small cell lung) and are known to cause cognitive impairment. Mounting evidence from our lab and others implicates the bioactive sphingolipid, sphingosine-1-phosphate (S1P), in neuroinflammatory processes associated with CNS disorders.
Aims: Here we investigated alterations of S1P signaling at sphingosine-1-phosphate receptor 1 (S1PR1) and downstream molecular pathways in the CNS following chemotherapy, as well as the effects of S1PR1 antagonists on cognitive functions.
Results: Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus (key cognitive areas), revealed that cisplatin and paclitaxel increased the levels of S1P and led to the development of cognitive impairment. These effects were associated with mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes, and increased IL-1β formation. Blocking S1PR1 signaling with the FDA-approved functional antagonist FTY720 (fingolimod), attenuated neuroinflammation, mitochondrial dysfunction and the resulting cognitive impairment. Similar results were obtained with ozanimod, another FDA-approved S1PR1 antagonist with improved efficacy and selectivity. Interestingly, mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, identifying astrocytes as a primary cellular target for S1PR1 antagonism in CICI. Further pharmacological and genetic investigations, coupled with computational modeling studies, provided evidence that activation of the toll-like receptor 4 (TLR4) in the brain is the linchpin in chemotherapy-induced S1P formation, S1P-mediated S1PR1 activation, and cognitive deficits.
Conclusions: These findings established for the first time S1PR1 as a therapeutic target in CICI and could expedite proof-of-concept clinical studies with FTY720 and/or ozanimod as an adjunct to chemotherapy.
This research was funded by the National Institute of Health Grant R01CA261979 (NIH) to Daniela Salvemini in Saint Louis University. All authors claim there are no conflicts.