Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment
Silvia Squillace, … , Susan A. Farr, Daniela Salvemini
Silvia Squillace, … , Susan A. Farr, Daniela Salvemini
Published September 1, 2022
Citation Information: J Clin Invest. 2022;132(17):e157738. https://doi.org/10.1172/JCI157738.
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Concise Communication Neuroscience Oncology

Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment

Abstract

Cancer-related cognitive impairment (CRCI) is a major neurotoxicity affecting more than 50% of cancer survivors. The underpinning mechanisms are mostly unknown, and there are no FDA-approved interventions. Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus, key sites of cognitive function, revealed that cisplatin increased levels of the potent signaling molecule sphingosine-1-phosphate (S1P) and led to cognitive impairment. At the biochemical level, S1P induced mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain–containing protein 3 inflammasomes, and increased IL-1β formation. These events were attenuated by systemic administration of the functional S1P receptor 1 (S1PR1) antagonist FTY720, which also attenuated cognitive impairment without adversely affecting locomotor activity. Similar attenuation was observed with ozanimod, another FDA-approved functional S1PR1 antagonist. Mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, implicating involvement of astrocytic S1PR1. Remarkably, our pharmacological and genetic approaches, coupled with computational modeling studies, revealed that cisplatin increased S1P production by activating TLR4. Collectively, our results identify the molecular mechanisms engaged by the S1P/S1PR1 axis in CRCI and establish S1PR1 antagonism as an approach to target CRCI with therapeutics that have fast-track clinical application.

Authors

Silvia Squillace, Michael L. Niehoff, Timothy M. Doyle, Michael Green, Emanuela Esposito, Salvatore Cuzzocrea, Christopher K. Arnatt, Sarah Spiegel, Susan A. Farr, Daniela Salvemini

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Figure 3

TLR4 activation in the CNS was required for cisplatin-induced S1P alterations and cognitive impairment.

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TLR4 activation in the CNS was required for cisplatin-induced S1P altera...
(A and B) In WT mice, cisplatin increased TLR4 expression in both the hippocampus (HC) (A) and PFC (B) (n = 6/group). (C and D) WT, but not Tlr4–/– mice, developed memory and learning deficits in the T-maze (C) and NOPRT (D) following cisplatin. (E and F) Cisplatin did not increase S1P levels in the hippocampus (E) and PFC (F) from Tlr4–/– mice, as determined by LC-ESI-MS/MS (n = 6/group). (G and H) WT mice receiving i.c.v. infusion of the TLR4 antagonist TAK-242 during cisplatin treatment did not develop cognitive deficit in the T-maze (G) and NOPRT (H), confirming the relevance of TLR4 activation in the CNS for the development of cisplatin-induced cognitive impairment (n = 7–8/group). Data are presented as mean ± SEM. *P < 0.05 vs. Veh; †P < 0.05 vs. Cis; by 2-tailed, unpaired Student’s t test (A and B), 2-tailed, 2-way ANOVA with Bonferroni’s test (C–F), or 2-tailed, 1-way ANOVA with Dunnett’s test (G and H).