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Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive
Silvia Squillace1,2, Michael L Niehoff2,3, Timothy M Doyle1,2
1Department of Pharmacology and Physiology, and.
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.
Insights
Chemotherapy can cause cognitive impairment by increasing sphingosine-1-phosphate (S1P). Blocking the S1P receptor 1 (S1PR1) pathway may offer a new treatment for cancer-related cognitive impairment (CRCI).
Area of Science:
- Neuroscience
- Oncology
- Pharmacology
Background:
- Cancer-related cognitive impairment (CRCI) affects over 50% of survivors, with unknown mechanisms and no approved treatments.
- Chemotherapy-induced neurotoxicity is a significant concern for cancer patient quality of life.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying CRCI.
- To identify potential therapeutic targets for mitigating chemotherapy-induced cognitive deficits.
Main Methods:
- Sphingolipidomic analysis in mouse prefrontal cortex and hippocampus.
- Biochemical assays to assess mitochondrial function and inflammasome activation.
- Pharmacological inhibition and genetic deletion of S1P receptor 1 (S1PR1) in vivo.
- Computational modeling to investigate cisplatin-induced S1P production.
Main Results:
- Cisplatin treatment increased sphingosine-1-phosphate (S1P) levels, leading to cognitive impairment, mitochondrial dysfunction, and inflammasome activation.
- Administration of S1PR1 antagonists (FTY720, ozanimod) attenuated cognitive deficits.
- Astrocyte-specific S1PR1 deletion highlighted the role of astrocytic S1PR1 in mediating FTY720's effects.
- Cisplatin-induced S1P production was linked to Toll-like receptor 4 (TLR4) activation.
Conclusions:
- The sphingosine-1-phosphate (S1P)/S1P receptor 1 (S1PR1) axis is a key mediator of chemotherapy-induced cognitive impairment.
- S1PR1 antagonism represents a promising therapeutic strategy for CRCI with potential for rapid clinical translation.
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