Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment
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 f...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI157738 |
| _version_ | 1797634567491813376 |
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| author | Silvia Squillace Michael L. Niehoff Timothy M. Doyle Michael Green Emanuela Esposito Salvatore Cuzzocrea Christopher K. Arnatt Sarah Spiegel Susan A. Farr Daniela Salvemini |
| author_facet | Silvia Squillace Michael L. Niehoff Timothy M. Doyle Michael Green Emanuela Esposito Salvatore Cuzzocrea Christopher K. Arnatt Sarah Spiegel Susan A. Farr Daniela Salvemini |
| author_sort | Silvia Squillace |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:28Z |
| format | Article |
| id | doaj.art-1997f1a57945403ea08d3af60277e069 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:28Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-1997f1a57945403ea08d3af60277e0692023-11-07T16:19:17ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-09-0113217Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairmentSilvia SquillaceMichael L. NiehoffTimothy M. DoyleMichael GreenEmanuela EspositoSalvatore CuzzocreaChristopher K. ArnattSarah SpiegelSusan A. FarrDaniela SalveminiCancer-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.https://doi.org/10.1172/JCI157738NeuroscienceOncology |
| spellingShingle | Silvia Squillace Michael L. Niehoff Timothy M. Doyle Michael Green Emanuela Esposito Salvatore Cuzzocrea Christopher K. Arnatt Sarah Spiegel Susan A. Farr Daniela Salvemini Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment The Journal of Clinical Investigation Neuroscience Oncology |
| title | Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment |
| title_full | Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment |
| title_fullStr | Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment |
| title_full_unstemmed | Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment |
| title_short | Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment |
| title_sort | sphingosine 1 phosphate receptor 1 activation in the central nervous system drives cisplatin induced cognitive impairment |
| topic | Neuroscience Oncology |
| url | https://doi.org/10.1172/JCI157738 |
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