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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.

SUBMITTER: Squillace S

PROVIDER: S-EPMC9433103 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Squillace Silvia S Niehoff Michael L ML Doyle Timothy M TM Green Michael M Esposito Emanuela E Cuzzocrea Salvatore S Arnatt Christopher K CK Spiegel Sarah S Farr Susan A SA Salvemini Daniela D

The Journal of clinical investigation 20220901 17

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 dy ...[more]

PMID: 36047496

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Project description:BackgroundEpidemiological studies have indicated that patients with heart failure (HF) who experience cognitive impairment (CI) have a poor prognosis. While poor self-management and compliance are suggested as contributing factors, they do not fully explain the underlying mechanisms of high risk of cardiac events in HF patients with CI. Given the interconnectedness of CI and the autonomic nervous system (ANS), both regulated by the central nervous system, this study investigated the relationship among cognitive function, metabolism in ANS-related brain regions, and major arrhythmic events (MAEs) in patients with HF with reduced ejection fraction (HFrEF).ResultsWe retrospectively enrolled 72 patients with HFrEF who underwent gated myocardial perfusion imaging, heart and brain 18F-FDG positron emission tomography/computed tomography imaging, and cognitive testing. Cognitive function was evaluated using the Mini-Mental State Examination. During the follow-up period, 13 patients (17.8%) experienced MAEs. Patients with MAEs exhibited decreased cognitive function across various domains, including orientation, registration, and language and praxis (all p < 0.05). Patients with CI displayed a prolonged heart rate-corrected QT (QTc) interval and hypometabolism in the left hippocampus and bilateral caudate nuclei (all p < 0.05). Significant correlations were observed between cognitive function, QTc interval, and metabolism in ANS-related brain regions (all p < 0.05). Cox regression model analysis showed that the predictive value of cognitive function is not independent of the QTc interval and there is a significant interaction. The mediation analyses suggested that a prolonged QTc interval resulting from ANS disorder increased risk of MAEs in HFrEF patients with CI. Patients with CI exhibited reduced central autonomic network (CAN) connectivity.ConclusionANS dysfunction, exacerbated by reduced metabolism in ANS-related brain regions and CAN connectivity, contributed to an increased risk of MAEs in HFrEF patients with CI.

Project description:IntroductionCancer-related cognitive impairment (CRCI) can have detrimental effects on quality of life, even among patients with non-central nervous system (CNS) cancers. Several studies have been conducted to explore different markers associated with CRCI to understand its pathobiology. It is proposed that the underlying mechanisms of CRCI are related to a cascade of physiological adaptive events in response to cancer and/or treatment. Hence, peripheral blood would be a logical source to observe and identify these physiological events. This paper outlines the protocol for a scoping review being conducted to summarise the extant literature regarding blood-based biomarkers of CRCI among patients with non-CNS cancer.Methods/analysisMethods will be informed by the updated guidelines of Arksey and O'Malley. The systematic search for literature will include electronic databases, handsearching of key journals and reference lists, forward citation tracking and consultation with content experts. Study selection will be confirmed by duplicate review and calculation of inter-rater reliability. Data to be charted will include study design, sample size, cancer and treatment characteristics, demographic characteristics, cognitive variable/s and biomarkers assessed, associations between cognitive functioning and biomarkers (including statistics used), and rigour in biomarker sample collection and processing. Results will be presented through: (1) a descriptive numerical summary of studies, including a flow diagram based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, (2) a list of blood-based biomarkers associated with CRCI and (3) a narrative overview developed through collaboration among the research team and consultation with content experts.DisseminationThe findings of this review will highlight current directions and gaps in the current body of evidence that may lead to improved rigour in future CRCI investigations. The dissemination of this work will be facilitated through the involvement of clinicians and researchers on the research team, an external consultation process and the presentation of the results through scholarly publication and presentation.

Dataset Information

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

Publications

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

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