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Fingolimod Alleviates Cognitive Deficit in Type 2 Diabetes by Promoting Microglial M2 Polarization via the pSTAT3-jmjd3 Axis

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Abstract

Sphingosine receptors (S1PRs) are implicated in the progression of neurodegenerative diseases and metabolic disorders like obesity and type 2 diabetes (T2D). The link between S1PRs and cognition in type 2 diabetes, as well as the mechanisms that underpin it, are yet unknown. Neuroinflammation is the common pathology shared among T2D and cognitive impairment. However, the interplay between the M1 and M2 polarization state of microglia, a primary driver of neuroinflammation, could be the driving factor for impaired learning and memory in diabetes. In the present study, we investigated the effects of fingolimod (S1PR1 modulator) on cognition in high-fat diet and streptozotocin-induced diabetic mice. We further assessed the potential pathways linking microglial polarization and cognition in T2D. Fingolimod (0.5 mg/kg and 1 mg/kg) improved M2 polarization and synaptic plasticity while ameliorating cognitive decline and neuroinflammation. Sphingolipid dysregulation was mimicked in vitro using palmitate in BV2 cells, followed by conditioned media exposure to Neuro2A cells. Mechanistically, type 2 diabetes induced microglial activation, priming microglia towards the M1 phenotype. In the hippocampus and cortex of type 2 diabetic mice, there was a substantial drop in pSTAT3, which was reversed by fingolimod. This protective effect of fingolimod on microglial M2 polarization was primarily suppressed by selective jmjd3 blockade in vitro using GSK-J4, revealing that jmjd3 was involved downstream of STAT3 in the fingolimod-enabled shift of microglia from M1 to M2 polarization state. This study suggested that fingolimod might effectively improve cognition in type 2 diabetes by promoting M2 polarization.

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Data Availability

The data that support the findings of this study is available in the manuscript as well as supplementary information file. In addition, data can be available from the corresponding author upon reasonable request.

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Acknowledgements

All authors are thankful to the Department of Pharmacology and Toxicology, NIPER Hyderabad and Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India.

Funding

This work is supported by National Institute of Pharmaceutical Education and Research, Hyderabad and Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India.

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  1. Valencia Fernandes and Kumari Preeti share equal contribution.

Authors and Affiliations

  1. Molecular & Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana, 500037, Hyderabad, India

    Anika Sood, Valencia Fernandes, Kumari Preeti, Mayuri Khot, Dharmendra Kumar Khatri & Shashi Bala Singh

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All authors take responsibility for the integrity and accuracy of this manuscript. Anika Sood, Dharmendra Kumar Khatri, and Shashi Bala Singh contributed to the conceptualization designing and execution of the research; Anika Sood performed studies, evaluated data, and wrote manuscript; Valencia Fernandes, and Kumari Preeti performed studies, evaluated data and reviewed the manuscript; Dharmendra Kumar Khatri, and Shashi Bala Singh reviewed, editied the manuscript, and supervised the research work.

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Sood, A., Fernandes, V., Preeti, K. et al. Fingolimod Alleviates Cognitive Deficit in Type 2 Diabetes by Promoting Microglial M2 Polarization via the pSTAT3-jmjd3 Axis. Mol Neurobiol 60, 901–922 (2023). https://doi.org/10.1007/s12035-022-03120-x

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