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bioRxiv · 10.1101/2024.05.23.595523

Potential Benefits of Ketone Therapy as a Novel Immunometabolic Treatment for Schizophrenia

Huizer, K.·Soni, S.·Schmidt, M. A.·Cakici, N.·de Haan, L.·Dyck, J. R. B.·van Beveren, N. J. M.
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Abstract

RationaleCurrent treatment options for patients with schizophrenia-spectrum disorders (SSD) remain unsatisfactory, leaving patients with persistent negative and cognitive symptoms and metabolic side effects. Therapeutic ketosis was recently hypothesized to target the bio-energetic pathophysiology of SSD. However, neuro-inflammation plays an important role in the pathobiology of SSD as well. Ideally, novel treatments would target both the bio-energetic, and the inflammatory aspects of SSD. In this study, we aimed to investigate the effects of ketone bodies on neuro-inflammation in an acute inflammation mouse model. Methods8-week-old male C57BL/6 N mice (n=11) were treated with either ketone ester (KE) or vehicle for 3 days. On day 3, a single intraperitoneal injection of lipopolysaccharide (LPS) or phosphate buffered saline (PBS) was administered. Mice were euthanized 24 h after LPS/PBS injection. Whole brain gene expression analysis using RT-PCR was done for Tnf-a, Il-6 and Il-1b. ResultsLPS caused a potent transcriptional upregulation of Tnf-a, Il-6 and Il-1b in the vehicle-treated mouse brain compared to PBS-injected controls. KE strongly and significantly attenuated the increased transcription of pro-inflammatory cytokines (Tnf-a, Il-6 and Il-1b) in the brain upon LPS injection compared to vehicle. ConclusionsKE potently dampened neuro-inflammation in this acute inflammation mouse model. Ketone therapy holds great promise as a treatment for SSD patients by simultaneously targeting two main pathophysiological disease pathways. We encourage more research into the immunometabolic potential of therapeutic ketosis in SSD. HighlightsO_LIA brain bio-energetic deficit and neuro-inflammation are involved in schizophrenia C_LIO_LIKetone therapy is being investigated as a bio-energetic treatment of schizophrenia C_LIO_LIKetone ester inhibits neuro-inflammation in an acute inflammation mouse mode C_LIO_LITherapeutic ketosis could target both pathophysiological pathways in SSD C_LIO_LIThe Immunometabolic potential of ketone therapy for SSD warrants further attention C_LI

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Huizer, K., Soni, S., Schmidt, M. A., Cakici, N., de Haan, L., Dyck, J. R. B., van Beveren, N. J. M.. 2024-05-23. Potential Benefits of Ketone Therapy as a Novel Immunometabolic Treatment for Schizophrenia. https://doi.org/10.1101/2024.05.23.595523

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