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Benserazide, an Inhibitor of Peripheral Kynurenine Metabolism, Attenuates Olanzapine-Induced Weight Gain, Insulin Resistance, and Dyslipidemia in C57Bl/6j Mice

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Abstract

Schizophrenia (Sz) patients, especially treated with atypical antipsychotics, are at high risk of the development of metabolic syndrome that increases morbidity and mortality and impairs compliance with treatment. Mechanism of the high association of metabolic syndrome with the use of atypical antipsychotics is not clear. Literature and our data suggest that chronic inflammation- or stress-induced dysregulation of the peripheral down-stream kynurenine (Kyn) metabolism, shared by both Sz and metabolic syndrome, contributes to the development of metabolic syndrome in Sz patients treated with atypical antipsychotics. Correction of dysregulation of the peripheral down-stream metabolism of Kyn would prevent/treat metabolic syndrome. This is a pre-clinical trial of the effect of benserazide (BRZ), an inhibitor of the key enzymes of Kyn metabolism, on olanzapine-induced mouse model of metabolic syndrome. Olanzapine is one of the most effective atypical antipsychotics but has high potential to induce metabolic syndrome. Olanzapine (4 mg/kg, p.o) and/or BRZ (100 mg/day, p.o.) were administered to 6-week-old C57Bl/6 female mice, 5 days/week, for 10 weeks. The study was approved by the Tufts Medical Center Institutional Animal Care and Use Committee. BRZ attenuated olanzapine-induced excessive weight gain, impairment of glucose tolerance, and elevation of plasma cholesterol and triglycerides. Present results suggest that peripheral down-stream Kyn metabolism is a new target for prevention/treatment of olanzapine-induced metabolic syndrome. BRZ has a high translational potential as medication already approved for human use.

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Abbreviations

3HK:

3-Hydroxykynurenine

ANA:

Anthranilic acid

IDO:

Idoleamone-2,3-dioxygenase 1

KAT:

Kynurenine aminotransferase

KMO:

Kynurenine 3-monooxygenase

Kyn:

Kynurenine

KYNA:

Kynurenic acid

Kynase:

Kynureninase

NAD+:

Nicotinamide adenine dinucleotide.

Sz:

Schizophrenia

TDO:

Tryptophan-2,3-dioxygenase 2

XA:

Xanthurenic acid

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Authors and Affiliations

  1. Psychiatry and Inflammation Program, Department of Psychiatry, Tufts University School of Medicine/Tufts Medical Center, Boston, MA, 02111, USA

    Gregory Oxenkrug & Paul Summergrad

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  1. Gregory Oxenkrug
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  2. Paul Summergrad
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Correspondence to Gregory Oxenkrug.

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Conflict of Interest

The results discussed here are the subject of a pending patent application.

P. Summergrad is a non-promotional speaker for CME outfitters, Inc., and Pharmasquire and receives royalties from Springer, Harvard University Press, and the American Psychiatric Publishing. He is a consultant for Mental Health Data Services, Inc. and Quartet Health, Inc. The other author declares no conflict of interest.

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Oxenkrug, G., Summergrad, P. Benserazide, an Inhibitor of Peripheral Kynurenine Metabolism, Attenuates Olanzapine-Induced Weight Gain, Insulin Resistance, and Dyslipidemia in C57Bl/6j Mice. Mol Neurobiol 57, 135–138 (2020). https://doi.org/10.1007/s12035-019-01763-x

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