Kynurenine monooxygenase blockade reduces endometriosis-like lesions, improves visceral hyperalgia, and rescues mice from a negative behavioural phenotype in experimental endometriosis

Higgins, B.; Simitsidellis, I.; Zheng, X.; Collins, F.; Homer, N.; Denham, S.; Simpson, J.; Millar, M.; Boswell, L.; Lee, H. Y.; Kim, Y. G.; Park, K. H.; Park, L. C.; Sweeney, P. J.; Feraille, G.; Taddei, A.; Chagras, D.; Alvarez, T.; Webster, S. P.; Horne, A. W.; Saunders, P. T.; Mole, D. J.

doi:10.1101/2024.05.13.593856

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bioRxiv · 10.1101/2024.05.13.593856

Kynurenine monooxygenase blockade reduces endometriosis-like lesions, improves visceral hyperalgia, and rescues mice from a negative behavioural phenotype in experimental endometriosis

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Abstract

Endometriosis is a common and debilitating neuro-inflammatory disorder that is associated with chronic pain. Definitive diagnosis is based on the presence of endometrial-like tissue (lesions) in sites outside the uterus. Kynurenine monooxygenase (KMO) is a mitochondrial enzyme of tryptophan metabolism that regulates inflammation and immunity. Here, we show that KMO is expressed in epithelial cells in human endometriosis tissue lesions and in corresponding lesions in a mouse model of endometriosis. In mice, oral treatment with the potent KMO inhibitor KNS898 induced a biochemical state of KMO blockade with accumulation of kynurenine, diversion to kynurenic acid and ablation of 3-hydroxykynurenine production. In the mouse model of endometriosis, KMO inhibition improved histological outcomes and endometriosis pain-like behaviours, even when KNS898 treatment commenced one week after initiation of lesions. Taken together, these results suggest that KMO blockade is a promising new non-hormonal therapeutic modality for endometriosis.

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Higgins, B., Simitsidellis, I., Zheng, X., Collins, F., Homer, N., Denham, S., Simpson, J., Millar, M., Boswell, L., Lee, H. Y., Kim, Y. G., Park, K. H., Park, L. C., Sweeney, P. J., Feraille, G., Taddei, A., Chagras, D., Alvarez, T., Webster, S. P., Horne, A. W., Saunders, P. T., Mole, D. J.. 2024-05-15. Kynurenine monooxygenase blockade reduces endometriosis-like lesions, improves visceral hyperalgia, and rescues mice from a negative behavioural phenotype in experimental endometriosis. https://doi.org/10.1101/2024.05.13.593856

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