Kynurenine monooxygenase blockade reduces endometriosis-like lesions, improves visceral hyperalgesia, 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.
Show 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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