Kynurenine Monooxygenase Inhibition Reduces Endometriosis Lesions and Improves Pain Behaviors in a Mouse Model

Core Concepts

Inhibition of the enzyme kynurenine monooxygenase (KMO) reduces the development of endometriosis lesions and improves pain-related behaviors in a mouse model of the disease.

Abstract

This study investigated the potential of targeting the enzyme kynurenine monooxygenase (KMO) as a novel non-hormonal therapy for endometriosis. The key findings are:

KMO is expressed in epithelial cells of human endometriosis lesions and in corresponding lesions in a mouse model of endometriosis.

Oral administration of the KMO inhibitor KNS898 in mice resulted in a dose-dependent inhibition of KMO activity, as evidenced by increased levels of the KMO substrate kynurenine and its metabolite kynurenic acid, and decreased levels of the cytotoxic metabolite 3-hydroxykynurenine.

In the mouse model of endometriosis, KMO inhibition with KNS898 reduced the number of endometriosis-like lesions that developed, even when treatment was started one week after the initiation of lesions.

KMO inhibition also improved visceral hyperalgesia (reduced mechanical allodynia) and restored normal cage exploration behavior in mice with endometriosis, suggesting an improvement in pain-related symptoms.

The histopathology of the experimental endometriosis lesions was similar to that observed in human endometriosis, and KMO expression was localized to the epithelial layers of the lesions in both human and mouse samples.

In conclusion, these results indicate that KMO inhibition is a promising new non-hormonal therapeutic approach for the treatment of endometriosis, as it can reduce lesion development and improve pain-related symptoms in a preclinical model.

Stats

Plasma KNS898 levels were 0.18 ± 0.01 ng/mL at 0.01 mg/kg, 88.8 ± 22.6 μg/mL at 5 mg/kg, and 483.9 ± 84.0 μg/mL at 25 mg/kg.
Plasma kynurenine levels increased by approximately 14-fold at maximal KMO inhibition (25 mg/kg) compared to the 0.01 mg/kg dose.
Plasma kynurenic acid levels increased by approximately 25-fold at maximal KMO inhibition (25 mg/kg) compared to the 0.01 mg/kg dose.
Plasma 3-hydroxykynurenine levels decreased by approximately 30-fold at maximal KMO inhibition (25 mg/kg) compared to the 0.01 mg/kg dose.

Quotes

"KMO blockade resulted in a reduction in endometriosis severity compared to untreated mice with endometriosis, specifically in terms of reducing i) the number of mice that developed endometriosis tissue lesions, and ii) the number of lesions per mouse in those that did develop lesions."
"KMO inhibition improved visceral hyperalgia (reduced mechanical allodynia) and restored normal cage exploration behavior in mice with endometriosis, suggesting an improvement in pain-related symptoms."

Key Insights Distilled From

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

by Higgins,B., ... at www.biorxiv.org 05-15-2024

https://www.biorxiv.org/content/10.1101/2024.05.13.593856v1

Deeper Inquiries

What are the potential mechanisms by which KMO inhibition reduces endometriosis lesion development and improves pain-related behaviors in this model

In the context of endometriosis, KMO inhibition reduces lesion development and improves pain-related behaviors through several potential mechanisms. Firstly, KMO is involved in the metabolism of tryptophan, a precursor to serotonin, which plays a role in pain perception and inflammation. By inhibiting KMO, there is a shift in the kynurenine pathway towards the production of kynurenic acid, which has anti-inflammatory properties. This shift may help reduce the inflammatory response associated with endometriosis lesions, leading to decreased lesion development and pain.
Additionally, KMO inhibition results in the accumulation of kynurenine, which has been linked to neuroinflammation and pain sensitization. By blocking KMO and diverting kynurenine towards kynurenic acid production, the neuroinflammatory response may be dampened, thereby reducing pain-related behaviors in the model. Furthermore, the reduction in 3-hydroxykynurenine production, a cytotoxic metabolite, may also contribute to the overall improvement in endometriosis symptoms.
Overall, KMO inhibition likely exerts its beneficial effects in endometriosis by modulating the kynurenine pathway, reducing inflammation, and altering the balance of metabolites involved in pain perception and sensitization.

Could KMO inhibition have broader applications beyond endometriosis, such as in other chronic pain conditions associated with inflammation

KMO inhibition could indeed have broader applications beyond endometriosis, particularly in other chronic pain conditions associated with inflammation. The kynurenine pathway, regulated by KMO, is implicated in various inflammatory and neuroinflammatory processes that contribute to chronic pain states. By targeting KMO and modulating the production of kynurenine metabolites, it may be possible to alleviate pain and inflammation in conditions such as rheumatoid arthritis, neuropathic pain, and inflammatory bowel disease.
Moreover, KMO inhibition's ability to shift the balance towards anti-inflammatory metabolites like kynurenic acid could be beneficial in mitigating the inflammatory response in a range of chronic pain disorders. This approach may offer a novel therapeutic strategy for managing pain in conditions where inflammation plays a significant role in symptomatology.
Further research and clinical studies are warranted to explore the potential of KMO inhibition in treating various chronic pain conditions beyond endometriosis.

How do the kynurenine pathway metabolites altered by KMO inhibition, such as kynurenine and kynurenic acid, influence the pathogenesis and symptoms of endometriosis

The altered kynurenine pathway metabolites resulting from KMO inhibition, such as kynurenine and kynurenic acid, play crucial roles in influencing the pathogenesis and symptoms of endometriosis.
Kynurenine, accumulated due to KMO blockade, has been associated with neuroinflammation and pain sensitization. Its presence can contribute to the inflammatory response and heightened pain perception in endometriosis. By inhibiting KMO and increasing kynurenine levels, there may be a modulation of the neuroinflammatory processes that exacerbate pain in this condition.
On the other hand, the diversion of kynurenine towards kynurenic acid production is beneficial in the context of endometriosis. Kynurenic acid is known for its anti-inflammatory properties and ability to regulate glutamatergic neurotransmission, which can help in dampening the inflammatory response and reducing pain sensitivity associated with endometriosis.
Therefore, the balance between kynurenine and kynurenic acid, influenced by KMO inhibition, plays a critical role in shaping the pathophysiology and symptomatology of endometriosis.