Antagonizing the corticotropin releasing hormone receptor 1 with antalarmin reduces the progression of endometriosis

Abstract

Endometriosis is a disorder in which endometrial tissue is found outside the uterus causing pain, infertility and stress. Finding effective, non-hormonal and long-term treatments for endometriosis still remains one of the most significant challenges in the field. Corticotropin releasing hormone (CRH) is one of the main signaling peptides within the hypothalamic pituitary adrenal (HPA) axis released in response to stress. CRH can affect nervous and visceral tissues such as the uterus and gut via activation of two types of CRH receptors: CRHR1 and CRHR2. Our aim was to determine if blocking CRHR1 with antalarmin will reduce endometriosis progression. In experiment 1 we induced endometriosis in female rats by suturing uterine horn tissue next to the intestinal mesentery and allowed to progress for 7 days. We determined that after 7 days, there was a significant increase in CRHR1 within endometriotic vesicles as compared to normal uterus. In Experiment 2, we induced endometriosis and administered either antalarmin (20 mg/kg, i.p.) or vehicle during the first 7 days after surgery. A separate group of sham surgery rats served as non-endometriosis controls. Endometriosis was allowed to progress until 60 days after surgery, at which time rats were tested for anxiety behaviors. At the time of sacrifice, endometriotic vesicles, uterus and blood were collected. Treatment with antalarmin significantly reduced the size (67% decrease) and number (30% decrease) of endometriotic vesicles. Antalarmin also prevented the increase in CRH and CRHR1 mRNA within endometriotic vesicles but not of glucocorticoid receptor. Endometriosis did not change anxiety behaviors in the open field and zero-maze tests and prior antalarmin administration did not modify this. Our data provides the first in-vivo demonstration for use of CRHR1 antagonist for the treatment of endometriosis opening the possibility for further exploring CRH signaling as a treatment target for this debilitating disease.

Short treatment with antalarmin alters adrenal gland receptors in the rat model of endometriosis

“…Endometriosis and sham groups were sacrificed on day 60 after endometriosis induction surgery. While the number of animals per group in our previous publication [22] was larger, here we are reporting the adrenal weight, ACTH and corticosterone of a subset of only 12 rats in the endo-vehicle, 12 rats in the endo-antalarmin and 11 rats in the sham group. Rats weights, estrous cycle distribution, were previously reported [22].…”

“…Adrenal tissue was collected from experimental animals used in our prior published experiments [22]. Experimental procedures were previously approved by the Ponce Health Sciences University (protocol #202) and the University of Texas at Rio Grande Valley (protocol #2016-004) Institutional Animal Care and Use Committees and adhere to the NIH Guide for the Care and Use of Laboratory Animals.…”

“…injection (between 09:00- Diagram of experimental protocols. The protocol for tissue collection used in the current manuscript is similar to the one previously published [22]. Two separate cohorts of rats were used: one that received endometriosis or sham surgery and allowed to progress until 7 days after surgery, and one that received antalarmin or vehicle with endometriosis surgery which was allowed to progress until day 60.…”

“…All protocols were conducted as previously described [22] using the same chemicals. The following running protocol was used for cDNA synthesis: 25˚C for 5 min, 46˚C for 20 min, 95˚C for 1 min.…”

“…This drug belongs to the family of pyrrolopyrimidine derivatives and readily crosses the blood brain barrier. Antalarmin can lessen the severity of endometriosis in the auto-transplantation rat model, but caused a prolonged increase in ACTH levels [22]. In light of clinical and animal Treatment Of Endometriosis.…”