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Title: Assessment of novel drugs for treating preterm labour using a translational model
Author: Mohammed, Ammar
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2020
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The uterus and placenta are essential organs playing key roles in reproductive processes. Labour is modulated by several factors such as sex hormones, nitric oxide, prostaglandins and the ROCK pathway, which stimulate the uterus via the phosphorylation of myosin-light chain (MLC). Abnormal function of these factors may lead to preterm labour (PTL) which still has no effective management strategies. The aims of this project were to: (i) examine the regulation of myometrial contractility in non-pregnant and pregnant mice, (ii) assess the ability of ripasudil (a ROCK inhibitor) to diminish uterine contractions, (iii) evaluate the effect of NO on myometrial contractility, and (iv) investigate the influence of administrating empty and NO-loaded liposomes on the level of lipid mediators in the uterus and placenta from C57 and eNOS KO pregnant mice at term. Results showed a significant higher contractility of the upper segment of uterus as compared to the lower segment (p < 0.05). During pregnancy, stimulation of the uterus by oxytocin, U46619 and 5-HT upregulates the production of the di-phosphorylated MLC by 378.1%, 379.6% and 271%, respectively. Ripasudil was able to inhibit spontaneous and drug-induced myometrial contractility in non-pregnant and pregnant mice. Ripasudil inhibited the mono- and di-phosphorylation of MLC in the myometrium from both mice; it was more effective on ppMLC formation (88.61% and 86.76%). The lack of NO caused a significant increase in myometrial (by 132.5%) and amplitude of contractions (by 132.1%) in eNOS KOs. Vehicle- and SE175-Liposome treatments led to a significant reduction in the level of Cyclooxygenase (COX) and Lipoxygenase (LOX) derived lipid mediators in the myometrium and placentas from pregnant C57 WT and eNOS KO mice. Exposure to the SE175-Liposome significantly increased the level of myometrial DHETs (by 199.1%, 153% and 450.6%) and placental DiHDPA (by >4×108 ) compared with the Free SE175. SE175 significantly increased the concetration of the 15 HETrE. The majority of lipid mediators detected were the LOXderived (myometrium) and COX-derived (placenta). In conclusion, the data support the higher myogenic activity of uterus in pregnant mice. It demonstrated for the first time that ppMLC is expressed in mouse myometrium and that ROCK inhibition is a promising tocolytic candidate for the treatment of PTL. Targeted liposomes were effective in modulating the level of certain lipid mediators. Administration of NOdonors at late pregnancy can regulate uterine activity and control placental blood flow.
Supervisor: Harris, Lynda ; Marshall, Kay ; Fischer, Deborah Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: COX ; Placenta ; SE175 ; Liposomes ; LOX ; lipid mediators ; Targeted Drug Delivery ; Uterine stimulants ; Rock inhibitors ; Ripasudil ; Mouse oestrous cycle ; Nitric oxide ; Pregnancy complications ; Preterm Labour