Endometriosis is a steroid-dependent common gynecological condition characterized by the growth of endometrial epithelial and stromal cells outside of its cavity. Estrogen dependence, progesterone resistance, in situ estrogen production, increased inflammation, resistance to apoptosis, active cell growth and proliferation, and overall disease’s heterogeneity makes it challenging to treat patients without compromising fertility. BDNF and its high affinity receptor TrkB has been shown to be dysregulated in women with endometriosis suggesting their role in disease progression. Immunocompromised mice (Rag2γc) (n=25) underwent an implantation surgery during which a cell suspension consisting of human endometrioma cells was injected into the animals’ peritoneal cavity. Upon lesion stablishment all animals were divided into five groups and treated with either high (7.5mg/kg/day), medium (5mg/kg/day) or low (2.5mg/kg/day) dose of TrkB inhibitor cyclotraxin-b, negative control (saline) or 0.04mg/kg/day letrozole. After four weeks of treatment all animals were sacrificed, all major organs were collected and assessed with routine histology for potential adverse effects of the treatment, all endometriotic implants were analyzed with routine histology and IHC for a panel of markers: BDNF, TrkB, anti-human mitochondrial protein, CD31, VEGFa, VEGFR1, VEGFR2. Treatment did not cause any significant side effects. There was a dose-dependent trend in reduction of endometriotic implants’ volume and number. IHC confirmed expression of the angiogenic markers within endometriotic implants. A larger study may be required to replicate results and advance the search for novel non-hormonal endometriosis treatment. / Thesis / Master of Science in Medical Sciences (MSMS) / Endometriosis is a chronic pain condition affecting more than 176 million women worldwide. Despite its commonality and severity its gold standard diagnosis is performed through invasive laparoscopy and there is no cure resulting in low quality of both physical and mental health of the affected individuals. Levels of a neurotrophic factor - BDNF and its high affinity receptor TrkB have been found increased in women with endometriosis and thus, BDNF-TrkB signaling cascade appears to be a promising therapeutic target. This study investigated an effect of TrkB inhibitor – cyclotraxin-b on reduction of endometriotic lesion number and volume within an immunocompromised model. Replication of results and increase of sample size may provide more details about cyclotraxin-b clinical relevance for treatment of endometriosis.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/26140 |
| Date | January 2021 |
| Creators | Leonova, Anna |
| Contributors | Foster, Warren, Delaney, Kathleen, Scattolon, Sarah, Health Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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