УДК 61

Alpha-7 nicotinic acetylcholine receptor role in inhibition of the development of endometriosis by regulating inflammation

Камерзан Ольга Геннадьевна – студент Института фармации, химии и биологии Белгородского государственного национального исследовательского университета.

Научный руководитель Гусакова Наталья Леонидовна – кандидат психологических наук, Белгородский государственный национальный исследовательский университет.

Abstract: Endometriosis is a common gynecological disease that occurs in women of childbearing age, the main symptoms of which are infertility and severe pain. Endometriosis is characterized by the formation of tissues outside the lining of the uterus, a tissue that is very similar to the endometrium. The process can be genital and include pelvic organs (fallopian tubes, ovaries, ligamentous apparatus) or/ and extragenital, involving abdominal organs, bladder, lung tissue. In recent years, there has been a clear trend towards an increase in the frequency of endometriosis, which occupies one of the leading places in the structure of gynecological diseases.

Аннотация: Эндометриоз – распространенное гинекологическое заболевание, которое возникает у женщин детородного возраста, основными симптомами являются бесплодие и сильные боли. Эндометриоз характеризуется образованием тканей вне слизистой оболочки матки, ткани, которая очень похожа на эндометрий. Процесс может быть генитальным и включать органы малого таза (фаллопиевы трубы, яичники, связочный аппарат) или/и экстрагенитальным, вовлекающим органы брюшной полости, мочевой пузырь, легочную ткань. В последние годы наблюдается четкая тенденция к увеличению частоты эндометриоза и занимает одно из ведущих мест в структуре гинекологических заболеваний.

Keywords: Endometriosis, Alpha-7 nicotinic acetylcholine receptor, macrophages, expression, cytokine.

Ключевые слова: Эндометриоз, Альфа-7 никотиновый ацетилхолиновый рецептор, макрофаги, экспрессия, цитокины.

Endometriosis is a process in which outside the uterine depression grow benign apkins analogous in morphological and functional parcels on the endometrium. Difficulties in the treatment of cases with endometriosis are due to extremely variable clinical picture and severe course of the complaint. The tactics of treatment is determined the age of the cases, the form of the complaint, the nature of the symptoms, as well as the pitfalls, side goods and cost- effectiveness of the treatment. In exceptional situations, endometriosis is considered as a habitual relapsing complaint that requires constant attention and treatment. Pain with endometriosis is pronounced during menstrual days and weakens after they end. Pain is associated with inflammatory disorders occurring in the endometrium, as well as parallel changes in the nerve ganglia and adhesions in the lower intestines. With a long-term course of the disease, the pain loses its frequency, a chronic pain syndrome occurs. Often there is pain also during defecation and urination, and patients also experience discomfort during intercourse. The variety of localizations of endometriosis has led to a great number of suppositions of its origin. Still, none of them can easily explain the emergence and proliferation of endometrioid towel outside the uterine mucosa. Although the etiology of endometriosis is not completely defined, multitudinous pieces of substantiation suggest that inflammation plays the most important part in the pathogenesis of the complaint, and that an alteredanti-inflammatory terrain in the tummy supports the survival and growth of endometriotic cells. Traditional medicine remedy is designed to reduce pain by colorful mechanisms, including reducing inflammation, interposing or suppressing cyclic hormone product by the ovaries, inhibiting the action and conflation of estradiol, reducing or stopping period. It's extremely delicate to determine this disease without gynecological opinion. Every month, in the case ofnon-fertilization of the egg, the uterine apkins prepared for the attachment of the fetus are rejected. still, it may be that along with the blood inflow, the endometrium gets back into the fallopian tubes and begins to grow. This is the morning of the development of endometriosis. The complaint affects women of travail age, women who are more likely to be stressed than others. There are some ways to cure endometriosis but they aren't completely delved . Surgical approaches to relieving endometriosis- related pain can be used as first- line remedy or initiated after failed medicine remedy. Surgery to remove endometrial towel can help ameliorate the chances of conceiving, although there's no guarantee that it'll be possible to conceive after treatment. [1, c. 52]. The strength of the pain leads to an incorrect opinion of endometriosis as appendicitis or ectopic gestation. The pain is localized depending on the place of circumstance of endometriosis- for illustration, it can do during defecation or urination. The correct opinion of endometriosis is the first step to the successful cure of endometriosis. Endometriosis is insulated

• genital (localization of the pathological process in the internal and external genitalia)
• extragenital (development of endometrioid implants in other organs and systems of a woman's body).

According to numerous experts, endometriosis is a gynecological incarnation of a systemic pathology that has arisen as a result of a violation of the regulation of vulnerable and hormonal processes. Threat factors for endometriosis are complicated labor and delivery over the age of 30, cesarean section, revocations, as well as cervical diathermocoagulation, which is frequently used to treaterosions.However, also there's a high probability of the preface of endometrial cells into the crack face with the posterior development of endometrioid growths in the consistence of the cervix and pelvic depression, If this intervention is performed on the dusk of period. The implantation proposition of endometriosis assumes that the rejected patches of the endometrium in certain situations, for illustration, surgical revocations, traumatic parturition, throwing menstrual blood from the uterus into the tubes during discontinuous condensation of the uterus during menstrual pain, settle on the ovaries, tubes, peritoneum and give rise to the development of endometriosis. The development of endometriosis can also be affected by operations with the opening of the uterine depression, seditious conditions of the genitals, menstrual cycle diseases, heritable predilection, fat, alcohol and caffeine. [2, c. 1467] It's possible to speak with confidence about the opinion only on the base of the results of an fresh study. In agreement with the suggestions, ultrasound and laparoscopy are performed, hysteroscopy/ hysterosalpingography, vivisection( examination of apkins of pathological areas). presently, hysteroscopy is extensively used for the opinion of intrauterine pathology.( 3,c. 185) Treatment of endometriosis can be divided into hormone remedy and surgery, and there's also a combination of styles. Medical treatment of endometriosis consists in the appointment of hormonal medicines that the case takes for a long time. They homogenize the work of the ovaries and help the appearance of new foci. still, this system is effective only at the original stage of the complaint, when excrescencies haven't yet appeared. It should be noted that with retrocervical endometriosis, hormone remedy is ineffective. Early opinion makes it possible to avoid surgical intervention, limited to medical styles. It should be noted that indeed optimal treatment rules for cases with endometriosis with presently being means are doubtful to give an absolute clinical effect. It seems necessary to search for new styles of remedy for this complaint, taking into account the mechanisms of its pathogenesis, which are responsible for the implantation and development of foci of endometriosis. Cigarette smoking is an established threat factor for cancer and cardiovascular complaint and is one of the leading causes of preventable complaint in utmost countries. Less well given possible positive goods, several studies suggest that there may be inverse associations of smoking with endometriosis. Despite the fact that in utmost cases the factual medium is inadequately understood or not understood at each, it's generally believed that the main salutary effect is due to the fitted nicotine and that the preface of nicotine without smoking can be just as salutary as smoking without a advanced health threat due to the navigator and other constituents contained in tobacco. also, theanti-inflammatory and antinociceptive goods of nicotine acetylcholine receptors and their associated mechanisms have been well studied. mortal endometriotic lesions have been innervated by cholinergic, sensitive, and adrenergic whim-whams filaments, suggesting that these jitters may contribute to a critical link in the etiology of pain and inflammation in endometriosis. This fact suggests that nicotinic acetylcholine receptors could be a new remedial target. [5, c.1481] It has also been shown that the numerous cytokines and growth factors involved in endometriotic lesions originate from activated macrophages and endometriotic cells. IL-1ß is produced by macrophages and is a key molecule involved in the disease process. In addition, induced chemokines such as MCP-1 and IL-8 from endometriotic cells cause accumulation of white blood cells in the abdomen and alter the inflammatory environment. Breaking the cycle of inflammation between macrophages and endometriosis by tic lesions therefore has potential as a new endometriosis therapy. Macrophages express the -7 nicotinic acetylcholine receptor (nAChR), which is activated by nicotine, acetylcholine and specific receptor agonists. However, little information is available on the expression of -7 nAChR in human peritoneal macrophages or on the action of – 7 nAChR on the pathogenesis of endometriosis.

Several studies have been performed which have shown us that NACHR mRNA was expressed in human PFMC from both patients with endometriosis and patients without endometriosis. As a positive control of mRNA expression, -7 nAChR peripheral blood mononuclear cells (PBMC) and a line of human monocyte cells, THP-1 cells, were used. Some populations of monocytes/macrophages have a high affinity for the -subunit of nicotinic acetylcholine -receptor found. A total of 26 women (aged 28 to 44 years) undergoing laparoscopy for pain or infertility were included in this study. All women had normal menstrual cycles and none were taking hormonal medications for at least 3 months prior to laparoscopy. Briefly, the PFS from patients with benign ovarian tumors were layered for 30 minutes on the lymphoprene centrifuged at 377 g. PFMC was removed from the surface of the section and washed with PBS. In a pilot study, it was found that 1 mol L−1 nicotine is the optimal concentration for this study. [1, c. 52] Several studies have examined the expression of -7 nAChR in human peripheral macrophages and mouse peritoneal macrophages. This is the first study dedicated to the expression and role of -7 nAChR in human PFMC. Human PFMC was found to express -7 nAChR and activation of the receptor by a nicotinic or -7 nAChR agonist resulted in suppression of IL-1 production independent of the presence of endometriosis. These results indicate that -7 nAChR function on PFMC was not impaired in endometriosis patients. Consequently, the abdominal inflammatory status in patients with endometriosis may be associated with an increase in the ligands that activate PFMC or a decrease in the -7-nAChR ligand, such as acetylcholine. Further research is required to validate this hypothesis. [4, c. 536] Furthermore, activation of -7 nAChR was found to suppress LPS-induced phosphorylation of the p38 pathway but not suppress phosphorylation of NF-kB. Previous publications have reported that nicotine inhibits the inflammatory pathway in synoviocytes by inhibiting suppresses activation of the NF-kB pathway, suggesting that the mechanism for suppressing inflammation is heterogeneous. In several disease models in mice, such as colitis and encephalomyelitis, activation of -7 nAChR leads to symptom relief by suppressing the inflammatory status. Therefore, it was investigated whether administration of the -7 nAChR agonist in the endometriotic model was effective in mice. IL-1 mRNA expression in PFMC was significantly suppressed in the -7 nAChR agonist group 1 week after in vivo endometrial inoculation. As observed in the in vitro study , the -7 nAChR agonist repressed LPS-induced IL-1 expression, while the basal level of IL-1 expression remained unchanged. [4, c. 555] In addition, it was shown that the -7-nAChR agonist significantly reduced the formation of endometriotic lesions in total mass and quantity after 3 weeks of treatment in the mouse endometriosis model. This overwhelming effect of the -7-nAChR agonist was confirmed by the introduction of the -7 nAChR antagonists, suggesting that -7 nAChR was involved in the process. It was previously reported that suppression of inflammatory cytokines by p38 MAPK inhibitors resulted in a decrease in the formation of endometriotic lesions on the animal model. [4, c. 546] Conversely, inflammatory cytokines increase the number of endometriosis cells. These results support the notion that activation of -7 nAChR can regulate inflammation in endometriotic lesions, leading to the control of endometriotic lesion growth. [1, c. 58] Several studies suggest that there's an inverse relationship between cigarette smoking and endometriosis, but the factual medium has not been linked. The present study has shown that nicotine may be a seeker for reducing inflammation and endometriosis. Interestingly, cigarette smoking is known to reduce other seditious conditions similar as ulcerative colitis in humans. Nicotine was recently reported to suppress acute colitis and colitis-associated oncogenesis and shown to be related to activation of -7 nAChR using a mouse model. These results could confirm our findings that nicotine and the – 7-NACHR agonist inhibit inflammation and the development of endometriosis. Hormonal agents that suppress the functions of the ovaries and uterus are presently used to treat cases with endometriosis. Since gravidity is a symptom of endometriosis, the development of a new remedy that preserves reproductive function is needed. Although cigarette smoking can potentially have remedial goods on endometriosis, it can beget side goods similar as carcinogenesis and cardiovascular complaint. Therefore, a nicotine patch or an -7 nAChR agonist may be candidates for the treatment of endometriosis before pregnancy. Inflammation of the peritoneum is the hallmark of endometriosis, and ample evidence supports a significant role of immune and inflammatory factors in the development of endometriosis. The present study demonstrated that activation of the -7 nAChR agonist suppresses cytokine levels in PFMC and progression of endometriotic lesions. However, this does not prove that suppressing inflammation by activating -7 nAChR directly causes a reduction in endometriotic lesions. Further studies are required to confirm this hypothesis. According to the above scientific analysis, nAChR agonists are considered to have promising therapeutic effects in the treatment of EMs and should be treated as a new EMs therapy. To evaluate this hypothesis, we anticipate that in vitro and in vivo studies in EMs-associated cells and animal models are required to assess the safety and efficacy of nAChR agonists. After that, clinical trials should be conducted to evaluate the efficacy of nAChR agonists and provide stronger evidence for possible future use.

References

1. Albuquerque EX, Pereira EFR, Castro NG, Alkondon M, Reinhardt S, Schröder G, Maelicke A : Nicotinic receptor function in the mammalian central nervous system, 1995. – С. 47–72
2. Alkondon M, Albuquerque EX: Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes. J Pharmacol Exp Ther volume, 1993. – С. 1455–1473
3. Lena C, Changeux J–P: Allosteric modulations of the nicotinic acetylcholine receptor. Trends Neurol Sci volume, 1993. – С. 181–186
4. McGehee DS, Role LW: Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu Rev Physiol volume, 1995. – С. 521–546.
5. Pereira E, Reinhardt–Maelicke S, Schrattenholz A, Maelicke A, Albuquerque EX: Identification and functional characterization of a new agonist site on nicotinic acetylcholine receptors of cultured hippocampal neurons. J Pharmacol Exp Therap volume, 1993. – С. 1474–1491.