Part Two | Study On Neuroendocrine-immune Function Of Phenylethanoid Glycosides Of Desertliving Cistanche Herb in Perimenopausal Rat Model

Part Two How does the effective ingredient Phenylethanoid Glycosides of Cistanche improve immunity?

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4. Discussion

4.1 Selection of animal models

With the development of the research on perimenopausal syndrome, the preparation methods of various perimenopausal animal models are also emerged continuously, such as castration animal models, X-ray irradiation destruction of

ovarian animal model(Li et al., 2012), 4-vinyl ring Animal model of ethylene follicle depletion(Brooks et al., 2016), an animal model of alcohol-induced ovarian injury(Huang et al., 2007), an animal model of perimenopausal depression(Miao et al., 2017), the animal model of peri-menopausal syndrome with hot flashes( Zhang et al., 2010), natural peri-menopausal animal model(Cai et al., 2007), etc. Different animal models have their own applications and their characteristics. This study is based on animal model analysis of the characteristics of clinical symptoms of the perimenopausal syndrome(Tian et al., 2015) according to the new method of evaluation of traditional Chinese medicine animal model established in the early stage of our laboratory(Tian et al., 2017) and the drafting of animal model for the perimenopausal syndrome(Draft)(Miao et al., 2018). This study was used perimenopausal model rats with the incomplete castration method, and this animal model is widely used to study perimenopausal women with osteoporosis, obesity, atherosclerosis, and other conditions, and it also used the studies on factors related to estrogen action, such as the relationship between estrogen and neuroimmune, cancer(Sun and Jin, 2005), and the model has high success rate, mature and stable, and is widely used by researchers. In addition, because the ovary not only synthesizes estrogen but also participates in the body's immune function, secreting and synthesizing other hormones. And the function of the human perimenopausal ovaries is not completely lost, the animal model of incomplete castration is closer to human perimenopause. It is more consistent with the characteristics of clinical symptoms.

4.2 Selection of positive control

This study took Gengnian'an capsule as the positive control drug, Gengnian'an capsule is a clinically recognized drug for the treatment of perimenopausal syndrome, it can effectively improve the perimenopausal syndrome clinical symptoms of tidal fever with sweating, vertigo, and tinnitus, wakefulness, restlessness, and others. And clinical and experimental studies have shown that Gengnian'an capsule regulates the endocrine and immune functions of perimenopausal patients as a whole, and could improve the clinical symptoms of perimenopausal women in various ways. It has a good therapeutic effect on perimenopausal syndrome(Ou et al., 2011; Wang et al., 2010; Yu et al., 2010; Li and Liu, 2001; Xie., 2003).

4.3 Effects on the neuroendocrine system

The human HPO axis is a coordinated neuroendocrine system, and it is controlled by the central nervous system. Under normal circumstances, the hypothalamus secretes GnRH and promotes the synthesis and release of FSH and LH in the pituitary, thereby promoting the secretion of sex hormones and the growth and development of the follicles. The interaction of HPO keeps female reproductive endocrine relatively stable. When women enter the perimenopausal period, the ovarian function declines, the secretion of estrogen decreases, and the negative feedback to the hypothalamus and pituitary is weakened, the pituitary gland secretes a large amount of FSH and LH, leading to an imbalance of HPO, a disorder of an endocrine system, and thus attend the symptoms of hot flashes, sweating, osteoporosis, and other related symptoms.

The changes of FSH and LH content are a direct expression of pituitary secretion function. The changes in GnRH and β-EP content directly reflect the secretion state of the hypothalamus in the HPO axis. The secretion of E2 and T is determined by the functional status of the ovary. The hypothalamus, pituitary, uterus, and other tissues have ER distribution, AR is widely distributed in the central nervous system and cerebral cortex, so it can represent the function of the HPO axis and reflect the state of the neuroendocrine system which the detection of FSH, LH, GnRH, β-EP, E2, T, ER, AR in the relevant tissues, serum, and plasma. In addition, the level of BGP can directly reflect the activity of osteoblasts(Xun and Wang, 2017), estrogen can inhibit the number and activity of osteoclasts, it has an impact on bone metabolism, the determination of this index can reflect the perimenopausal rat's osteoporosis case. Therefore, this experiment tested the above biochemical indicators, and observed the pathological changes of uterus and ovary in perimenopausal rats, in order to better determine the effect of phenylethanoid glycosides on the neuroendocrine system of perimenopausal rats.

4.4 Effects on immune function

The thymus gland is an important central immune organ(Han and Lu, 2017), and it is also an endocrine organ. During the perimenopause period, due to the lack of physiological estrogen stimulation and the reduction of intracellular estrogen receptors, the thymus structure can be reduced and the secretion of thymosin can be reduced, the atrophy of the thymus will inevitably directly affect the cellular immune function and it has an indirect effect on humoral immunity. The immune-active cells of the thymus can release polypeptide factors, and pass the information into the neuroendocrine system, producing relevant physiological or pathophysiological responses, such as the level of estrogen is lowered, it can reduce the production of IL-2, β-EP, and other immunomodulatory substances in immune cells. The spleen is the largest peripheral immune organ and it is also a place to receive antigenic stimulation and immune response. The spleen and thymus are important components of the body's immune system. Therefore the body's immune function can indirectly react with the thymus and spleen index.

In this paper, through the study of the thymus, spleen organ index, histopathological changes, thymus cortical thickness, the thickness of splenic nodules, etc., it responses that PGC has the effect on improving the immune function of perimenopausal model rats, and improving the pathological changes of the thymus and spleen.

5. Conclusion

Each dose of PGC could not only counteract the disorder of sex hormones (E2, T, FSH, LH) in perimenopausal syndrome, increase sex hormone levels, but also improve the imbalance of the levels of the androgen receptor (ER, AR), and is also improving the body's immune function and correcting osteoporosis, it can enhance and restore the organ index of the related organizations and improve the pathological changes of uterus, thymus, and spleen. In addition, compared with GC, PGC has no significant difference in the horizontal-vertical movement, organ index, sex hormone disorder, etc. Even at the improvement of the E2 level in the serum, reduced the level of FSH in serum, improved the expression level of ER in the uterus and hypothalamic, and the pathological changes of related tissues which have more effective than GC, especially the PGC-HD and PGC-MD. This indicates that the PGC is regulated by the endocrine and immune system as a whole, it does not merely play the role of estrogen but improves the symptoms and quality of life by various mechanisms, it provides an experimental basis for a wide range of clinical applications for Desertliving Cistanche herb and new drug development for traditional Chinese medicines. In the follow-up of this study, relevant mechanisms are being carried out in order to clarify the specific mechanism of action of phenylethanoid glycosides from the neuroendocrine-immune network in the treatment of the perimenopausal syndrome.

In addition, this study showed that PGC could increase the level of BGP in serum of perimenopausal model rats, and it has an effect on bone metabolism, it suggesting that PGC may have a better therapeutic effect on osteoporosis caused by perimenopause syndrome, the relevant research that the osteoporosis caused by perimenopause syndrome can be carried out in the later stage, and develop new applications. This study provides a good experimental basis for the new clinical use of PGC, and it provides a new research idea for the study of similar drugs.

Authorcontributionsstatement

Mingan Miao and Xiumin Li designed and guided the experiments, Mingsan Miao, Xiumin Li, Shuo Tian, Ming Bai, Yanyi Wu, and Zhenzhen Wei conducted the experiments and analyzed the measured data, Miao Mingsan and Xiumin Li made the final conclusion. Both authors reviewed the manuscript.

Acknowledgments

National international cooperation base (2016-65); Scholar of central China (162101510003); Science and technology breakthrough of Henan province (162102310181). We thank Mr. Henry Ehrlich for reading and editing our manuscript.