| According the 5th census in november 2000 shows that the number of older than 65 years has reached 88,110,000, Accounting for 6.96% of the total. The population of over 60 years old has reached 130,000,000. Accounting for 10.2% of the total. According to international standards, Our country has entered the aging society, The speed of aging quickly than the rate of population growth of national and of world, Even quickly than the speed of economic development, Showing a feature of "old earlier than rich". Attention aging disease. Carry out the reserch on the mechanism of aging diseases occurrence and development has important significance to individual and socio-economic structure. Many demography studies shows that the average life expectancy of female longer than male, The incidence of aging diseases such as dementia, hypertension, CHD, Diabetes, cancer and so on has presence difference between gender. Besides, Female, for example, the state of health and occurrence and development of diseases has appear differents before and after menopuse. It demonstrate, different of kinds and levels of hormones may influence the process of aging.Brain aging is a important aspect of aging, can be expressed as the recession of mobility and learning and memory. Conclusions of the studies on the relations of gender hormone and brain from rodents shows a significant correlation between them, But not yet consistent. Same studies have shown that thebrain male-development and the cycle of testosterone was significantly correlated, this male-development rely on estradiol by aromatase from testosterone and through estrogen receptor. However, if the characterized by male-oriented of brain is by testosterone transformate into estrogen and through estrogen receptors, then thebrain function of rodents in male, female performance should be similar in experimental. However, such as water maze experiment, there are a large differnt results between male and female, and think the results from DHT, which is achieved through the androgen receptor. So, understand the function of androgen receptor in the brain learning and memory has a importent meaning in the relation between androgen and the brain function. In our experiments, through different kinds of models of C57 mice and testicular feminization (tfm) mouse, self-activity, water maze test, passive avoidance shuttle test as a standard to evaluate brain function the different models of brain aging in mice, and through the oxygen free radicals level in brain and the implementation of learning and memory function of the brain the main areas-the hippocampus CA1 region to observe the morphology of the brain changes.In addition to brain function decline, the aging of the cardiovascular system to produce a significant effect, such as hypertension, coronary heart disease, etc. The most common occurrence and development of aging diseases. Large number of epidemiological studies have shown a significant different between men and women in cardiovascular disease, there are significant gender differences. In pre-menopausal the incidence of cardiovascular of women less than men while after menopause, women's cardiovascular disease incidence increased significantly close to or even exceeded that of men. These differences in the incidence between the sexes strongly suggests the occurrence of sex hormones on cardiovascular disease development.Mechanism of hypertension, coronary heart disease, etc. cardiovascular diseases, various internal and external factors derived inflammation of blood vessels within the vascular endothelial cell injury, is the beginning of its important factors. In our study, also from inflammatory response of blood vessels to explore the role of androgen receptors in vascular inflammation of blood vessels.In vascular inflammation, the sex hormones play an important regulatory role. Some studies have shown that estrogen can reduce a variety of vascular inflammatory markers. In clinical investigation of hormone replacement therapy have similar results. The androgen effects on vascular inflammatory response is inconsistent, and some research suggests that testosterone on vascular inflammatory response is negative, but more literature suggests that more physiological levels of testosterone can be weakened blood vessel inflammation.In many literatureIn which demonstrated the protective effect of testosterone, the differences lies in whether the effects of testosterone, such protection is achieved through transfer to estradiol, the number of experimental use dihydrotestosterone which can not converted to estradiol to prove that the protective effect of testosterone achieved not by estradiol, but there are yet a lot of literature shows that abnormal estrogen receptor in male patients may lead to endothelial dysfunction. atherosclerosis is an inflammatory vascular disease, endothelial dysfunction is the starting point of atherosclerosis, so these documents can still prompt testosterone transfer to estrogen plays an important role in the inflammatory response in blood vessels.The purpose of this study is from tfm mice, exogenous testosterone in them to returned to normal level, after stimulated by endotoxin (LPS), observed the different of blood vessels inflammatory response between C57 and tfm mice to stimulidifferent, to judge the role of classic androgen receptor play.In a variety of inflammatory reactions, PGE2, NO are important regulator of endotoxemia and inflammatory response, which can increased histamine levels, increased permeability of blood vessel wall and promote inflammatory exudation, increase the inflammatory response. Especially in the early stage of inflammation to migrate inflammation cell to sites of inflammation in the process. In the inflammation process, can induce neutrophils, vascular endothelial cell interactions, resulting in hemodynamic changes and organ damage; can also directly induce apoptosis in target organs, causing organ failure. In our experiment, PGE2, NO as the indicators of inflammation.The body produce oxygen free radicals by enzyme system, which can attack polyunsaturated fatty acids on biofilms, induced lipid peroxidation, and thus produce lipid peroxides. Such as:formyl (malondialdehyde MDA), ketone, hydroxyl, hydrogen peroxide, and the new oxygen free radicals, etc. Lipid peroxidation not only reactive oxygen species into active chemical agent, that is, radical decomposition products of lipids, and enlarge the role of reactive oxygen species by chain reaction or branched-chain chain reaction, Therefore, the initial reactive oxygen species can lead to a lot of lipids in the formation of decomposition products of these decomposition products, some are harmless, others can lead to cell dysfunction, and even death. Oxygen free radicals not only through the biofilm polyunsaturated fatty acid peroxides to cause cell damage, but also cause cell damage through the lipid products of the decomposition of hydrogen peroxide. Therefore the amount of MDA reaction of the body can often be the extent of lipid peroxidation and indirectly reflects the extent of cell damage. Superoxide dismutase (SOD) is an important biological antioxidant enzymes in vivo, can eliminate the organisms in the metabolism of harmful substances generated in the process, is widely distributed in a variety of creatures. SOD has a special physiological activity, is the primary biological material in vivo free radical scavenging. The level of SOD is a visual indicator of aging and death. Determination of MDA and SOD is often complement each other, the level of SOD activity indirect response the ability to clear oxygen free radicals, while the level of MDA also indirectly reflects the severity of body's cells by free radicals attack.Tfm mice we uesd in this studies can not express normal androgen receptoris because of gene mutations, their testosterone levels in vivo only 10%-20% of in normal mice, and testis can not development normally,, the performance of its external genitalia like female, so tfm mouse is an ideal model which can observe the function of classic androgen receptor.D-galactose (D-gal) is one of the most commonly way to create aging model, D-gal in body would be reduced to galactitol, which can not be further metabolism and can not accumulated in cells, affecting the osmotic pressure leading to cell swelling, metabolic disorders, oxygen free radicals. This process is similar to the aging process in the body. This experiment use D-gal to make subacute aging model, to observed the roles of T through the AR in aging in miceSo, this study carry out from three aspects::1. the effects of physiological levels of testosterone on subacute aging mice behavior.The current accepted behavioral detection indicators:passive avoidance and water maze test shuttle experiment to evaluate the ability of learning and memory of mice brains, and to observe the changed of morphology of the hippocampus CA1 area. Removal of 4-week-old male C57 mice testes, produced a significant decline in testosterone levels in castrated mice, followed by daily subcutaneous injection of 900mg/kg of D-galactose in neck back, other D-galactose group accept subcutaneous injection of testosterone propionate lmg/kg promoting as intervention factors, hippocampal CA1 area of mice were observed morphological changes, and to detect the level of MDA SOD in mouse brain of each group. The results showed that the ability of behavior of castration and D-galactose group were significantly worse than control group mice, hippocampal CA1 area of the cell morphology and cell number was significantly less than the control group. The behavioralof testosterone propionate group better than OVX group and D-galactose group, the levels of MDA, SOD significantly improved in brain tissue, hippocampal CA1 area of the cell morphology, the number of cells are improve too, the differences between the control group and testosterone propionate without statistical significance.It can be seen that the physiological doses of testosterone propionate can be improved behavior ability of subacute aging mice, this effect may be related to the decreased levels of oxygen free radicals in brain tissue, to CA1 area cells number and morphology of improvement.2. The role of androgen receptor in the effect of physiological doses of testosterone on the behavior in mice.To further explore the mechanism of improve effect of testosterone on learning and memory capacity, we have used tfm mice, compare the indicators tfm mice with the physiological dose of testosterone and ovariectomized C57 mice to deduced the role of androgen receptors. Similarly, made models of C57 control group, castrated C57 mice, C57 mice with testosterone propionate group, tfm mice and tfm mice group with testosterone propionate group. After the detection of various groups of mice independent of activity, passive avoidance and water maze test as well as the shuttle brain morphology in hippocampal CA1 area and the number of cells.Like the first experiment, learning and memory ability of ovariectomized mice was significantly lower than control group, but testosterone group was significantly improved, learning and memory ability and hippocampal CA1 area cells of tfm group and tfm with testosterone propionate groups mice were inferior to the control group, and was no significant difference with castration group. There are no statistically difference in the indicators between tfm group and tfm with testosterone propionate group.In the absence of normal androgen receptor, even if supplemented the normal level of testosterone in body can not improve the funcation of brain, suggesting that effect of male hormones on restore learning and memory ability in mice brain, increasing autonomous mobility, improve cell morphology in hippocampal CA1 area and increase the number of neurons is through the pathway of androgen- androgen.3. The effect of physiological dose of testosterone thought androgen receptor pathway on vascular inflammatory response in mice.The third part is about the effect of physiological doses of testosterone on vascular inflammatory response in vessel stimulated by exogenous endotoxin by androgen receptor. Like the second part of the study, establishing the control group, ovariectomized group, testosterone propionate group, tfm group and tfm + testosterone propionate groups. In the condition of sterile, removed thoracic aorta and divided into two parts, placed in DMEM at condition of 37℃,5% CO2 concentration in hatching boxes for 30 min, and then placed in DMEM with or without LPS for 6 hours, followed by replace the fresh DMEM solution incubated 30min, using ELISA to detect the levels of PGE2 and NO in DMEM, the levels of MDA and SOD in DMEM with LPS minus without LPS, that is the amount producted by LPS. And then take the abdominal artery in mice, milling with saline produced as 10% homogenate to detect the level of oxygen free radicals. The results suggest that the level oxygen free radical and inflammation of castrated mice were significantly higher, while the levels of testosterone propionate group was significantly decreased, with no statistical difference between the control group. The levels of these indicators of tfm group and tfm+testosterone propionate group were the lowest, inflammation and oxygen free radical level of tfm+testosterone propionate group were significantly lower than the castration+testosterone propionate group, (P<0.05). The tfm+testosterone propionate group of vascular inflammation and oxygen free radicals are weaker than tfm mice, their differences were statistically significant.These results indicate that loss of physiological testosterone, inflammation stimulated by LPS will be more serious, Absence of normal androgen receptor and supplement physiological dose of testosterone to tfm mouse, the vascular injury is not only weaker than tfm, but also weaker than castration+testosterone propionate group.ConclutionThrough this study, we can draw the following conclusions:1. Physiological doses of testosterone can increase the spontaneous motors test, maintenance the ability of learning and memory in mice, but also improve the ability of learning and memory of subacute aging mice. This effect may be related to lower tissue oxygen free radicals in mouse brain, improving brain morphology in hippocampal CA1 neurons and increase the number of neurons.2. The improve effect Physiological dose of testosterone on learning and memory ability may through the classical androgen receptor. Without expression of normal androgen receptor, whether the androgen below or reach the level of physical can not observed these effect.3. Physiological doses of exogenous testosterone can reduced the oxygen free radicals and inflammatory response of blood vessels which stimulate by LPS, compare with these mice whom expresse normal AR, these protecte effect are more distinctly. Therefore, it can be assumed that AR approach would increase the inflammatory response, testosterone propionate reduced vascular inflammation is achieved by means of non-AR.4. AR in different parts can play different effects, at least in the brain, testosterone propionate can play a anti-aging effect by AR, but in the vascular tissue, androgen increased the degree of inflammatory response.
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