温肾方对甲状腺功能减退症大鼠脑神经细胞凋亡及基因表达的影响
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摘要
目的 甲状腺功能减退症是一种常见的内分泌综合症侯群，可导致全身多个系统病变，引起各种合并症。甲状腺功能减退症合并脑功能损害临床较为常见，这种甲减性脑损害，随着病情加重，几乎所有病例都会出现，表现为不同程度神经精神症状。目前，临床对甲减性脑损害并无专门的治疗，现代医学仅是针对甲状腺功能减退本身，采用甲状腺素替代治疗，忽视对脑功能损害自身的治疗，疗效不如人意。发挥中医优势，运用中医药治疗甲减合并症，有利于提高本病的疗效。温肾方临床效果良好，不仅可改善甲减本身的征状，而且对神经精神症状改善明显。我们在温肾方治疗甲减性脑损害的临床的基础上，以甲状腺功能减退症动物模型为实验对象，运用现代医学的理论和试验方法，对温肾方治疗甲减性脑损害的作用及其机理进行了研究，从而为临床提供了理论与实验依据。
方法 将受试大鼠随机分为五组：正常对照组、模型组、甲状腺片组、中药小剂量组、中药大剂量组。后四组予以造模，模型大鼠按1.35ml／200g体重／只，每日灌服0.04％他巴唑混悬液，共计造模45天。造模完成后开始灌服相应药物，连续15天。然后各实验组分别进行如下指标的检测：采用放射免疫法测定血清FT_3、FT_4、TSH水平；选用水迷宫法、穿梭箱法观察药物对模型大鼠行为学障碍的影响；运用电镜观察细胞超微结构的变化；TUNEL法检测细胞凋亡；逆转录-多聚酶联反应(RT-PCR)检测模型大鼠脑神经细胞bcl-2基因的表达情况。
结果：
1．模型组大鼠造模后出现阳虚的行为学改变，反映甲减程度的临床指标血清FT_3、FT_4的含量显著低于正常对照组，血清TSH的含量显著高于正常对照组。中药组尤其中药大剂量组不仅能明显改善试验大鼠甲减症状，而且能明显升高FT_3、FT_4水平，降低TSH含量，但不强于甲状腺片组。
2 与正常组相比，甲减模型大鼠具有显著的行为学障碍；温肾方对甲减
湖北中医学院博士研究生论文-
性脑病大鼠行为学障碍有不同程度的改善作用，并且中药大剂量组优于甲状
腺片组。
3在脑神经细胞超微结构的观察中，模型组可见高尔基体增多肥大，线
粒体减少、凋亡小体形成，线粒体气泡化或变形，光面内质网扩张增多。中
药治疗后细胞浆空泡化，线粒体减少。温肾方大剂量脑神经细胞结构基本正
常，小剂量组细胞基质稍减少，结构基本正常。
4与正常组相比，甲减模型大鼠脑神经细胞凋亡数量明显增加。中药治
疗后鼠脑神经细胞凋亡数量明显减少。
5与正常组相比，甲减模型大鼠模型组脑神经细胞bcl一2基因表达明显
降低，中药治疗后bcl一2基因表达明显增加，且剂量增加，效果更明显。
结论:温肾方能明显改善甲减模型大鼠的行为学障碍;能明显升高T3、T;、
FT3、FT;水平，降低TSH含量;改善脑神经细胞超微结构;降低脑神经细胞凋
亡数量;增加bcl一2基因表达。表明温肾方对甲状腺功能减退性脑损害有明
显改善作用。
Objective Hypothyroidism is a common disease of endocrine system, which could to lead to pathological changes and syndromes of many systems. It is common in clinical that hypothyroidism merging the impairment of brain and with the development of hypothyroidism, every patient have the impairment of brain, showing neurotic and psychiatric symptoms. Now only thyroxine sodium is used in treatment of hypothyroidism itself and has no specially therapeutic methods for the impairment of brain caused by hypothyroidism in clinic, and the effect is dissatisfaction. So it is therapeutic current with Chinese medicine for prevention and treatment of the impairment of brain caused by hypothyroidism by giving full play to the advantages of Traditional Chinese Medicine. It was confirmed that the therapeutic effect of Wenshentang in clinic is well. It could improve the symptoms not only hypothyroidism itself but also the impairment of brain caused by hypothyroidism. We study the function of Wenshentang on the impairment of brain caused by hypothyroidism, and its mechanism under the basic theory and experimental methods of modern medicine with the hypothyroidism animal model in order to provide a theory and experimental base for the clinical practice.
Methods The rats were randomly divided into 5 groups, such as normal control group, model group, thyroxin group, small dosage group of Wenshentang and the large dosage of Wenshentang. The rats of the latter 4 groups were made model by infusing 0.04% tapazole suspension 1.35%/200g/day for 45 days. After that, the rats were treated with corresponding medicines for 15 days. Then radioimmunoassay method was
used on serum FT3, FT4, T3, T4 and TSH; Water labyrinth and shuttling box methods were used on the behavior changes; TUNEL methods was used on the cell apoptosis, RT-PCR method was used on the expression of bcl-2 in the nerve cell of hypothyroidism rats.
Results (1)In the rats of model group, the behavior changes of kidney yang-insufficiency in hypothyroidism were appeared, and the indexes which may imply the severe degree of hypothyroidism presented the decreasing of FT3, FT4 and the increasing of TSH compared with the normal control group. Wenshentang, especially with large dosage had not only improved the symptoms of hypothyroidism, but also increased the content of FT3, FT4 and decreased the content of TSH, but the effect was not better than that of thyroxin group. (2) In the rats of model group, there have the decreasing of FT3, FT4and the increasing of TSH compared with the normal control group. The large dosage of Wenshentang and thyroxin could significantly improve those changes and the small dosage of Wenshentang could significantly only improve the change of FT4. (3) Compared with the normal control group, the Golgi body increase and fat, mitochondrion decrease or out of shape or bubbled, apoptosis corpuscle formed, smooth endoplasmic reticulum expand or increase in the ultrastructural of nerve cells of the hypothyroidsm rats. After treatment with Wenshentang, cell starch bubbled, mitochondrion decrease and the structure was basic normal and in small dosage cell ground substance decrease slightly, the structure was basic normal. (4) Compared with the normal control group, the count of apoptosis nerve cells of the hypothyroidsm rats was increase significantly and it was decrease significantly after treatment with Wenshentang. (5) Compared with the normal control group, the expression of bcl-2 was decrease significantly in nerve cells of
the hypothyroidsm rats. It was increase significantly after treatment with Wenshentang and the more the dose the more the effect.
Conclusion Wenshentang significantly improve the behavior disorder of the hypothyroidsm rats, increase the content of FT3, FT4 and decrease the content of TSH, improve the ultrastructural of nerve cells, decrease the count of apoptosis nerve cells, increase the expression of bcl-2.Those implied that Wenshentang could improve the brain impairment caused by Hypothyroidism significantly.
方法 将受试大鼠随机分为五组：正常对照组、模型组、甲状腺片组、中药小剂量组、中药大剂量组。后四组予以造模，模型大鼠按1.35ml／200g体重／只，每日灌服0.04％他巴唑混悬液，共计造模45天。造模完成后开始灌服相应药物，连续15天。然后各实验组分别进行如下指标的检测：采用放射免疫法测定血清FT_3、FT_4、TSH水平；选用水迷宫法、穿梭箱法观察药物对模型大鼠行为学障碍的影响；运用电镜观察细胞超微结构的变化；TUNEL法检测细胞凋亡；逆转录-多聚酶联反应(RT-PCR)检测模型大鼠脑神经细胞bcl-2基因的表达情况。
结果：
1．模型组大鼠造模后出现阳虚的行为学改变，反映甲减程度的临床指标血清FT_3、FT_4的含量显著低于正常对照组，血清TSH的含量显著高于正常对照组。中药组尤其中药大剂量组不仅能明显改善试验大鼠甲减症状，而且能明显升高FT_3、FT_4水平，降低TSH含量，但不强于甲状腺片组。
2 与正常组相比，甲减模型大鼠具有显著的行为学障碍；温肾方对甲减
湖北中医学院博士研究生论文-
性脑病大鼠行为学障碍有不同程度的改善作用，并且中药大剂量组优于甲状
腺片组。
3在脑神经细胞超微结构的观察中，模型组可见高尔基体增多肥大，线
粒体减少、凋亡小体形成，线粒体气泡化或变形，光面内质网扩张增多。中
药治疗后细胞浆空泡化，线粒体减少。温肾方大剂量脑神经细胞结构基本正
常，小剂量组细胞基质稍减少，结构基本正常。
4与正常组相比，甲减模型大鼠脑神经细胞凋亡数量明显增加。中药治
疗后鼠脑神经细胞凋亡数量明显减少。
5与正常组相比，甲减模型大鼠模型组脑神经细胞bcl一2基因表达明显
降低，中药治疗后bcl一2基因表达明显增加，且剂量增加，效果更明显。
结论:温肾方能明显改善甲减模型大鼠的行为学障碍;能明显升高T3、T;、
FT3、FT;水平，降低TSH含量;改善脑神经细胞超微结构;降低脑神经细胞凋
亡数量;增加bcl一2基因表达。表明温肾方对甲状腺功能减退性脑损害有明
显改善作用。
Objective Hypothyroidism is a common disease of endocrine system, which could to lead to pathological changes and syndromes of many systems. It is common in clinical that hypothyroidism merging the impairment of brain and with the development of hypothyroidism, every patient have the impairment of brain, showing neurotic and psychiatric symptoms. Now only thyroxine sodium is used in treatment of hypothyroidism itself and has no specially therapeutic methods for the impairment of brain caused by hypothyroidism in clinic, and the effect is dissatisfaction. So it is therapeutic current with Chinese medicine for prevention and treatment of the impairment of brain caused by hypothyroidism by giving full play to the advantages of Traditional Chinese Medicine. It was confirmed that the therapeutic effect of Wenshentang in clinic is well. It could improve the symptoms not only hypothyroidism itself but also the impairment of brain caused by hypothyroidism. We study the function of Wenshentang on the impairment of brain caused by hypothyroidism, and its mechanism under the basic theory and experimental methods of modern medicine with the hypothyroidism animal model in order to provide a theory and experimental base for the clinical practice.
Methods The rats were randomly divided into 5 groups, such as normal control group, model group, thyroxin group, small dosage group of Wenshentang and the large dosage of Wenshentang. The rats of the latter 4 groups were made model by infusing 0.04% tapazole suspension 1.35%/200g/day for 45 days. After that, the rats were treated with corresponding medicines for 15 days. Then radioimmunoassay method was
used on serum FT3, FT4, T3, T4 and TSH; Water labyrinth and shuttling box methods were used on the behavior changes; TUNEL methods was used on the cell apoptosis, RT-PCR method was used on the expression of bcl-2 in the nerve cell of hypothyroidism rats.
Results (1)In the rats of model group, the behavior changes of kidney yang-insufficiency in hypothyroidism were appeared, and the indexes which may imply the severe degree of hypothyroidism presented the decreasing of FT3, FT4 and the increasing of TSH compared with the normal control group. Wenshentang, especially with large dosage had not only improved the symptoms of hypothyroidism, but also increased the content of FT3, FT4 and decreased the content of TSH, but the effect was not better than that of thyroxin group. (2) In the rats of model group, there have the decreasing of FT3, FT4and the increasing of TSH compared with the normal control group. The large dosage of Wenshentang and thyroxin could significantly improve those changes and the small dosage of Wenshentang could significantly only improve the change of FT4. (3) Compared with the normal control group, the Golgi body increase and fat, mitochondrion decrease or out of shape or bubbled, apoptosis corpuscle formed, smooth endoplasmic reticulum expand or increase in the ultrastructural of nerve cells of the hypothyroidsm rats. After treatment with Wenshentang, cell starch bubbled, mitochondrion decrease and the structure was basic normal and in small dosage cell ground substance decrease slightly, the structure was basic normal. (4) Compared with the normal control group, the count of apoptosis nerve cells of the hypothyroidsm rats was increase significantly and it was decrease significantly after treatment with Wenshentang. (5) Compared with the normal control group, the expression of bcl-2 was decrease significantly in nerve cells of
the hypothyroidsm rats. It was increase significantly after treatment with Wenshentang and the more the dose the more the effect.
Conclusion Wenshentang significantly improve the behavior disorder of the hypothyroidsm rats, increase the content of FT3, FT4 and decrease the content of TSH, improve the ultrastructural of nerve cells, decrease the count of apoptosis nerve cells, increase the expression of bcl-2.Those implied that Wenshentang could improve the brain impairment caused by Hypothyroidism significantly.
引文
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2. GoldsteinGW, BetzAl. Recentadvancesinunderstandingbraincapillaryfunction[J], AnnNeurol, 1983, (14)
3．陈霞，等．新生儿暂时性甲状腺功能减退症1例．新生儿科杂志，2002；17：1
4．王慕逖．儿科学．人民卫生出版社，1996第四版．北京．393-396
5．曹其湘．新生儿筛查发现的非典型甲状腺功能减退症7例报告．临床儿科杂志，1993；(11)：301
6．朱铁虹．甲状腺疾病的神经并发症．国外医学内分泌学分册，1994；14(1)：26-28．
7．俞淑静 费大东．老年甲状腺功能减退症六例误诊为精神疾病．临床误诊误治，1999：12(5)：330
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