胶原诱导关节炎伴发抑郁症动物模型的建立及中药干预机理的研究
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摘要
目的：采用胶原诱导联合慢性轻度不可预见性应激复合孤养建立胶原诱导关节炎伴发抑郁大鼠模型,并评价补肾活血解郁方对胶原诱导关节炎伴发抑郁大鼠模型干预作用。
方法：实验一、二选择雌性Wistar大鼠,随机分为正常组、模型组、关节炎组、抑郁组4组。正常组正常饲养；模型组单笼饲养,经牛Ⅱ型胶原诱导关节炎免疫后1周给予慢性不可预知的温和应激方法；关节炎组经牛Ⅱ型胶原诱导关节炎免疫后正常饲养；抑郁组单笼饲养,给予慢性不可预知的温和应激方法。造模结束后进行行为学测定、关节滑膜病理学观察、下丘脑单胺类神经递质测定。实验三、四选择雌性Wistar大鼠,随机分为正常组、模型组、中药组、西药组4组。正常组正常饲养；模型组、中药组、西药组单笼饲养,经牛Ⅱ型胶原诱导关节炎免疫后1周给予慢性不可预知的温和应激方法。造模结束后,中药组予补肾活血解郁方灌胃,西药组予盐酸氟西汀灌胃,每日1次,共6周。灌胃结束后进行行为学测定、下丘脑单胺类神经递质含量测定。
结果：实验一结果：关节炎组和模型组大鼠关节肿胀度、关节炎指数明显高于正常组,有非常显著性差异(P<0.01)；关节炎组和模型组的滑膜组织充血、水肿,滑膜细胞排列不规则,可见炎性细胞浸润及纤维组织增生,有血管翳形成,有软骨和骨质破坏；模型组和抑郁组大鼠的蔗糖水摄入量明显减少,水平活动和垂直活动减少与正常组相比有非常显著性差异(P<0.01)。实验二结果：模型组和抑郁组大鼠下丘脑的5-HT、5-HIAA、NA、DA含量与正常组相比明显降低,有非常显著性差异(P<0.01)。实验一和实验二结果证实了胶原诱导关节炎伴发抑郁症大鼠模型复制成功。
实验三结果：中药组和西药组蔗糖水饮用量虽然低于正常组(P<0.01),但较模型组明显增加(P<0.01),且中药组和西药组无显著性差异(P>0.05)；西药组和中药组水平活动得分和垂直活动得分明显高于模型组(P<0.01),且中药组和西药组无显著性差异(P>0.05)。实验四结果：模型组的5-HT、5-HIAA、NA、DA含量较正常组明显降低,有非常显著性差异(P<0.01)；中药组和西药组5-HT、5-HIAA含量较模型组升高,并且中药组升高更明显(P<0.01)；中药组和西药组的NA含量与模型组相比无显著性差异(P>0.05)；西药组的DA含量与模型组相比无显著性差异(P>0.05),中药组的DA含量较模型组升高,有非常显著性差异(P<0.01)。
结论：采用胶原诱导关节炎复合慢性不可预见性温和应激刺激及孤养三种经典的模型相结合方式,制备的胶原诱导关节炎伴发抑郁症动物模型是较为理想的用于研究类风湿性关节炎伴发抑郁症动物模型；补肾活血解郁方对类风湿性关节炎伴发抑郁症的抗抑郁作用明显,初步考虑其治疗类风湿性关节炎伴发抑郁的作用机制与提高脑内神经递质含量有关。
OBJECTIVE:To establish rat model of collagen-induced arthritis with depression, the rats were induced arthritis with collagen first,and then were separately raised and put into chronic unpredictable mild stress.And evaluate the effects of intervention bushen huoxue jieyu prescription on rat model of collagen-induced arthritis with depression.
METHODS:In experiment one and two,female Wister rats were randomly divided into normal group,model group,arthritis group and depression group.Normal group were raised normaly;model group were separately raised and put into chronic unpredictable mild stress after being induced arthritis with typeⅡcollagen; arthritis group were raised normaly afer being induced arthritis with typeⅡcollagen;depression group were separately raised and put into chronic unpredictable mild stress.After modeling,all rats were carried on behavior test、synovial pathological observation、determination of monoamine neurotransmitter in hypothalamus. In experiment three and four, female Wister rats were randomly divided into normal group, model group, western medicine group and chinese medicine group. Normal group were raised normaly;model group,western medicine group and chinese medicine group were separately raised and put into chronic unpredictable mild stress after being induced arthritis with typeⅡcollagen. After modeling,they received intragastric administration of double distilled water,fluoxetin and bushen huoxue jieyu prescription respectively once a day for 6 weeks from the first day after the establishment of model.After that,the behavioral evaluation were done and monoamine neurotransmitter in hypothalamus were determined.
RESULTS:Results of experiment one:The degree of joint swelling and arthritis index of arthritis group and model group were higher than normal group and there was great difference (P< 0.01).In arthritis group and model group,synovial tissue was hyperemia, synovial cells was irregular,inflammatory cells was infiltration,fibrous tissue was hyperplasia,and there was pannus formation with cartilage and bone destruction. In model group and depression group,the amount of sugar-water consumption by the rats,both the crossing time and rearing time in the open-field test,was much less than that by the rats in the normal group (P< 0.01). Results of experiment two:Compared with normal group, the contents of 5-HT、5-HIAA、NA、DA of model group and depression group were much less,and there was great difference (P< 0.01).The results of experiment one and two confirmed that rat model of collagen-induced arthritis with depression was established successfully.
Resluts of experiment three:Compared with normal group, the amount of sugar-water consumption of chinese medicine group and western medicine group was much less (P< 0.01),but was much more than model group's (P< 0.01),and there was no difference between chinese medicine group and western medicine group (P> 0.05).Both the crossing time and rearing time of chinese medicine group and western medicine group in the open-field test were higher than model group's (P < 0.01), and there was no difference between chinese medicine group and western medicine group (P> 0.05). Results of experiment four:The contents of 5-HA、5-HIAA、NA and DA of model group decreased significantly, compared with normal group (P< 0.01).The contents of 5-HA and 5-HIAA of chinese medicine group and western medicine group increased,and chinese group increased more,compared with model group (P< 0.01). There was no great difference on the contents of NA between chinese medicine group and western medicine group and model group (P> 0.05).Compared with model group,there was no great difference in western medicine group (P> 0.05),but great difference in chinese group (P< 0.01).
CONCLUSION:was an ideal animal model of composite collagen-induced arthritis、chronic unpredictable mild stress and isolated raising to prepare rat model of collagen-induced arthritis with depression for reseaching collagen-induced arthritis with depression.Bushen huoxue jieyu prescription has obvious effect antidepressant for rheumatoid arthritis with depression,and we considered the mechanisms of the treatment of rheumatoid arthritis with depression relating to improving brain neurotransmitters.
方法：实验一、二选择雌性Wistar大鼠,随机分为正常组、模型组、关节炎组、抑郁组4组。正常组正常饲养；模型组单笼饲养,经牛Ⅱ型胶原诱导关节炎免疫后1周给予慢性不可预知的温和应激方法；关节炎组经牛Ⅱ型胶原诱导关节炎免疫后正常饲养；抑郁组单笼饲养,给予慢性不可预知的温和应激方法。造模结束后进行行为学测定、关节滑膜病理学观察、下丘脑单胺类神经递质测定。实验三、四选择雌性Wistar大鼠,随机分为正常组、模型组、中药组、西药组4组。正常组正常饲养；模型组、中药组、西药组单笼饲养,经牛Ⅱ型胶原诱导关节炎免疫后1周给予慢性不可预知的温和应激方法。造模结束后,中药组予补肾活血解郁方灌胃,西药组予盐酸氟西汀灌胃,每日1次,共6周。灌胃结束后进行行为学测定、下丘脑单胺类神经递质含量测定。
结果：实验一结果：关节炎组和模型组大鼠关节肿胀度、关节炎指数明显高于正常组,有非常显著性差异(P<0.01)；关节炎组和模型组的滑膜组织充血、水肿,滑膜细胞排列不规则,可见炎性细胞浸润及纤维组织增生,有血管翳形成,有软骨和骨质破坏；模型组和抑郁组大鼠的蔗糖水摄入量明显减少,水平活动和垂直活动减少与正常组相比有非常显著性差异(P<0.01)。实验二结果：模型组和抑郁组大鼠下丘脑的5-HT、5-HIAA、NA、DA含量与正常组相比明显降低,有非常显著性差异(P<0.01)。实验一和实验二结果证实了胶原诱导关节炎伴发抑郁症大鼠模型复制成功。
实验三结果：中药组和西药组蔗糖水饮用量虽然低于正常组(P<0.01),但较模型组明显增加(P<0.01),且中药组和西药组无显著性差异(P>0.05)；西药组和中药组水平活动得分和垂直活动得分明显高于模型组(P<0.01),且中药组和西药组无显著性差异(P>0.05)。实验四结果：模型组的5-HT、5-HIAA、NA、DA含量较正常组明显降低,有非常显著性差异(P<0.01)；中药组和西药组5-HT、5-HIAA含量较模型组升高,并且中药组升高更明显(P<0.01)；中药组和西药组的NA含量与模型组相比无显著性差异(P>0.05)；西药组的DA含量与模型组相比无显著性差异(P>0.05),中药组的DA含量较模型组升高,有非常显著性差异(P<0.01)。
结论：采用胶原诱导关节炎复合慢性不可预见性温和应激刺激及孤养三种经典的模型相结合方式,制备的胶原诱导关节炎伴发抑郁症动物模型是较为理想的用于研究类风湿性关节炎伴发抑郁症动物模型；补肾活血解郁方对类风湿性关节炎伴发抑郁症的抗抑郁作用明显,初步考虑其治疗类风湿性关节炎伴发抑郁的作用机制与提高脑内神经递质含量有关。
OBJECTIVE:To establish rat model of collagen-induced arthritis with depression, the rats were induced arthritis with collagen first,and then were separately raised and put into chronic unpredictable mild stress.And evaluate the effects of intervention bushen huoxue jieyu prescription on rat model of collagen-induced arthritis with depression.
METHODS:In experiment one and two,female Wister rats were randomly divided into normal group,model group,arthritis group and depression group.Normal group were raised normaly;model group were separately raised and put into chronic unpredictable mild stress after being induced arthritis with typeⅡcollagen; arthritis group were raised normaly afer being induced arthritis with typeⅡcollagen;depression group were separately raised and put into chronic unpredictable mild stress.After modeling,all rats were carried on behavior test、synovial pathological observation、determination of monoamine neurotransmitter in hypothalamus. In experiment three and four, female Wister rats were randomly divided into normal group, model group, western medicine group and chinese medicine group. Normal group were raised normaly;model group,western medicine group and chinese medicine group were separately raised and put into chronic unpredictable mild stress after being induced arthritis with typeⅡcollagen. After modeling,they received intragastric administration of double distilled water,fluoxetin and bushen huoxue jieyu prescription respectively once a day for 6 weeks from the first day after the establishment of model.After that,the behavioral evaluation were done and monoamine neurotransmitter in hypothalamus were determined.
RESULTS:Results of experiment one:The degree of joint swelling and arthritis index of arthritis group and model group were higher than normal group and there was great difference (P< 0.01).In arthritis group and model group,synovial tissue was hyperemia, synovial cells was irregular,inflammatory cells was infiltration,fibrous tissue was hyperplasia,and there was pannus formation with cartilage and bone destruction. In model group and depression group,the amount of sugar-water consumption by the rats,both the crossing time and rearing time in the open-field test,was much less than that by the rats in the normal group (P< 0.01). Results of experiment two:Compared with normal group, the contents of 5-HT、5-HIAA、NA、DA of model group and depression group were much less,and there was great difference (P< 0.01).The results of experiment one and two confirmed that rat model of collagen-induced arthritis with depression was established successfully.
Resluts of experiment three:Compared with normal group, the amount of sugar-water consumption of chinese medicine group and western medicine group was much less (P< 0.01),but was much more than model group's (P< 0.01),and there was no difference between chinese medicine group and western medicine group (P> 0.05).Both the crossing time and rearing time of chinese medicine group and western medicine group in the open-field test were higher than model group's (P < 0.01), and there was no difference between chinese medicine group and western medicine group (P> 0.05). Results of experiment four:The contents of 5-HA、5-HIAA、NA and DA of model group decreased significantly, compared with normal group (P< 0.01).The contents of 5-HA and 5-HIAA of chinese medicine group and western medicine group increased,and chinese group increased more,compared with model group (P< 0.01). There was no great difference on the contents of NA between chinese medicine group and western medicine group and model group (P> 0.05).Compared with model group,there was no great difference in western medicine group (P> 0.05),but great difference in chinese group (P< 0.01).
CONCLUSION:was an ideal animal model of composite collagen-induced arthritis、chronic unpredictable mild stress and isolated raising to prepare rat model of collagen-induced arthritis with depression for reseaching collagen-induced arthritis with depression.Bushen huoxue jieyu prescription has obvious effect antidepressant for rheumatoid arthritis with depression,and we considered the mechanisms of the treatment of rheumatoid arthritis with depression relating to improving brain neurotransmitters.
引文
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