一种白僵菌代谢产物提取物（BCEF0083）的抗抑郁作用及其机制
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摘要
BCEF0083是从一种虫生真菌白僵菌代谢产物中提取的新型生物活性物质，具有一定的抗单胺氧化酶作用及较强的清除自由基活性。本室前期研究结果表明其具有一定的抗抑郁作用。本课题旨在前期研究的基础上，采用未预知的大鼠慢性应激抑郁模型，进一步探讨BCEF0083抗抑郁作用及其机制。主要实验结果如下：
1．BCEF0083对慢性应激大鼠开野行为和糖水消耗量的影响
通过不可预见性慢性应激造成大鼠抑郁模型，运用开野实验检测动物的行为，采用糖水消耗量法观测动物的奖赏反应。
BCEF0083(25、50mg·kg~(-1)，ig，qd×21d)可不同程度增加慢性应激大鼠开野实验中的水平活动次数与垂直活动次数；BCEF0083(25、50、100mg·kg~(-1)，ig，qd×21d)可不同程度增加慢性应激大鼠糖水消耗量，改善慢性应激大鼠的奖赏反应。
2．BCEF0083对慢性应激大鼠睡眠的影响
运用脑立体定位、多导睡眠描记(PSG)观察BCEF0083对慢性应激抑郁模型大鼠睡眠觉醒周期的影响。
BCEF0083 50mg·kg~(-1)(ig，qd×21d)能够使慢性应激大鼠快动眼睡眠(rapid eye movement sleep，REMS)百分比减少；BCEF0083(25、50、100 mg·kg~(-1)，ig，qd×21d)能够使慢性应激大鼠REMS潜伏期(latency)明显延长。提示BCEF0083能够抑制REMS睡眠，减少浅睡眠，增加深睡眠，改善慢性应激大鼠睡眠异常。
3．BCEF0083对慢性应激大鼠脂质过氧化的影响
运用紫外分光光度计法检测超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性及丙二醛(MDA)含量。
BCEF0083(25、50、100mg·kg~(-1)，ig，qd×21d)能够不同程度增强慢性应激大鼠血浆中SOD和GSH-Px活性，降低慢性应激大鼠血浆中MDA含量。
安徽医科大学硕士学位论文
4.BCEF0083对慢性应激大鼠下丘脑一垂体一肾上腺轴的影响
运用放射免疫分析法检测精氨酸加压素(AVP)含量，运用半定量逆转录聚合
酶链反应法(R工PCR)检测海马神经元糖皮质激素受体(GR)mRNA的表达。
BCEF0083(25、50、loomg·kg一l，19，qdxZld)能够不同程度降低慢性应激
大鼠下丘脑、垂体灯P的含量;BeEFoo83(50、loomg·kg一，，19，qdx21d)能够
不同程度使慢性应激大鼠海马神经元GR rrlRNA表达上调。
5.BCEFOO83对慢性应激大鼠海马神经元的影响
运用HE染色法、免疫组织化学法、半定量逆转录聚合酶链反应法检测海马神
经元数目、海马神经元脑源性神经营养因子(BDNF)含量、BDNF mRNA表达。
BCEF0083(25、somg·kg.‘，19，qdxZld)能够不同程度增加慢性应激大鼠海
马神经元数目、海马神经元B恻F的含量;BeEFoos3(50、xoomg·kg“，，19，qdxZld)
能够明显增加慢性应激大鼠海马神经元Bl)N F mRNA表达。
结论:BCEFO083能够增加慢性应激大鼠开野实验中的水平活动次数与垂直活动次
数，增加慢性应激大鼠糖水消耗量，改善慢性应激大鼠睡眠，提示其具有一定的
抗抑郁作用。其作用机制可能与抗脂质过氧化、改善H队轴功能紊乱、促进海马
神经元的营养及再生有关。
BCEF0083 is a new type of bioactive compounds from Entomogenous fungi, which acts both as an inhibitor of monoamine oxidase and an effctive free radical scavenger. In our former studies, we have found BCEF0083 possesses antidepressant effect on different animal models. Based on these foundations, this study is intended to further investigate the antidepressant effect and possible mechanisms of BCEF0083 in chronic unpredictable stress rat model. The main results are as follows:
1. Effect of BCEF0083 on behaviour in open-field test and consumption of saccharu water in chronic stressed rats
The model was induced by giving the rats different unpredictable stresses in 21days. The behavior was tested in open-field test. We detected animal's awarding response by calculating the 24hour consumption of saccharu water.
BCEF0083(25,50mg kg-1,ig,qdx21d) could increase ambulation and rearing score in chronic stressed rats in open-field test.BCEF0083(25,50,100mg kg-1,ig,qdx21d) could increase 24hour consumption of saccharu water and ameliate animal's awarding response .
2. Effect of BCEF0083 on sleep-weekfulness cycle in chronic stressed rats
Stereotaxic and polysomnography were used to record the sleep-wakefulness cycle.
BCEF0083 50mg kg-1ig, qdx21d) could attenuate REMS percent in chronic stressed rats. BCEF0083 (25,50,100 mg kg-1,ig,qdx21d) could prolong REMS latency in chronic stressed rats.The results suggested that BCEF0083 could ameliate abnormal sleep-wakefulness in chronic stressed rats.
3. Effect of BCEF0083 on lipid peroxidation in chronic stressed rats
UV spectrophotometer analysis technique was used to detect the SOD, GSH-PX
activity and MDA content.
BCEF0083(25,50,100 mg kg-1,ig,qdx21d) could enhance the activities of SOD,GSH-PX and decrease the content of MDA in chronic stressed rats.
4. Effect of BCEF0083 on Hypothalamic-pituitary-adrenal axis in chronic stressed rats
Radio-immunity analysis technique was used to detect the content of AVP. Semi-quantitative RT-PCR technique was used to detect the GR mRNA.
BCEF0083(25,50,100mg kg-1,ig,qdx21d) could decrease the content of AVP in hypothalamus and pituitary in chronic stressed rats. BCEF0083(50,100 mg kg-1, ig, qdx21d) could enhance the expression of GR mRNA in hippocampus in chronicstressed rats.
5. Effect of BCEF0083 on hippocampus neuron in chronic stressed rats
HE staining, immunohistochemistry and Semi-quantitative RT-PCR technique were used.
BCEF0083(25,50mgxkg-1,ig,qdx21d) could increase the numbers and content of BDNF in hippocampus neuron in chronic stressed rats. BCEF0083(50, 100mg kg-1, ig, qdx21d) could increase expression of BDNF mRNA in hippocampus neuron in chronic stressed rats.
Conclusions: BCEF0083 could increase ambulation as well as rearing score in open-field test, 24hour consumption of saccharu water in chronic stressed rats and ameliate abnormal sleep-wakefulness in chronic stressed rats. The result of this study suggested that BCEF0083 possess certain antidepressant effect. The possible mechanisms might be attribute to anti-lipid peroxidation, restore the disorder of HPA , accelerate the nutrition and regeneration of hippocampus neuron.
1．BCEF0083对慢性应激大鼠开野行为和糖水消耗量的影响
通过不可预见性慢性应激造成大鼠抑郁模型，运用开野实验检测动物的行为，采用糖水消耗量法观测动物的奖赏反应。
BCEF0083(25、50mg·kg~(-1)，ig，qd×21d)可不同程度增加慢性应激大鼠开野实验中的水平活动次数与垂直活动次数；BCEF0083(25、50、100mg·kg~(-1)，ig，qd×21d)可不同程度增加慢性应激大鼠糖水消耗量，改善慢性应激大鼠的奖赏反应。
2．BCEF0083对慢性应激大鼠睡眠的影响
运用脑立体定位、多导睡眠描记(PSG)观察BCEF0083对慢性应激抑郁模型大鼠睡眠觉醒周期的影响。
BCEF0083 50mg·kg~(-1)(ig，qd×21d)能够使慢性应激大鼠快动眼睡眠(rapid eye movement sleep，REMS)百分比减少；BCEF0083(25、50、100 mg·kg~(-1)，ig，qd×21d)能够使慢性应激大鼠REMS潜伏期(latency)明显延长。提示BCEF0083能够抑制REMS睡眠，减少浅睡眠，增加深睡眠，改善慢性应激大鼠睡眠异常。
3．BCEF0083对慢性应激大鼠脂质过氧化的影响
运用紫外分光光度计法检测超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性及丙二醛(MDA)含量。
BCEF0083(25、50、100mg·kg~(-1)，ig，qd×21d)能够不同程度增强慢性应激大鼠血浆中SOD和GSH-Px活性，降低慢性应激大鼠血浆中MDA含量。
安徽医科大学硕士学位论文
4.BCEF0083对慢性应激大鼠下丘脑一垂体一肾上腺轴的影响
运用放射免疫分析法检测精氨酸加压素(AVP)含量，运用半定量逆转录聚合
酶链反应法(R工PCR)检测海马神经元糖皮质激素受体(GR)mRNA的表达。
BCEF0083(25、50、loomg·kg一l，19，qdxZld)能够不同程度降低慢性应激
大鼠下丘脑、垂体灯P的含量;BeEFoo83(50、loomg·kg一，，19，qdx21d)能够
不同程度使慢性应激大鼠海马神经元GR rrlRNA表达上调。
5.BCEFOO83对慢性应激大鼠海马神经元的影响
运用HE染色法、免疫组织化学法、半定量逆转录聚合酶链反应法检测海马神
经元数目、海马神经元脑源性神经营养因子(BDNF)含量、BDNF mRNA表达。
BCEF0083(25、somg·kg.‘，19，qdxZld)能够不同程度增加慢性应激大鼠海
马神经元数目、海马神经元B恻F的含量;BeEFoos3(50、xoomg·kg“，，19，qdxZld)
能够明显增加慢性应激大鼠海马神经元Bl)N F mRNA表达。
结论:BCEFO083能够增加慢性应激大鼠开野实验中的水平活动次数与垂直活动次
数，增加慢性应激大鼠糖水消耗量，改善慢性应激大鼠睡眠，提示其具有一定的
抗抑郁作用。其作用机制可能与抗脂质过氧化、改善H队轴功能紊乱、促进海马
神经元的营养及再生有关。
BCEF0083 is a new type of bioactive compounds from Entomogenous fungi, which acts both as an inhibitor of monoamine oxidase and an effctive free radical scavenger. In our former studies, we have found BCEF0083 possesses antidepressant effect on different animal models. Based on these foundations, this study is intended to further investigate the antidepressant effect and possible mechanisms of BCEF0083 in chronic unpredictable stress rat model. The main results are as follows:
1. Effect of BCEF0083 on behaviour in open-field test and consumption of saccharu water in chronic stressed rats
The model was induced by giving the rats different unpredictable stresses in 21days. The behavior was tested in open-field test. We detected animal's awarding response by calculating the 24hour consumption of saccharu water.
BCEF0083(25,50mg kg-1,ig,qdx21d) could increase ambulation and rearing score in chronic stressed rats in open-field test.BCEF0083(25,50,100mg kg-1,ig,qdx21d) could increase 24hour consumption of saccharu water and ameliate animal's awarding response .
2. Effect of BCEF0083 on sleep-weekfulness cycle in chronic stressed rats
Stereotaxic and polysomnography were used to record the sleep-wakefulness cycle.
BCEF0083 50mg kg-1ig, qdx21d) could attenuate REMS percent in chronic stressed rats. BCEF0083 (25,50,100 mg kg-1,ig,qdx21d) could prolong REMS latency in chronic stressed rats.The results suggested that BCEF0083 could ameliate abnormal sleep-wakefulness in chronic stressed rats.
3. Effect of BCEF0083 on lipid peroxidation in chronic stressed rats
UV spectrophotometer analysis technique was used to detect the SOD, GSH-PX
activity and MDA content.
BCEF0083(25,50,100 mg kg-1,ig,qdx21d) could enhance the activities of SOD,GSH-PX and decrease the content of MDA in chronic stressed rats.
4. Effect of BCEF0083 on Hypothalamic-pituitary-adrenal axis in chronic stressed rats
Radio-immunity analysis technique was used to detect the content of AVP. Semi-quantitative RT-PCR technique was used to detect the GR mRNA.
BCEF0083(25,50,100mg kg-1,ig,qdx21d) could decrease the content of AVP in hypothalamus and pituitary in chronic stressed rats. BCEF0083(50,100 mg kg-1, ig, qdx21d) could enhance the expression of GR mRNA in hippocampus in chronicstressed rats.
5. Effect of BCEF0083 on hippocampus neuron in chronic stressed rats
HE staining, immunohistochemistry and Semi-quantitative RT-PCR technique were used.
BCEF0083(25,50mgxkg-1,ig,qdx21d) could increase the numbers and content of BDNF in hippocampus neuron in chronic stressed rats. BCEF0083(50, 100mg kg-1, ig, qdx21d) could increase expression of BDNF mRNA in hippocampus neuron in chronic stressed rats.
Conclusions: BCEF0083 could increase ambulation as well as rearing score in open-field test, 24hour consumption of saccharu water in chronic stressed rats and ameliate abnormal sleep-wakefulness in chronic stressed rats. The result of this study suggested that BCEF0083 possess certain antidepressant effect. The possible mechanisms might be attribute to anti-lipid peroxidation, restore the disorder of HPA , accelerate the nutrition and regeneration of hippocampus neuron.
引文
1. Breslav N. Epidemiologic studies of trauma, posttraumatic stress disorder, and other psychiatric disorders.Can J Psychiatry, 2002; 47(10): 923～929
2．卢艳花，谭仁祥．抗抑郁天然药物的研究进展．申草药，2000；31(9)：718～720
3．胡丰林，樊美珍，李增智．一种白僵菌代谢产物中生物活性物质的研究．菌物系统，2000：19(4)：522～525
4．周兰兰，明亮，程燕，等．BCEF0083抗单胺氧化酶作用的研究冲国药理学通报，2003；19(4)：404～407
5．周兰兰，明亮，程燕，等．一种白僵菌代谢产物提取物抗实验性抑郁的研究．中国药理学通报，2003；19(5)：568～570
6．晏忠，罗质璞．抗抑郁药理实验方法．见：张均田主编．现代药理实验方法(上册)(第一版)．北京：北京医科大学中国协和医科大学联合出版社，1998：1061～1062
7. Willner E Animal model of depression: an overview. Pharmac Ther, 1990; 45:425～455
8. Kohler U, Raucac. Effects of BCH325 on open field behavior after chronic stress procedure.Peptides, 1992; 13(1): 141～144
9．张有志，聂惠民，张德昌，等．柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究．中国中医基础杂志，2001；7(7)：30～32
10. Willner P. Validity, reliability and utility of the chronic mild stress model of depresson: a 10-year review and evaluation.[J]. Psychopharmacology(Berl), 1997; 134(4): 319～329
11．章功良，赵乐章，张瑾，等．腹外侧视前核微量注射 5-羟色胺酸和麦角新碱对大鼠睡眠-觉醒周期的影响．安徽医科大学学报，2003；38(1)：6～8
12. Jun Lu, Mary Ann Greco, Priyattam Shiromani, et al. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. The Journal of Neuroscience, 2000; 20(10): 3830～3842
13．陈顺志，金有余，李常培，张增全．过氧化脂质TBA显色的三种方法学比较．临床检验杂志，1984；2(4)：8～10
14．韩玉慧，严进，郑兴东等．睫状神经营养因子对应激大鼠下丘脑、垂体精氨酸加压素含量的影响．解剖学杂志，2000；23(6)：491～495
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2．卢艳花，谭仁祥．抗抑郁天然药物的研究进展．申草药，2000；31(9)：718～720
3．胡丰林，樊美珍，李增智．一种白僵菌代谢产物中生物活性物质的研究．菌物系统，2000：19(4)：522～525
4．周兰兰，明亮，程燕，等．BCEF0083抗单胺氧化酶作用的研究冲国药理学通报，2003；19(4)：404～407
5．周兰兰，明亮，程燕，等．一种白僵菌代谢产物提取物抗实验性抑郁的研究．中国药理学通报，2003；19(5)：568～570
6．晏忠，罗质璞．抗抑郁药理实验方法．见：张均田主编．现代药理实验方法(上册)(第一版)．北京：北京医科大学中国协和医科大学联合出版社，1998：1061～1062
7. Willner E Animal model of depression: an overview. Pharmac Ther, 1990; 45:425～455
8. Kohler U, Raucac. Effects of BCH325 on open field behavior after chronic stress procedure.Peptides, 1992; 13(1): 141～144
9．张有志，聂惠民，张德昌，等．柴胡加龙骨牡蛎汤等经方治疗抑郁症的动物行为学研究．中国中医基础杂志，2001；7(7)：30～32
10. Willner P. Validity, reliability and utility of the chronic mild stress model of depresson: a 10-year review and evaluation.[J]. Psychopharmacology(Berl), 1997; 134(4): 319～329
11．章功良，赵乐章，张瑾，等．腹外侧视前核微量注射 5-羟色胺酸和麦角新碱对大鼠睡眠-觉醒周期的影响．安徽医科大学学报，2003；38(1)：6～8
12. Jun Lu, Mary Ann Greco, Priyattam Shiromani, et al. Effect of lesions of the ventrolateral preoptic nucleus on NREM and REM sleep. The Journal of Neuroscience, 2000; 20(10): 3830～3842
13．陈顺志，金有余，李常培，张增全．过氧化脂质TBA显色的三种方法学比较．临床检验杂志，1984；2(4)：8～10
14．韩玉慧，严进，郑兴东等．睫状神经营养因子对应激大鼠下丘脑、垂体精氨酸加压素含量的影响．解剖学杂志，2000；23(6)：491～495
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