金银花注射液对兔IL-1_β性发热的解热作用及机制的实验研究
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摘要
目的
本实验用新西兰兔复制IL-1_β发热模型，在观察金银花注射液(Jinyinhua injection，JYH)解热作用的基础上，应用原位杂交技术检测静脉注射JYH对白介素-1_β(interleukin-1_β，IL-1_β)作用下新西兰兔视前区-下丘脑前部(preoptic anterior hypothalamus，POAH)组织中前列腺素E受体(E-type prostaglandin receptor，EP)EP_3 mRNA表达的影响，以及通过微电极细胞外放电记录技术观察JYH对IL-1_β作用下POAH温度敏感神经元放电频率的影响，以阐明金银花注射液的中枢解热机制，为其临床应用提供实验依据和理论指导。
方法
1．JYH解热作用的研究：
健康新西兰兔24只，体重1.5-2.5 kg，基础体温38.5-39.2℃，适应实验环境3d后，随机分为4组，分别为生理盐水组(NS)：静脉注射NS，1 ml／只；IL-1_β组：静脉注射IL-1_β，100 ng／只；JYH+IL-1_β组：静脉注射JYH，1 ml／只，30 min后再静脉注射IL-1_β(100 ng／只)；JYH组：静脉注射JYH，1 ml／只。给药后每隔10min测结肠温度1次，连续70 min，观察各组新西兰兔的体温变化。
2．JYH的解热作用机制研究：
(1) 动物处理同前，于给药70 min后，用多聚甲醛作灌注固定，取下丘脑做冰冻切片，用原位杂交法测EP_3 mRNA。
(2) 取健康新西兰兔，麻醉后固定在立体定位仪上，引出POAH神经元放电，并鉴定神经元的温度敏感性；待放电稳定约10 min后，静脉注射IL-1_β 100ng／只，当放电频率明显改变时，注射JYH 1 ml／只，观察放电频率的变化。同时用生理盐水作对照。
Objective
To study the antipyretic effect and the mechanisms of Jinyinhua injection (JYH) , we chose the IL-1_β-induced febrile rabbits as the experiment models and observed the antipyretic effect of JYH. To further investigated the mechanisms, we observed the expression of EP3 mRNA by using ISH (in situ hybridization) and the firing rate of thermosensitive neurons by using extracellular microelectrode technique in the POAH( preopric anterior hypothalamus, POAH ).
Methods
1. The experimental research on antipyretic effect of JYH:
The experiment were performed on 24 New-zealand white rabbits of both sexes weighting 1.5-2.5 kg. All rabbits were kept in the experimental environment for 3 days before the experiment. The environmental temperature was maintained at 23 ±1℃ during experiment. 24 rabbits were devided into four groups randomly: (1) NS control group; (2) JYH treatment group; (3) IL-1_β treatment group; (4) JYH and IL-1β treatment group. We observed the colonic temperature of the all groups and noted every 10 min until 70 min. Then all rabbits were decapitated quickly and their hypothalamus tissues were taken out for the next experiments.
2. The experimental research on the mechanisms of antipyretic effect of JYH: (1) The expression of EP_3 mRNA in the POAH of febrile rabbits:
This part, we used the prepared hypothalamus tissues to carry out frozen sections, then detected the expression of EP_3 mRNA in the POAH by
.
本实验用新西兰兔复制IL-1_β发热模型，在观察金银花注射液(Jinyinhua injection，JYH)解热作用的基础上，应用原位杂交技术检测静脉注射JYH对白介素-1_β(interleukin-1_β，IL-1_β)作用下新西兰兔视前区-下丘脑前部(preoptic anterior hypothalamus，POAH)组织中前列腺素E受体(E-type prostaglandin receptor，EP)EP_3 mRNA表达的影响，以及通过微电极细胞外放电记录技术观察JYH对IL-1_β作用下POAH温度敏感神经元放电频率的影响，以阐明金银花注射液的中枢解热机制，为其临床应用提供实验依据和理论指导。
方法
1．JYH解热作用的研究：
健康新西兰兔24只，体重1.5-2.5 kg，基础体温38.5-39.2℃，适应实验环境3d后，随机分为4组，分别为生理盐水组(NS)：静脉注射NS，1 ml／只；IL-1_β组：静脉注射IL-1_β，100 ng／只；JYH+IL-1_β组：静脉注射JYH，1 ml／只，30 min后再静脉注射IL-1_β(100 ng／只)；JYH组：静脉注射JYH，1 ml／只。给药后每隔10min测结肠温度1次，连续70 min，观察各组新西兰兔的体温变化。
2．JYH的解热作用机制研究：
(1) 动物处理同前，于给药70 min后，用多聚甲醛作灌注固定，取下丘脑做冰冻切片，用原位杂交法测EP_3 mRNA。
(2) 取健康新西兰兔，麻醉后固定在立体定位仪上，引出POAH神经元放电，并鉴定神经元的温度敏感性；待放电稳定约10 min后，静脉注射IL-1_β 100ng／只，当放电频率明显改变时，注射JYH 1 ml／只，观察放电频率的变化。同时用生理盐水作对照。
Objective
To study the antipyretic effect and the mechanisms of Jinyinhua injection (JYH) , we chose the IL-1_β-induced febrile rabbits as the experiment models and observed the antipyretic effect of JYH. To further investigated the mechanisms, we observed the expression of EP3 mRNA by using ISH (in situ hybridization) and the firing rate of thermosensitive neurons by using extracellular microelectrode technique in the POAH( preopric anterior hypothalamus, POAH ).
Methods
1. The experimental research on antipyretic effect of JYH:
The experiment were performed on 24 New-zealand white rabbits of both sexes weighting 1.5-2.5 kg. All rabbits were kept in the experimental environment for 3 days before the experiment. The environmental temperature was maintained at 23 ±1℃ during experiment. 24 rabbits were devided into four groups randomly: (1) NS control group; (2) JYH treatment group; (3) IL-1_β treatment group; (4) JYH and IL-1β treatment group. We observed the colonic temperature of the all groups and noted every 10 min until 70 min. Then all rabbits were decapitated quickly and their hypothalamus tissues were taken out for the next experiments.
2. The experimental research on the mechanisms of antipyretic effect of JYH: (1) The expression of EP_3 mRNA in the POAH of febrile rabbits:
This part, we used the prepared hypothalamus tissues to carry out frozen sections, then detected the expression of EP_3 mRNA in the POAH by
.
引文
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11．路秀英，杨贵贞，姜文．膈下迷走神经切断降低LPS所致大鼠发热及室旁核神经元放电频率[J]．中国应用生理学杂志，2002，18(4)：337-339．
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2. Jefferies C, Bowie A, Brady G, et al. Transactivation by the p65 subunit of NF-kappaB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Racl [J]. Mol Cell Biol, 2001,21 (14): 4544-4552.
3. Mantovani A, Locati M, Vecchi Aet al. Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines[J].Trends Immunol, 2001,22(6): 328-336.
4. Virta M, Hurme M, Helminen M. Increased plasma levels of pro-andanti-inflammatory cytokines in patients with febrile seizures[J]. Epilepsia,2002,43(8): 920-923.
5. Kozak W, Kluger MJ, Soszynski D, et al. IL-6 and IL-1beta in fever. Studies using cytokine-deficient (knock out)mice[J]. Ann N Y Acad Sci, 1998, (856): 33-47.
6. Leon LR, Kozak W. Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice[J]. Am J Physiol, 1997,272(2): 563-569.
7. Benigini F, Fantuzzi G, Sacco S, et al. Six different cytokines that share GP130 as a receptor subnuit, induce serum amyloid A and potentiate the induction ofinterleukin-6 and the activation of the hypothalamus-pituitary-adrenal axis by intedeukin-1[J]. Blood, 1996,87(5): 1851-1859.
8. Sundgren AK, Ostlund P, Bartfai T, et al. IL-6 is essential in TNF-α-induced fever[J]. Am J Physiol, 1998,275(6): 2028-2034.
9. McLay RN, Kastin A J, Zadina JE, et al. Passage of interleukin-l-beta across the blood-brain barrier is reduced in aged mice: a possible mechanism for diminished fever in aging[J]. Neuroimmunomodulation, 2000,8(3): 148-153.
10. Pan W, Kastin AJ. TNF alpha transport across the blood-brain barrier in abolished inreceptor knockout mice[J]. Exp Neurol,2002,174 (2): 193-200.
11．路秀英，杨贵贞，姜文．膈下迷走神经切断降低LPS所致大鼠发热及室旁核神经元放电频率[J]．中国应用生理学杂志，2002，18(4)：337-339．
12．杨永录，支东学，王绪明．胆碱能阻断剂对梭曼引起大鼠降温效应的影响[J]．中国病理生理杂志，2004，20(1)：60-62．
13. Lyudmila V, Borovikova, Svetlana Ivanova, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin[J]. Nature, 2000, 405 (6785): 458-462.
14. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha-7 subunit is an essential regulator of inflammation [J]. Nature,2003,421(6921): 384-388.
15. Quan N, Chronic overexpression of proinflammatory cytokines and histopathology in the brains of rats infected with trypanosoma brucei[J]. J Comp Neurol, 1999, 414(1):114-130.
16. Yamagata K, Matsumura K, Inoue W,et al.Coexpression of microsomal-type prostagladin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever[J]. J Neurosci. 2001,21 (8), 2669-2677.
17. Dinarello CA. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed Journal of Endotoxin Research, 2004, 10 (4): 201-222.
18. Ek M, Engblom D, Saha S, et al. Inflammatory response: pathway across he blood brain barrier[J]. Nature, 2001, 410 (6827): 544-549.
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