臺灣博碩士論文加值系統

葛根素 (puerarin) 為野葛 (Pueraria lobata) 主要活性成分之一，係 isoflavones 類化合物，是中醫臨床上常用之清熱解表藥物，已知為 beta-adrenergic receptor 阻斷劑，具有解痙、抗心率不整、降血壓等作用，此外還具有解熱等作用，但有關 puerarin 解熱降溫作用之機轉至今仍並未見有研究報告提出；因此本研究擬就 puerarin 對清醒大鼠之解熱降溫作用機轉進行探討，期能有助於中藥之科學化。
研究結果顯示，由側腦室給予puerarin (100mg/kg, intracerebroventricular injection; i.c.v.) 可引起室溫下 (24±1℃) 正常清醒大鼠體溫降低作用，且腹腔給予 puerarin (5-30mg/kg, intraperitoneal administration; i.p.) 可引起一具劑量依存性之體溫降低作用，並同步降低大鼠下視丘 serotonin (5-HT) 之濃度；此降溫作用會因側腦室給予 serotonin neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 200mg/10ml, i.c.v.) 或皮下給予5-HT1A 受體之拮抗劑 (-)-pindolol (0.05, 0.5mg/kg, subcutaneously injection; s.c.)所減弱，但可被皮下給予 5-HT1A 受體之致效劑 8-hydroxy-dipropylaminotetralin (8-OH-DPAT; 0.05mg/kg; s.c.) 所加強。此外，puerarin 誘發之降溫作用亦會被5-HT2 受體之致效劑 (±)-2,5-dimethoxy-4-iodoamphetamine (DOI; 5, 10mg/10ml; i.c.v.; 0.5, 1mg/kg; i.p.)、quipazine (0.1, 1mg/kg; i.p.) 所拮抗，或為 5-HT2 受體之拮抗劑 pirenperone (0.2mg/kg; s.c.)、ketanserin (1mg/kg; i.p.) 所加強。由此可推知 puerarin 可能藉由降低下視丘 serotonin 之濃度，並作用於 postsynaptic serotonin 受體，致活 5-HT1A 受體及阻斷 5-HT2 受體，而達到降低體溫之作用。
其次，puerarin (10,30mg/kg; i.p.) 對室溫下細菌內毒素 lipopolysaccharide (LPS; 100mg/kg; i.p.) 所誘發發燒之大鼠，具有明顯及劑量依存性之解熱作用；puerarin (100mg/10ml, i.c.v.; 10, 30mg/kg; i.p.) 對側腦室給予內生性致熱原 IL-1b (10ng/10ml) 誘發之發燒反應與下視丘 serotonin 濃度增加現象，亦具有抑制作用。此外，puerarin (10, 30mg/kg; i.p.) 可明顯抑制 NO donor (S-nitroso-N-acetylpenicillamine; SNAP, 10mg/10ml; i.c.v.)、NO releaser (sodium nitroprusside; SNP; 20mg/10ml; i.c.v.) 和 cGMP 之類似物 8-Bromo-cGMP (100mg/10ml) 及 PGE2 (100mg/10ml; i.c.v.) 或 cAMP 之類似物 8-Bromo-cAMP (40mg/10ml, intrahypothalamic injection; i.h.)等熱原媒介物質物所誘發之發燒反應。
綜合以上結果，puerarin 具明顯之解熱降溫作用，其作用機轉可能是藉由抑制中樞 serotonin、nitric oxide 及 prostaglandin 等系統之活性所達成。

Puerarin is an isoflavone compound isolated from Pueraria lobata. The Puerariae radix has been used for antipyretic in Chinese. Puerarin, a beta-adrenergic receptor blocker, possesses anticonvulsive, antiarrhythmic and antihypertension effects. It also reduces 2,4-dinitrophenol-induced hyperthermia. However, the effects of puerarin on normal body temperature and pyrogenic fever are unknown. On this account, in the present study, experiments were carried out to assess the effects of puerarin on thermoregulatory responses in unanesthetized rats.
Puerarin (100mg/10ml,i.c.v.;5-30mg/kg, i.p.) caused a dose-related fall in both colonic temperature and the 5-HT release in the hypothalamus at room temperature. The serotonin release in the hypothalamus was monitored with a microdialyzed probe is association with microdialysis-high perforemance liquid chromatography. Puerarin induced hypothermia was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT; a serotonin neurotoxin, 200mg/10ml; i.c.v., one week ago), or (-)-pindolol (a 5-HTIA receptor/b adrenoceptor antagonist; 0.05, 0.5mg/kg; s.c.) but potentiated by (±)-8-hydroxydiopropylamino-teralin (8-OH-DPAT; a 5-HT1A receptor agonist; 0.05mg/kg; s.c.). In addition, the puerarin induced hypothermia was attenuated by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI; 5-HT2 receptor agonist; 5, 10mg/10ml; i.c.v.; 0.5, 1mg/kg; i.p.) or quipazine (a 5-HT2 receptor agonist; 0.5, 1mg/kg; i.p.), but potentiated by ketanserin (5-HT2 receptor antagonist; 1mg/kg; i.p.) or pirenperone (5-HT2 receptor antagonist; 0.2mg/kg; s.c.). These results indicate that puerarin may act through 5-HT1A receptor activation or 5-HT2 receptor antagonism within the brain to induce its hypothermia.
The fever induced by either lipopolysaccharide (LPS, 100mg/kg; i.p.) or interleukin-1b (IL-1b, 10ng/10ml; i.c.v.) was attenuated by treatment with puerarin (100mg/10ml, i.c.v.; 10, 30mg/kg, i.p.). Our microdialysis data revealed that puerarin (10, 30mg/kg; i.p.) reduces the increased 5-HT release in the hypothalamus and fever provoked by IL-1b injection. The hyperthermia induced by either S-nitroso-N-acetylpenicillamine (nitric oxide donor, 10mg/10ml; i.c.v.), sodium nitroprusside (NO releaser, 20mg/10ml; i.c.v.), 8-Bromo-cGMP (cGMP analogue, 100mg/10ml; i.c.v.), PGE2 (100mg/10ml; i.c.v.), or 8-Bromo-cAMP (cAMP analogue, 40mg/10ml; i.h.) was attenuated by treatment with puerarin (10, 30mg/kg; i.p.) in rats.
In conclusion, puerarin exerts its thermoregulatory response mainly through the serotoninergic, nitrergic or prostaglandinergic pathways in the central nervous system of rat brain.

中文摘要!
英文摘要iii
第一章緒 言1
第二章總 論4
第一節葛根之本草及文獻考察4
一、葛根之本草考察4
二、葛根之主要成分考察14
三、葛根藥理作用文獻考察16
第二節葛根素之文獻考察22
一、來源22
二、葛根素之結構與理化性質22
三、葛根素之藥理作用考察23
第三節體溫調節作用28
第三章實驗之部31
第一節實驗試劑31
第二節實驗動物32
第三節實驗方法32
一、大鼠之訓練與肛溫之測量方法32
二、室溫下 puerarin 對正常大鼠肛溫變化之影響32
三、大鼠腦內給藥管之安裝技術33
四、Puerarin 對正常大鼠下視丘 serotonin 濃度之影響33
五、破壞腦內 serotoninergic system 藥物對 puerarin 降溫作用之影響35
六、改變腦內 serotoninergic system 藥物對 puerarin 降溫作用之影響35
七、Puerarin 對 LPS 誘發大鼠發燒溫度變化之影響36
八、Puerarin 對 IL-1b 誘發大鼠發燒及下視丘 serotonin 濃度之影響37
九、Puerarin 對 S-nitroso-N-acetylpenicillamine (SNAP)、sodium nitroprusside (SNP) 與 8-Bromo-cGMP 誘發大鼠發燒溫度變化之影響37
十、Puerarin 對 prostaglandin E2 (PGE2) 與 8-Bromo-cAMP 誘發大鼠發燒溫度變化之影響38
十一、統計學分析38
第四節實驗結果39
一、室溫下 puerarin 對正常大鼠肛溫變化之影響39
二、Puerarin 對正常大鼠下視丘 serotonin 濃度之影響41
三、破壞腦內 serotoninergic system 藥物對 puerarin 降溫作用之影響43
四、改變腦內 serotoninergic system 藥物對 puerarin 降溫作用之影響44
五、Puerarin 對 LPS 誘發大鼠發燒溫度變化之影響51
六、Puerarin 對 IL-1b 誘發大鼠發燒及下視丘 serotonin 濃度之影響52
七、Puerarin 對 S-nitroso-N-acetylpenicillamine (SNAP)、sodium nitroprusside (SNP) 與 8-Bromo-cGMP 誘發大鼠發燒溫度變化之影響55
八、Puerarin 對 prostaglandin E2 (PGE2) 與 8-Bromo-cAMP 誘發大鼠發燒溫度變化之影響56
第四章討論57
第五章結論65
參考文獻66
表 目 錄
Table 1.The effects of puerarin on the hypothalamic serotonin (5-HT) release in the normal rats .41
Table 2.The effects of puerarin on the colonic temperature in rats treated by the 5,7-DHT..43
Table 3.The effects of puerarin on the colonic temperature in the hyperthermia rats induced by lipopolysaccharide (LPS).51
Table 4.The effects of puerarin on the colonic temperature in the hyperthermia rats induced by interleukin-1b (IL-1b)..52
Table 5.The effects of puerarin on the colonic temperature and hypothalamic 5-HT release in the hyperthermia rats induced by interleukin-1b (IL-1b)..53
Table 6.Effects of puerarin on the hyperthermia induced by intracerebroventricular injection (i.c.v.) of S-nitroso-N-acetylpenicillamine (SNAP) or sodium nitroprusside (SNP) or 8-Bromo-cGMP.55
Table 7.Effects of puerarin on the hyperthermia induced by intracerebroventricular injection (i.c.v.) of prostaglandin E2 (PGE2) or intrahypothalamic injection (i.h.) of 8-Bromo-cAMP.56
圖 目 錄
Fig. 1葛根之本草系統圖 13
Fig. 2Puerarin之結構22
Fig. 3Time course of the effects of intraperitioneal administraction of puerarin on colonic temperature in rats39
Fig. 4Time course of the effects of intracerebronventricular administraction of puerarin on colonic temperature in rats40
Fig. 5Time course of the effects of intraperitioneal administraction of puerarin on (a) colonic temperature (Tco) and (b) hypothalamic 5-hydroxytryptamine (5-HT) release in five control rats42
Fig. 6Effects of (-)-pindolol (0.05, 0.5mg/kg; s.c.) on the hypothermic response of puerarin in rats44
Fig. 7Effects of 8-OH-DPAT (0.01, 0.05mg/kg; s.c.) on the hypothermic response of puerarin in rats45
Fig. 8Effects of ketanserion (0.5, 1mg/kg; i.p.) on the hypothermic response of puerarin in rats46
Fig. 9Effects of pirenperone (0.05, 0.2mg/kg; s.c.) on the hypothermic response of puerarin in rats47
Fig.10Effects of quipazine (0.1, 1mg/kg; i.p.) on the hypothermic response of puerarin in rats48
Fig.11Effects of DOI (0.5, 1mg/kg; i.p.) on the hypothermic response of puerarin in rats49
Fig.12Effects of DOI (5, 10mg/rat; i.c.v.) on the hypothermic response of puerarin in rats50
Fig.13Time course of the effects of interleukin 1b (IL-1b; 10ng/10ml; i.c.v.) on (a) colonic temperature (Tco) and (b) hypothalamic 5-hydroxytryptamine (5-HT) release in vehicle (·) and 30mg/kg puerarin treated (a) rats (n=5 per group)54

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