本文選題：百可利 + 帕金森病震顫�。� 參考：《沈陽藥科大學(xué)》2012年博士論文

【摘要】：百可利(Baicalein),化學(xué)名稱為5, 6, 7 -三羥基黃酮,是最早從唇形科(Labiatae)黃芩屬(Scutellaria)多年生草本中藥植物黃芩(Scutellaria baicalensis Georgi)的干燥根中提取得到的黃酮類化合物,是黃芩的最主要活性成分之一。百可利具有多種藥理作用,如:抗菌、抗病毒、抗炎、抗變態(tài)反應(yīng)、抗氧化、清除氧自由基、抗腫瘤、抗凝等。百可利對多種疾病包括炎癥、腫瘤、纖維化性疾病、心腦血管性疾病具有良好的防治作用。最近研究表明百可利可以保護(hù)局部缺血的神經(jīng)元免受損傷,減輕炎癥介導(dǎo)的多巴胺能神經(jīng)元變性。這些研究結(jié)果提示百可利可能是一個有效的治療神經(jīng)退行性疾病的化合物。2007年本實(shí)驗(yàn)室經(jīng)過高通量篩選證明百可利對多巴胺和6-羥基多巴胺(6-OHDA)引起的多巴胺能神經(jīng)元損傷具有選擇性神經(jīng)保護(hù)活性,后經(jīng)多種篩選模型評價,證明其可靠的生物活性,并經(jīng)動物模型評價,顯示出一定的藥理作用,初步定為先導(dǎo)化合物,編號為DL0705。然而,百可利溶解性較差,在水中幾乎不溶,為此,課題組對其化學(xué)成分進(jìn)行了晶型研究,發(fā)現(xiàn)和證明其存在有多晶型現(xiàn)象。通過穩(wěn)定性實(shí)驗(yàn)與生物學(xué)試驗(yàn)證明:晶β型穩(wěn)定性好,生物利用度高,屬優(yōu)勢藥物晶型。臨床前研究結(jié)果表明:百可利能夠減輕帕金森病震顫癥狀及其所導(dǎo)致的神經(jīng)癥候、日常生活運(yùn)動障礙等,有望成為作用獨(dú)特的治療帕金森病的藥物,具有良好的藥用價值和新藥開發(fā)前景。在前期研究的基礎(chǔ)上,本論文在確證百可利治療帕金森病震顫有效的基礎(chǔ)上,對其作用機(jī)制進(jìn)行了探討。第一章百可利防治中樞神經(jīng)系統(tǒng)退行性疾病研究現(xiàn)狀本章首先在查閱了大量文獻(xiàn)的基礎(chǔ)上,對近幾十年的百可利的藥理學(xué)研究進(jìn)展作一綜述。該綜述包括七個方面:抗菌抗病毒作用、抗炎及抗變態(tài)反應(yīng)作用、抗氧化作用、抗腫瘤作用、抗纖維化作用、心腦血管保護(hù)作用以及神經(jīng)保護(hù)及促細(xì)胞轉(zhuǎn)化與分化作用。然后在第二節(jié)探討了百可利與神經(jīng)系統(tǒng)退行性疾病的關(guān)系,從抑制神經(jīng)細(xì)胞退行性改變的啟動因子、阻斷神經(jīng)細(xì)胞退行性改變的信號傳導(dǎo)過程以及激活內(nèi)源性神經(jīng)保護(hù)機(jī)制等方面探討百可利用于防治神經(jīng)系統(tǒng)退行性疾病的科學(xué)性。第三節(jié)是關(guān)于百可利與帕金森病的討論。本章最后對百可利防治帕金森病進(jìn)行了展望。第二章百可利對6-OHDA致帕金森病大鼠震顫癥狀抑制作用及機(jī)制研究本章采用6-OHDA前腦內(nèi)側(cè)束(MFB)定位注射建立偏側(cè)大鼠帕金森病動物模型,通過檢測行為學(xué),神經(jīng)遞質(zhì)和多巴胺能神經(jīng)元數(shù)目來評價百可利在體內(nèi)的活性和藥效。然后通過檢測酪氨酸羥化酶(TH),多巴胺轉(zhuǎn)運(yùn)體(DAT),囊泡單胺轉(zhuǎn)運(yùn)體2 (VMAT2),膠質(zhì)源性纖維蛋白(GFAP),小膠質(zhì)細(xì)胞特異性蛋白(0X42),谷氨酰胺合成酶(GS),GABA轉(zhuǎn)運(yùn)體(GABA-T),谷氨酸脫羧酶67 (GAD67),谷氨酸脫氫酶(GDH),細(xì)胞色素氧化酶亞單位Ⅰ (C0I),腺苷A2A受體(A2AR),D1受體(D1R),D2受體(D2R)和乙酰膽堿受體(AchR)等多種相關(guān)指標(biāo)來探討百可利可能的抗帕金森病作用機(jī)制。實(shí)驗(yàn)結(jié)果進(jìn)一步肯定了本實(shí)驗(yàn)室的前期研究工作成果,并得出以下結(jié)論:1.百可利可劑量和時間依賴性的減輕帕金森病(PD)大鼠的肌肉震顫頻率和震顫幅度,在給藥后1Omin即可出現(xiàn)藥效,30min達(dá)到最高,藥效可持續(xù)5個小時。其抗震顫作用的強(qiáng)度可優(yōu)于多巴胺遞質(zhì)補(bǔ)充劑美多芭。2.通過比較震顫型PD動物和旋轉(zhuǎn)型PD動物病理生理上的區(qū)別,發(fā)現(xiàn)以震顫癥狀為主的PD大鼠損傷主要累及黑質(zhì)致密部(SNc),且損傷程度較輕,功能紊亂主要出現(xiàn)在丘腦底核(STN)和外側(cè)蒼白球(GPe);而以旋轉(zhuǎn)癥狀為主的PD大鼠損傷主要累及黑質(zhì)內(nèi)側(cè)部(SNM)和黑質(zhì)外側(cè)部(SNL),且受損相對嚴(yán)重,功能紊亂主要出現(xiàn)在紋狀體。3.百可利可平衡PD大鼠基底神經(jīng)節(jié)區(qū)多巴胺(DA)、谷氨酸(Glu)和γ-氨基丁酸(GABA)的神經(jīng)遞質(zhì)的紊亂,增加GPe的抑制性輸出,抑制STN的興奮性輸出而拮抗基底神經(jīng)節(jié)過度的抑制性輸出,恢復(fù)丘腦皮層的正常興奮狀態(tài)。同時發(fā)現(xiàn)百可利對DA的作用明顯比Glu和GABA弱,可說明百可利治療PD震顫癥狀效果好,而對強(qiáng)直-運(yùn)動不能癥狀(大鼠的旋轉(zhuǎn)癥狀)效果差。4.百可利對神經(jīng)遞質(zhì)的調(diào)節(jié)作用與其增加DAT和GS的蛋白表達(dá),降低GABA-T的蛋白表達(dá)有明顯相關(guān)性。5.百可利可通過上調(diào)D1和D2受體,下調(diào)A2A受體而發(fā)揮其抗PD作用。6.百可利可拮抗PD狀態(tài)下星型膠質(zhì)細(xì)胞和小膠質(zhì)細(xì)胞的過度激活而發(fā)揮對DA神經(jīng)的保護(hù)作用。第三章百可利對MPTP帕金森病食蟹猴模型的治療作用及機(jī)制研究為進(jìn)一步確證百可利的抗PD震顫作用,本章采用了癥狀及病理、生化改變方面均酷似人類PD,而且穩(wěn)定可靠的1-甲基-4-苯基-1,2, 3, 6-四氫吡啶(MPTP)致帕金森病食蟹猴模型,進(jìn)一步觀察百可利對帕金森病動物行為學(xué)的影響,并深入探討其作用機(jī)制。結(jié)果表明,百可利能改善MPTP致帕金森病食蟹猴模型的行為學(xué)異常,對上肢精細(xì)運(yùn)動障礙、僵凍、運(yùn)動減緩和靜止震顫等PD癥狀均有不同程度的緩解。在行為學(xué)實(shí)驗(yàn)基礎(chǔ)上,本章通過realtime RT-PCR實(shí)驗(yàn),在基因水平上探討了與PD發(fā)病機(jī)制相關(guān)的幾種酶學(xué)的改變,結(jié)果發(fā)現(xiàn)百可利可上調(diào)PD猴THmRNA表達(dá),驗(yàn)證了百可利的神經(jīng)保護(hù)作用。此外,百可利可下調(diào)紋狀體兒茶酚氧位甲基轉(zhuǎn)移酶(COMT),單胺氧化酶B(MAO-B )和GABA-T mRNA的表達(dá),上調(diào)STN的GS mRNA的表達(dá),進(jìn)一步在基因水平上解釋了百可利調(diào)節(jié)基底神經(jīng)節(jié)DA ,Glu和GABA遞質(zhì)平衡的作用。COI、GAD67和GDHmRNA檢測結(jié)果表明,百可利可明顯增加PD猴GPe神經(jīng)元的活性,抑制GPi和STN的神經(jīng)元活性。這些結(jié)果進(jìn)一步證明了百可利通過平衡PD動物基底神經(jīng)節(jié)神經(jīng)遞質(zhì)的紊亂,使GPi、GPe和STN的活動恢復(fù)常態(tài),從而發(fā)揮其抗PD震顫的作用。第四章百可利抗Glu誘導(dǎo)的中腦DA能神經(jīng)元毒性作用及機(jī)制研究隨著對帕金森病的深入研究,人們逐漸認(rèn)識到Glu在PD的發(fā)病中扮演了重要角色。由于DA的減少,Glu 一方面通過氧化性神經(jīng)毒性和興奮性神經(jīng)毒性誘導(dǎo)DA神經(jīng)元變性壞死;另一方面,DA的減少可增加STN的谷氨酸能神經(jīng)元的興奮性使Glu釋放增多,導(dǎo)致基底神經(jīng)節(jié)運(yùn)動環(huán)路功能紊亂而參與PD運(yùn)動癥狀的產(chǎn)生。在第二、三章實(shí)驗(yàn)中發(fā)現(xiàn)百可利對Glu有明顯的拮抗作用,在此工作基礎(chǔ)上,本章通過體外培養(yǎng)中腦DA能神經(jīng)元,重點(diǎn)研究百可利對Glu誘導(dǎo)的氧化性神經(jīng)毒性和興奮性神經(jīng)毒性的拮抗作用,并對Glu介導(dǎo)的下游的幾個功能性蛋白進(jìn)行研究。結(jié)果發(fā)現(xiàn),百可利可明顯抑制Glu誘導(dǎo)的氧化性神經(jīng)毒性,表現(xiàn)在增加神經(jīng)元的存活率,降低細(xì)胞內(nèi)活性氧簇(ROS)含量,增加線粒體膜電位,抑制細(xì)胞凋亡率等。在采用熒光探針Fura-2/AM和鎘還原法對Glu誘導(dǎo)的細(xì)胞內(nèi)鈣離子增多和一氧化氮(NO)釋放增加的實(shí)驗(yàn)中發(fā)現(xiàn),百可利可明顯拮抗Glu介導(dǎo)的細(xì)胞內(nèi)鈣的增多和NO釋放增加,說明百可利可拮抗Glu介導(dǎo)的興奮性神經(jīng)毒作用,同時也間接反映了百可利可通過抑制Glu介導(dǎo)的鈣內(nèi)流而降低STN神經(jīng)元的興奮性,進(jìn)而控制PD的震顫癥狀。隨后我們觀察了百可利對Glu致大鼠原代中腦DA能神經(jīng)元損傷后神經(jīng)元型一氧化氮合酶(nNOS)、FOS和鈣/鈣調(diào)蛋白依賴性蛋白激酶Ⅱ(CaMKⅡ)蛋白表達(dá)的影響。免疫印記實(shí)驗(yàn)結(jié)果顯示百可利可明顯拮抗Glu誘導(dǎo)的nNOS的表達(dá),說明百可利的抗氧化和神經(jīng)元保護(hù)作用與抑制nNOS活性有關(guān)。FOS蛋白結(jié)果表明,百可利通過下調(diào)該蛋白的活性而對PD的震顫癥狀起到一個長期調(diào)節(jié)作用,而百可利對CaMKⅡ蛋白表達(dá)無影響。T型鈣通道是近年來新發(fā)現(xiàn)的抗帕金森病震顫的一個新靶點(diǎn)。帕金森病患者基底神經(jīng)節(jié)運(yùn)動環(huán)路功能紊亂而導(dǎo)致丘腦網(wǎng)狀核(NRT)產(chǎn)生抑制性突觸后電位(IPSP),隨后激活T型鈣通道而產(chǎn)生低閾值的鈣棘波(LTS),LTS可誘發(fā)NRT神經(jīng)元產(chǎn)生節(jié)律性的放電,這種節(jié)律性放電可誘導(dǎo)丘腦-皮層的節(jié)律性運(yùn)動和外周的肌肉震顫活動。這一過程被認(rèn)為是PD震顫的最后通路�；诖死碚�,本章探討了百可利對T型鈣通道蛋白表達(dá)的影響,結(jié)果發(fā)現(xiàn)百可利可明顯下調(diào)T型鈣通道CAV3. 1和CAV3. 3蛋白表達(dá),提示這可能是百可利抗PD震顫的一個新靶點(diǎn)。第五章黃酮類化合物及其組合抗帕金森病震顫作用比較本章對百可利與相關(guān)的黃酮類化合物及其組合抗帕金森病震顫作用進(jìn)行了比較。實(shí)驗(yàn)結(jié)果表明,與特發(fā)性震顫抑制劑普萘洛爾和經(jīng)典的抗PD震顫藥美多芭相比,黃酮類的抗PD震顫作用有明顯的優(yōu)勢。同時通過合用藥物的藥效來看,黃酮類藥物之間可能有相同或相似的作用機(jī)制。因此對黃酮類化合物抗PD作用機(jī)制做深一步的研究,尋找對神經(jīng)系統(tǒng)具有活性的先導(dǎo)化合物,從而發(fā)現(xiàn)潛在的高效低毒神經(jīng)藥物,對于帕金森病的治療具有非常深遠(yuǎn)的意義。綜合上述各章研究結(jié)果,可以認(rèn)為,百可利抗帕金森病震顫的作用主要是通過:1.上調(diào)DAT, GS蛋白表達(dá),下調(diào)GABA-T蛋白表達(dá),抑制COMT和MAO-B的mRNA的表達(dá);2.平衡PD大鼠基底神經(jīng)節(jié)區(qū)DA、Glu和GABA神經(jīng)遞質(zhì)的紊亂;3.上調(diào)D1和D2受體,下調(diào)A2A受體;4.抑制ROS含量,增加線粒體膜電位水平,抑制細(xì)胞凋亡率,拮抗Glu氧化性神經(jīng)毒性;5.抑制鈣內(nèi)流、nNOS表達(dá)和NO釋放而拮抗Glu興奮性神經(jīng)毒性;6.下調(diào)Glu誘導(dǎo)的FOS蛋白的表達(dá);7.下調(diào)T型鈣通道CAV3.1和CAV3. 3蛋白表達(dá)。
[Abstract]:Baicalein, the chemical name of 5, 6, 7 - three hydroxy flavones, is the first flavonoids extracted from the dry root of Labiatae baicalensis Georgi (Scutellaria) perennial herb (Scutellaria baicalensis Georgi) in the family of Huang Qinshu (Scutellaria). It is one of the most important active ingredients of Scutellaria. Use, such as antibacterial, antiviral, anti-inflammatory, antiallergic, antioxidant, scavenging oxygen free radicals, anti-tumor, anticoagulant, and so on. Cisco has a good prevention and control effect on many diseases including inflammation, tumor, fibrotic disease, cardiovascular and cerebrovascular diseases. These findings suggest that curco may be an effective compound for the treatment of neurodegenerative diseases in.2007, a high throughput screening test in the laboratory to demonstrate selective neuroprotective activity of curyl on dopaminergic neuron damage induced by dopamine and 6- hydroxy dopamine (6-OHDA). After evaluation of a variety of screening models, it proved its reliable biological activity, and was evaluated by animal model. It showed a certain pharmacological effect. It was preliminarily designated as a pilot compound, which was numbered DL0705., but the solubility of 100 Keli was poor and almost insoluble in water. Therefore, the research group has studied its chemical composition and found and proved its existence. The phenomenon of polycrystalline form. Through the stability test and biological test, it is proved that the stability of crystal beta type is good, the bioavailability is high, which belongs to the dominant drug type. The results of pre clinical study show that it can reduce the symptoms of Parkinson's disease and the symptoms of the nerve, the disturbance of daily life and so on, and it is expected to become a unique therapeutic Parkinson. The medicine of the disease has good medicinal value and the prospect of the development of the new medicine. On the basis of the earlier study, this paper has discussed the mechanism of its action on the basis of confirming the effectiveness of the treatment of the tremor of Parkinson's disease. On the basis of this review, the progress of pharmacology in the last few decades is reviewed. This review includes seven aspects: antiviral and antiviral action, anti-inflammatory and antiallergic effect, antioxidation, antitumor, anti fibrosis, cardio cerebral vascular protection, neuroprotection and cell differentiation and differentiation. The two section discusses the relationship between BALCO and neurodegenerative diseases, the scientific nature of the third section of the treatment of the degenerative diseases of the nervous system, from the starting factors that inhibit the degeneration of the nerve cells, the signal transduction process of blocking the degeneration of the nerve cells, and the activation of the endogenous neuroprotective mechanism. A discussion about the prevention and treatment of Parkinson's disease. In this chapter, a prospect of the prevention and treatment of Parkinson's disease in the present chapter. Second a study on the inhibition of the tremor symptoms of 6-OHDA induced Parkinson's disease in rats and the mechanism study on the establishment of an animal model of partial rat Parkinson's disease by 6-OHDA anterior medial fasciculus injection (MFB). The number of neurotransmitters and dopaminergic neurons to evaluate the activity and efficacy of cytosine in the body. Then by detecting tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), glial derived fibrin (GFAP), microglia specific protein (0X42), glutamine synthetase (GS), GABA transporter (GABA-T) ) glutamic acid decarboxylase 67 (GAD67), glutamic dehydrogenase (GDH), cytochrome oxidase subunit I (C0I), adenosine A2A receptor (A2AR), D1 receptor (D1R), D2 receptor (D2R) and acetylcholine receptor (AchR) were used to explore the mechanism of the anti Parkinson action of BCO, and the experimental results further affirmed the early stage of this laboratory. The results of the work are studied and the following conclusions are drawn: 100 the frequency of muscle tremor and the amplitude of tremor of Parkinson's disease (PD) rats can be reduced by dose and time dependence. The efficacy of 1Omin can be found after the administration, and the maximum of 30min is reached and the efficacy of the drug is sustainable for 5 hours. The strength of its anti tremor effect is superior to the dopamine supplement mdopa.2. By comparing the pathophysiological differences between the tremor type PD animals and the rotating PD animals, it is found that the PD rats with the main tremor symptoms mainly involve the dense part of the substantia nigra (SNc), and the damage degree is lighter. The dysfunction mainly occurs in the nucleus of the subthalamic nucleus (STN) and the lateral globus pallidus (GPe), and the damage of the PD rats mainly with rotation symptoms is mainly involved in the black. The medial part of the mass (SNM) and the lateral part of the substantia nigra (SNL) and the damage are relatively serious. The dysfunction mainly occurs in the Basilar Ganglion of the striatum, which can balance the dopamine (DA), the glutamic acid (Glu) and the gamma aminobutyric acid (GABA) neurotransmitter, adding the inhibitory output of GPe and inhibiting the excitatory output of STN and antagonizing the basilar nerve. It was found that the effect of coryl on DA was significantly lower than that of Glu and GABA, and that the effect of Corp on the symptoms of PD tremor was better, but the effect of the tetanic motion (rat's rotation symptoms) on the effect of.4. on the neurotransmitters was worse than that of DAT and GS. The protein expression of GABA-T has a significant correlation with the expression of GABA-T protein,.5. 100 can protect the DA nerve by up regulation of D1 and D2 receptor, down regulation of A2A receptor and its anti PD action,.6. 100 can antagonize the overactivation of astrocytes and microglia in PD state, and the third cap on MPTP Parkinson's disease The therapeutic effect and mechanism of cynomolgus monkey model to further confirm the anti PD tremor effect of cynoli, this chapter adopts the symptoms and pathology, and the biochemical changes resemble human PD, and the stable and reliable 1- methyl -4- phenyl -1,2, 3, 6- four hydropyridine (MPTP) induced Parkinson's disease cynomolgus monkey model, further observe the action of cork to Parkinson's disease The effect of physical behavior is discussed and the mechanism of action is discussed in depth. The results show that cynoli can improve the behavioral abnormality of MPTP induced Parkinson's disease cynomolgus monkey model. The PD symptoms such as fine motor obstacle, freeze, movement slowing down and static tremor are alleviated in different degrees. On the basis of the study, this chapter passes the realtime RT-PCR experiment. The changes in several enzymes related to the pathogenesis of PD were discussed at the gene level. The results showed that 100 could up regulate the expression of THmRNA in PD monkey and verify the neuroprotective effect of clonolis. In addition, Bai can downregulate the expression of corpus striatum catechol oxygen methyltransferase (COMT), monoamine oxidase B (MAO-B) and GABA-T mRNA, up regulation of STN GS M The expression of RNA further explains the role of cloni at the gene level to regulate the balance of DA, Glu and GABA transmitters in the basal ganglia,.COI, GAD67 and GDHmRNA detection results show that BCO can significantly increase the activity of GPe neurons in PD monkeys and inhibit the activity of GPi and STN neurons. These results further demonstrate that the BCO is balanced by the balance of PD animals. The disorder of neurotransmitters in the basal ganglia, making the activities of GPi, GPe and STN restored to normal, and thus exerting their anti PD tremors. Fourth the toxicity and mechanism of the Glu induced DA energy neurons in Glu, with the in-depth study of the disease, people gradually realized that Glu plays an important role in the pathogenesis of PD. Glu, on the one hand, induces degeneration and necrosis of DA neurons by oxidative neurotoxicity and excitatory neurotoxicity; on the other hand, the decrease of DA can increase the excitability of STN glutamate neurons and increase the release of Glu, leading to the dysfunction of the basal ganglia movement loop and the production of PD movement symptoms. In the second, third chapter, the experiment was conducted. It was found that BCO has obvious antagonism to Glu. On the basis of this work, this chapter focuses on the study of the antagonism of clori on the oxidative neurotoxicity induced by Glu and excitatory neurotoxicity induced by Glu in vitro by culture of DA energy neurons in the midbrain in vitro, and studies several active proteins in the downstream of Glu. The oxidative neurotoxicity induced by Glu was inhibited by increasing the survival rate of neurons, reducing the content of intracellular reactive oxygen species (ROS), increasing the mitochondrial membrane potential and inhibiting the rate of cell apoptosis. In the experiment using fluorescence probe Fura-2/AM and cadmium reduction method, the increase of intracellular calcium ion increase and nitric oxide (NO) release induced by Glu was increased. Now, 100 can obviously antagonize the increase of intracellular calcium and the increase of NO release mediated by Glu, indicating that 100 can antagonize the excitatory neurotoxicity mediated by Glu, and also indirectly reflect the inhibition of the excitatory properties of STN neurons by inhibiting the Glu mediated calcium influx, and controlling the tremor symptoms of PD. The effect of Glu on the expression of neuronal nitric oxide synthase (nNOS), FOS and calcium / calmodulin dependent protein kinase II (CaMK II) protein after DA neurons injury in the primary mesencephalon of rats. The results of immuno imprint experiment showed that 100 can obviously antagonize the expression of Glu induced nNOS, indicating the antioxidative and neuronal protection of centico The results of.FOS protein related to inhibition of nNOS activity showed that by down-regulation of the activity of the protein, cloni had a long-term regulatory effect on the tremor symptoms of PD, and the no influence of the.T type calcium channel on the expression of CaMK II protein was a new target for the recent discovery of the tremor of Parkinson's disease. The basal ganglia of Parkinson's disease patients The dysfunction of the motor loop causes the inhibitory postsynaptic potential (IPSP) of the thalamus reticular nucleus (NRT), and then activates the T calcium channel to produce a low threshold calcium spinous wave (LTS). LTS induces a rhythmic discharge of NRT neurons. This rhythmic discharge can induce the rhythmic movement of the thalamus cortex and the muscle tremor activity of the peripheral muscles. The process is considered to be the final pathway of PD tremor. Based on this theory, this chapter explores the effect of calcis on the expression of T type calcium channel protein. It is found that BCO can obviously reduce the expression of T type calcium channel CAV3. 1 and CAV3. 3 protein, suggesting that this may be a new target for the anti PD tremor of BCP. The fifth chapter flavonoids and their combination resistance. Comparison of the tremor effects of pranolol and related flavonoids and their combination against Parkinson's disease in Parkinson's disease. Experimental results show that the anti PD tremor effect of flavonoids is obviously superior to that of the idiopathic tremor inhibitor propranolol and the classic anti PD tremor. According to the drug effect, the flavonoids may have the same or similar mechanism of action. Therefore, a deep study on the anti PD mechanism of flavonoids is made to find the precursor compounds with active nerve system, and the potential highly effective and low toxic neurodrugs can be found. It has a profound meaning for the treatment of Parkinson's disease. According to the results of the above chapters, it is believed that the effect of tremule on Parkinson's disease is mainly through: 1. up regulation of DAT, GS protein expression, downregulation of GABA-T protein expression, inhibition of mRNA expression of COMT and MAO-B; 2. balance of DA in the basal ganglia, Glu and GABA neurotransmitters in PD rats; 3. up D1 and D2 receptors, down regulated receptors; 4 Inhibiting the ROS content, increasing the mitochondrial membrane potential, inhibiting the apoptosis rate and antagonizing the oxidative neurotoxicity of Glu; 5. inhibition of calcium influx, nNOS expression and NO release against Glu excitotoxicity; 6. down regulation of Glu induced FOS protein expression; 7. down regulation of T type calcium channel CAV3.1 and CAV3. 3 protein expression.

【學(xué)位授予單位】：沈陽藥科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R285.5;R-332

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