本文選題：精神分裂癥　切入點(diǎn)：左旋金黃紫堇堿　出處：《中國人民解放軍軍事醫(yī)學(xué)科學(xué)院》2016年碩士論文　論文類型：學(xué)位論文

【摘要】：精神分裂癥是一種嚴(yán)重的腦功能障礙疾病,臨床上根據(jù)癥狀表現(xiàn)一般可分為陽性癥狀(妄想、幻覺和幻聽)和陰性癥狀(社會功能退縮等),以及以注意力、執(zhí)行能力、解決問題能力和短期記憶能力缺失或減弱等為主的認(rèn)知障礙。目前臨床上的抗精神病藥物均能拮抗多巴胺D2受體,經(jīng)典抗精神病藥物氟哌啶醇對陽性癥狀有效,但對陰性癥狀和認(rèn)知障礙無效甚至加重;精神分裂癥的陰性癥狀和認(rèn)知障礙難于治療,有些病人即使長期服藥認(rèn)知障礙也有可能持續(xù)存在,因此改善病人陰性癥狀與認(rèn)知障礙是治療精神分裂癥的核心問題。為了開發(fā)對精神分裂癥的陰性癥狀和認(rèn)知障礙均有效的新型藥物,我們進(jìn)行了如下研究:實(shí)驗(yàn)?zāi)康?評價化合物左旋金黃紫堇堿(l-Scoulerine,l-SLR)對精神分裂癥陽性癥狀、陰性癥狀以及認(rèn)知障礙的作用,并運(yùn)用放射性配體競爭性拮抗實(shí)驗(yàn)對其機(jī)制進(jìn)行研究,旨在開發(fā)對精神分裂癥的陽性癥狀、陰性癥狀以及認(rèn)知障礙均有效且錐體外系不良反應(yīng)小或無的新型抗精神病藥。實(shí)驗(yàn)方法:采用自發(fā)活動實(shí)驗(yàn)測定化合物l-SLR是否具有鎮(zhèn)靜作用以及鎮(zhèn)靜作用持續(xù)時間。NMDA受體拮抗劑MK-801可引發(fā)精神分裂癥的各種臨床癥狀。采用前脈沖抑制實(shí)驗(yàn)和攀爬實(shí)驗(yàn)來評價化合物l-SLR對精神分裂癥陽性癥狀的作用。在前脈沖抑制實(shí)驗(yàn)中,以大鼠腹腔注射MK-801(0.3 mg/kg)引起的大鼠前脈沖抑制缺失進(jìn)行建模,觀察大鼠在注射化合物l-SLR(5,10,15 mg/kg)之后能否逆轉(zhuǎn)這種前脈沖抑制損傷,并將化合物l-SLR與典型抗精神病藥氟哌啶醇(0.2mg/kg)的作用進(jìn)行比較;在攀爬實(shí)驗(yàn)中,以小鼠皮下注射阿撲嗎啡(2 mg/kg)引起小鼠攀爬行為進(jìn)行建模,觀察小鼠在腹腔注射化合物l-SLR(10,30 mg/kg)之后對小鼠攀爬時間的影響,并將此作用與氟哌啶醇進(jìn)行比較。在精神分裂癥的陰性癥狀中,采用小鼠的社交回避實(shí)驗(yàn)對化合物l-SLR進(jìn)行藥效學(xué)評價,在此實(shí)驗(yàn)中,以給小鼠腹腔注射工具藥MK-801(0.2 mg/kg),使陌生的小鼠出現(xiàn)社交抑制進(jìn)行建模,測定小鼠在注射化合物l-SLR之后能否增加陌生成對小鼠的接觸時間,并比較化合物l-SLR和典型抗精神病藥氟哌啶醇對精神分裂癥陰性癥狀的作用。在精神分裂癥的認(rèn)知障礙中,采用y迷宮實(shí)驗(yàn)驗(yàn)證化合物l-slr抗精神分裂癥的作用,以小鼠在注射mk-801(0.2mg/kg)后出現(xiàn)空間分辨能力降低,即精神分裂癥的認(rèn)知障礙進(jìn)行建模,觀察注射化合物l-slr能否提高小鼠的空間認(rèn)知能力,并將此作用與經(jīng)典的抗精神病藥氟哌啶醇進(jìn)行比較。在錐體外系不良反應(yīng)方面,采用化合物l-slr與典型的抗精神病藥氟哌啶醇和類似物l-spd進(jìn)行比較,測定小鼠在注射氟哌啶醇(0.8mg/kg)、l-slr(10,30,60,80mg/kg)和l-spd(30,60,80mg/kg)之后的45和90分鐘后的木僵時間,比較不同化合物之間對錐體外系的不良反應(yīng)。在機(jī)制研究中,采用放射性生物配體的競爭性抑制測定化合物l-slr與多巴胺受體親和力。實(shí)驗(yàn)結(jié)果:在自發(fā)活動實(shí)驗(yàn)中,小鼠在注射l-slr后的前30分鐘內(nèi)活動性降低,而在之后的時間里活動性恢復(fù),說明化合物l-slr具有鎮(zhèn)靜作用,此作用的持續(xù)時間為30分鐘,在實(shí)驗(yàn)設(shè)計(jì)過程中要避免在此段時間內(nèi)進(jìn)行藥效學(xué)研究。在前脈沖抑制實(shí)驗(yàn)中,與veh組相比,mk-801(0.3mg/kg)能夠明顯降低大鼠的前脈沖抑制中的震驚反射(f5,44=6.696,p0.0001),而注射l-slr(10mg/kg、15mg/kg)和氟哌啶醇(0.2mg/kg)能夠明顯改善由mk-801引起的前脈沖抑制損傷(p0.01),這說明化合物l-slr和氟哌啶醇對mk-801引起的前脈沖抑制損傷均有效;在攀爬實(shí)驗(yàn)中,與veh組相比,阿撲嗎啡(2mg/kg)皮下注射能夠明顯增加小鼠的攀爬時間(f4,45=19.13,p0.0001),氟哌啶醇(0.2mg/kg)和l-slr(30mg/kg)能夠明顯抑制阿撲嗎啡所引起的攀爬行為,這說明化合物l-slr和氟哌啶醇對阿撲嗎啡引起的小鼠攀爬行為有效。在小鼠的群居接觸實(shí)驗(yàn)中,與veh組相比,mk-801能夠明顯抑制小鼠的群居接觸行為,使小鼠的群居接觸時間明顯降低(f3,36=7.566,p=0.0084),而典型的抗精神病藥氟哌啶醇卻不能使小鼠的群居接觸時間延長;與之相對應(yīng),化合物l-slr在30mg/kg時能夠明顯增加小鼠的群居接觸時間(f5,54=6.285,p=0.0001),說明l-slr在劑量為30mg/kg時對精神分裂癥的陰性癥狀有效,而氟哌啶醇無效。在精神分裂癥認(rèn)知障礙的y迷宮中,與veh組相比,mk-801能夠明顯地抑制小鼠的空間認(rèn)知能力(f3,36=10.60,p0.0001),給予氟哌啶醇并不能改善小鼠的這種空間認(rèn)知損傷;而化合物l-slr在劑量為30mg/kg時能夠明顯改善小鼠的空間認(rèn)知障礙(f5,54=11.58,p0.0001),說明l-slr在劑量為30mg/kg時能夠改善精神分裂癥的認(rèn)知損傷。在錐體外系不良反應(yīng)方面,與veh組相比,在給藥45分鐘后,氟哌啶醇(0.8mg/kg)和l-spd(60mg/kg、80mg/kg)能夠使小鼠的木僵時間明顯增加(f8,64=13.63,p0.001);給藥90分鐘以后,氟哌啶醇和l-SPD(30mg/kg、60 mg/kg、80 mg/kg)引起的木僵行為仍然存在(F8,64=14.54,P0.001),而l-SLR在30mg/kg、60 mg/kg并不產(chǎn)生木僵,說明l-SLR在抗精神分裂癥的有效劑量下不產(chǎn)生錐體外系的副作用。在化合物l-SLR的機(jī)制研究中,18F-Fallypride在進(jìn)入小鼠體內(nèi)有后迅速分布進(jìn)入小鼠大腦的各個部分,而在給予18F-Fallypride之后迅速給予l-SLR的小鼠中,18F-Fallypride在大腦各個部位的分布在給藥15分鐘以后均明顯低于FP組(P0.05),這說明化合物l-SLR能夠與腦內(nèi)的D2與D3受體相結(jié)合,從而能夠拮抗18F-Fallypride與之的結(jié)合。結(jié)論:從自發(fā)活動實(shí)驗(yàn)可以看出,化合物l-SLR具有鎮(zhèn)靜作用,而且鎮(zhèn)靜時間較短,因此我們在對化合物的藥效學(xué)研究中要避免在此段時間內(nèi)進(jìn)行。從前脈沖抑制實(shí)驗(yàn)和攀爬實(shí)驗(yàn)可以看出,化合物l-SLR能夠?qū)穹至寻Y的陽性癥狀的結(jié)論。從社交回避的實(shí)驗(yàn)中,化合物l-SLR對精神分裂癥的陰性癥狀有效。從Y迷宮實(shí)驗(yàn)可以看出,化合物l-SLR能夠改善精神分裂癥的認(rèn)知障礙。因此,在治療精神分裂癥的認(rèn)知障礙方面,l-SLR優(yōu)于氟哌啶醇。在錐體外系不良反應(yīng)方面,化合物l-SLR在有效劑量時不會引起小鼠的木僵,說明化合物l-SLR較少地引起小鼠錐體外系不良反應(yīng),相對于氟哌啶醇和l-SPD有顯著的優(yōu)勢。在受體結(jié)合的研究中,通過拮抗18F-Fallypride使各個腦區(qū)的放射性降低,說明化合物l-SLR能夠與多巴胺D2、D3受體結(jié)合。
[Abstract]:Schizophrenia is a severe brain dysfunction disease, according to clinical symptoms in general can be divided into positive symptoms (hallucinations and delusions, hallucinations) and negative symptoms (such as social function, and attention to withdrawal), executive ability, cognitive impairment based problem-solving ability and short-term memory capacity is absent or reduced. At present the Clinical Antipsychotic drugs can antagonize dopamine D2 receptor, antipsychotic drugs haloperidol effective on positive symptoms, negative symptoms and cognitive impairment but ineffective or aggravated; negative symptoms and cognitive impairment in schizophrenia is difficult to treatment, some patients even long-term medication of cognitive impairment may also continue to exist, so improving patients with negative symptoms and cognitive impairment is the key problem in the treatment of schizophrenia. In order to develop a model of schizophrenia with negative symptoms and cognitive impairment. Drug, we carry out the following research: Objective: To evaluate compound L - scoulerine (l-Scoulerine, l-SLR) of the positive symptoms of schizophrenia negative symptoms and cognitive impairment, and using radioligand competitive antagonism experiment to study its mechanism, aims to develop the positive symptoms of schizophrenia, and negative symptoms cognitive disorders are effective and extrapyramidal antipsychotic drugs have little or no adverse reactions. Methods: the spontaneous activity test compounds was determined whether l-SLR has a sedative effect and sedation for various clinical symptoms can cause schizophrenia with duration of.NMDA receptor antagonist MK-801. The pre pulse inhibition and climbing experiment evaluation of compound l-SLR on the positive symptoms of schizophrenia. The role in prepulse inhibition in rats by intraperitoneal injection of MK-801 (0.3 mg/kg) led The rats of prepulse inhibition were lack of modeling, rats in injection of compound l-SLR (5,10,15 mg/kg) can reverse the prepulse inhibition after injury, and the compound l-SLR with typical antipsychotic haloperidol (0.2mg/kg) were compared in the climbing effect; in the experiment, the mice subcutaneous injection of apomorphine (2 mg/kg) climbing behavior caused by modeling, were observed in mice after intraperitoneal injection of compound l-SLR (10,30 mg/kg) after impact on the climbing time of the mice, and the effects were compared with haloperidol. The negative symptoms of schizophrenia, the mice experiment on social avoidance efficacy evaluation of compound l-SLR, in this experiment, in order to give medicine intraperitoneal injection of MK-801 (0.2 mg/kg), the mice appeared strange social inhibition model of mice was measured after injection of compound l-SLR can increase into strange The contact time of mice, and compounds l-SLR and typical antipsychotics haloperidol on negative symptoms of schizophrenia. The cognitive deficits in schizophrenia, using Y maze experiment of compound l-slr anti schizophrenia effects in mice by injection of MK-801 (0.2mg/kg) after lower spatial resolution the schizophrenia cognitive impairment model, observation of injection compound l-slr can improve the spatial cognitive ability of mice, and compare the antipsychotic drug haloperidol for this role and classic. In extrapyramidal adverse reactions, the compounds of l-slr were compared with typical antipsychotic haloperidol and analogs of l-spd, determination the mice in the injection of haloperidol (0.8mg/kg), l-slr (10,30,60,80mg/kg) and l-spd (30,60,80mg/kg) after 45 and 90 minutes after the freezing time, different. The adverse reactions between the extrapyramidal system. In the research of the mechanism, determination of compound l-slr and inhibition of dopamine receptor affinity by competitive radioactive biological ligands. The experimental results in the spontaneous activity of mice in the experiment, 30 minutes after the injection of l-slr decreased activity before and after the time of recovery the result indicated that the compound l-slr has sedative effect, duration of this effect is 30 minutes, in the experimental design process to avoid the effect in this period of time. In the study of prepulse inhibition experiment, compared with the veh group, MK-801 (0.3mg/kg) can significantly reduce rat prepulse inhibition of startle reflex (f5,44=6.696 P0.0001), and l-slr (10mg/kg, 15mg/kg) injection and haloperidol (0.2mg/kg) can significantly improve the prepulse inhibition of injury caused by MK-801 (P0.01), indicating that the compound of l-slr and haloperidol on MK-801 The prepulse inhibition of injury are effective; in climbing experiment, compared with group veh, apomorphine (2mg/kg) subcutaneous injection can significantly increase mouse climbing time (f4,45=19.13, P0.0001), haloperidol (0.2mg/kg) and l-slr (30mg/kg) could significantly inhibit the climbing behavior induced by apomorphine, indicating that mice climbing behavior of compound l-slr and haloperidol on apomorphine induced effective social contact. In mice, compared with the veh group, the social contact behaviors of MK-801 can inhibit the growth of mice, the mice of the social contact time decreased significantly (f3,36=7.566, p=0.0084), and haloperidol typically cannot be gregarious the contact time of mice prolonged; correspondingly, the compound l-slr can significantly increase the social contact time of mice in the 30mg/kg (f5,54=6.285, p=0.0001), l-slr at the dose of 30mg/kg on sperm Schizophrenia negative symptoms effectively, and haloperidol is invalid. Cognitive deficits in schizophrenia Y maze, compared with group veh, the spatial cognitive ability of MK-801 could inhibit the mice (f3,36=10.60, P0.0001), haloperidol did not improve the spatial cognitive injury in mice; and the compound l-slr at the dose of 30mg/kg can significantly improve the spatial cognitive impairment in mice (f5,54=11.58, P0.0001, l-slr) that cognitive impairment at the dose of 30mg/kg can improve schizophrenia. In extrapyramidal adverse reactions, compared with the veh group, in 45 minutes after administration of haloperidol (0.8mg/kg) and l-spd (60mg/kg, 80mg/kg) to mice. The stupor time increased significantly (f8,64=13.63, p0.001); drug 90 minutes later, haloperidol and l-SPD (30mg/kg, 60 mg/kg, 80 mg/kg) wood stiff behavior cause still exist (F8,64=14.54, P0.001), and l- In SLR 30mg/kg 60, mg/kg does not produce side effects that stupor, l-SLR does not produce extrapyramidal in the effective dose of anti schizophrenia. The study on Mechanism of compound l-SLR in various parts of 18F-Fallypride into the mice quickly after distribution into mouse brains, but to give 18F-Fallypride quickly after the administration of l-SLR in mice in the distribution of 18F-Fallypride in various parts of the brain after 15 minutes of drug administration were significantly lower than group FP (P0.05), which shows that the compound l-SLR can D2 and D3 receptor in the brain and the combination, which can combine with the antagonism of 18F-Fallypride. Conclusion: the spontaneous activity test shows that compound l-SLR has sedative effects and calm in a relatively short time, so we in the efficacy of the compound in the study to avoid in this period of time. Before experiment and experiment of pulse suppression can be seen climbing The compound l-SLR can, the positive symptoms of schizophrenia. The conclusion from the social avoidance experiment, compound l-SLR on the negative symptoms of schizophrenia. From the Y maze test can be seen, the compound l-SLR can improve the cognitive impairment of schizophrenia. Therefore, in the treatment of cognitive impairment of schizophrenia, l-SLR better than haloperidol. In extrapyramidal adverse reactions, compound l-SLR does not cause mice stupor in the effective dose, indicating less compound l-SLR induced extrapyramidal adverse reactions, compared with haloperidol and l-SPD have significant advantages. In the study of receptor binding in the various brain regions through antagonism of 18F-Fallypride radioactivity decreased, indicating the compound l-SLR can and dopamine D2, D3 receptors.

【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R965

【相似文獻(xiàn)】

相關(guān)碩士學(xué)位論文 前1條

1 高峗峗;四氫原小檗堿先導(dǎo)化合物l-SLR抗精神分裂癥的藥效學(xué)和機(jī)制研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2016年

，

本文編號：1617880