本文選題：癲癇發(fā)作 + 三磷酸腺苷二磷酸水解酶�。� 參考：《鄭州大學》2016年博士論文

【摘要】：研究背景與現(xiàn)狀癲癇是神經(jīng)系統(tǒng)較為常見且容易反復發(fā)作的疾病,癲癇致殘率高、病程長,全世界癲癇患者數(shù)以千萬,中國作為人口大國,癲癇患者有900多萬,癲癇反復發(fā)作給患者及家庭造成極大的心理負擔和經(jīng)濟負擔。癲癇是以腦神經(jīng)元過度放電所致的暫時性中樞神經(jīng)功能紊亂為基本特征的腦組織慢性疾病,發(fā)作性、短暫性、重復性以及刻板性是其臨床四大特點。近期,許多學者對癲癇病因、發(fā)病機制及病理學改變和治療方法進行了研究并取得了較大進展。目前普遍認為,癲癇發(fā)生與突觸重塑、神經(jīng)遞質受體、神經(jīng)膠質細胞、離子通道、遺傳因素、苔蘚纖維發(fā)芽等多方面密切相關,癇性放電的開始伴有離子異常跨膜運動,通過突觸聯(lián)系和易化使放電逐漸傳播,最終通過主動抑制和負反饋來終止癇性放電。但癲癇發(fā)作的的具體機制尚未明了,每次癲癇發(fā)作開始和終止的具體機制也未闡明。許多難治性癲癇患者應用多種抗癲癇藥物并無顯著效果,說明仍然需要尋找新的藥理學作用靶點。因此,研究癲癇的發(fā)病機制、研究新的藥理學作用靶點,對改善癲癇患者的預后及降低死亡率有重要的臨床意義。許多相關研究表明,腺苷系統(tǒng)是腦組織中重要的抗癲癇和腦保護系統(tǒng)。其通過腺苷與G蛋白偶聯(lián)腺苷受體相互作用來抑制腦組織內(nèi)的神經(jīng)元活性,急性癲癇發(fā)作后腺苷水平顯著升高,隨后發(fā)作終止,腺苷系統(tǒng)被稱為“內(nèi)源性抗癲癇系統(tǒng)”,可溶性核苷酸酶可與胞外核苷酸酶協(xié)同作用產(chǎn)生腺苷而在癇性發(fā)作中起著重要的調(diào)節(jié)作用。目前腺苷酸酶活性與癲癇的關系已引起廣大醫(yī)學工作者的重視。目前,癲癇發(fā)作后,患者血清ATP、ADP及AMP水解率改變以及血清可溶性磷酸二酯酶活性變化的相關報道較少;不同癲癇發(fā)作類型的血清ATP、ADP及AMP水解率改變以及血清可溶性磷酸二酯酶活性變化的是否相同未見有報道;腺苷A_1R與模型海馬神經(jīng)元損傷的關系方面的研究也較少。本文主要采用前瞻性研究納入癲癇患者65例(全面性發(fā)作33例,部分性發(fā)作32例)和正常健康對照者35例,從第一部分和第二部分兩個部分分別探討了不同癲癇發(fā)作類型發(fā)作前后不同時間點血清ATP、ADP及AMP水解情況,不同癲癇發(fā)作類型發(fā)作前后不同時間點血清可溶性磷酸二酯酶活性變化情況,以了解腺苷酸酶活性與癲癇發(fā)作的關系以及不同癲癇發(fā)作類型腺苷酸酶活性有無差異,進一步探討腺苷酸酶活性在癲癇發(fā)作過程中的作用機制,并深入了解不同癲癇發(fā)作類型對腺苷酸酶活性的敏感性,為臨床選藥提供依據(jù);第三部分通過建立杏仁核點燃癲癇大鼠模型,從而對點燃癲癇大鼠各個時間段海馬神經(jīng)元的病理組織學和凋亡的影響進行分析,探討腺苷A_1R與模型海馬神經(jīng)元損傷的關系,了解其對腦神經(jīng)的保護作用,從而能更深刻的理解腺苷A_1R與癲癇間的關系,為癲癇的治療提供參考。第一部分不同癲癇發(fā)作類型發(fā)作間期和癲癇發(fā)作后血清ATP、ADP和AMP水解率的動態(tài)變化目的:探討患者發(fā)作間期和發(fā)作后血清ATP、ADP和AMP水解率的變化,分析ATP、ADP和AMP水解率與癲癇發(fā)作的關系,并分析不同癲癇發(fā)作類型癲癇發(fā)作后ATP、ADP和AMP水解率有無差異。方法:1.研究對象:收集2014年3月至2015年12月在我院神經(jīng)內(nèi)科治療的癲癇患者65例,納入病例組(全面性發(fā)作組33例,復雜部分性發(fā)作組32例)。病例組另外收集同期在我院門診進行常規(guī)體檢的正常人員35例作為健康對照組。2.觀測指標:采用紫外線吸收分光光度法,觀察病例組癲癇發(fā)作后5、10、20、30、60 min和10 h時的ATP、ADP和AMP水解率變化情況,與健康對照組比較;觀察全面性發(fā)作組和復雜部分性發(fā)作組癲癇發(fā)作后5、10、20、30、60 min和10 h時的ATP、ADP和AMP水解率變化情況,并進行比較。3.統(tǒng)計學方法:采用SPSS21.0版本統(tǒng)計學軟件進行數(shù)據(jù)處理,ATP或ADP或AMP水解率以(x±s)描述,采用重復測量數(shù)據(jù)的方差分析,組間比較采用t檢驗。結果:1.病例組患者在發(fā)作間期ATP水解率、ADP水解率、AMP水解率與對照組比較無統(tǒng)計學差異(P0.05);2.發(fā)作后5min時ATP水解率、ADP水解率、AMP水解率均明顯升高,其中ATP水解率在發(fā)作后20 min達峰值,之后逐漸下降,至發(fā)作后10 h恢復至發(fā)作間期水平;ADP水解率、AMP水解率在發(fā)作后5 min達峰值,隨后逐漸下降,至發(fā)作后60 min即恢復至發(fā)作間期水平(P0.05)。3.病例組發(fā)作后5min時患者血清ATP水解率、ADP水解率、AMP水解率均明顯升高,病例組患者ATP水解率與對照組相比在發(fā)作后20 min達峰值,之后逐漸下降,至發(fā)作后10 h恢復至發(fā)作間期水平;ADP水解率、AMP水解率在發(fā)作后5 min達峰值,隨后逐漸下降,至發(fā)作后60 min即恢復至發(fā)作間期水平(P0.05)。4.全面性發(fā)作組和部分性發(fā)作組相比,癲癇發(fā)作后5min,20 min血清ATP水解率、ADP水解率、AMP水解率升高更為顯著(P0.05)。結論:癲癇發(fā)作后腺苷酸水解率明顯升高,全面性發(fā)作患者與部分性發(fā)作患者相比,腺苷酸水解率升高的更為明顯,提示腺苷酸酶活性增高可能參與了與癲癇發(fā)作終止相關的調(diào)節(jié)機制。第二部分不同癲癇發(fā)作類型血清可溶性磷酸二酯酶活性與癲癇發(fā)作的關系目的:探討不同癲癇類型患者發(fā)作后血清可溶性磷酸二酯酶活性的變化情況,了解可溶性磷酸二酯酶活性在癲癇發(fā)作中的作用。方法:1.研究對象:收集2014年3月至2015年12月在我院神經(jīng)內(nèi)科治療的癲癇患者65例,納入病例組(全面性發(fā)作組33例,復雜部分性發(fā)作組32例)。同時收集常規(guī)體檢的正常人員35例作為健康對照組。2.觀測指標:采用紫外線吸收分光光度法,觀察病例組患者發(fā)作后5min、10 min、20min和10 h時磷酸二酯酶水平、乳酸脫氫酶(LDH)水平變化情況并與正常對照組比較。觀察全面性發(fā)作組和復雜部分性發(fā)作組癲癇發(fā)作后5min、10 min、20min和10 h時磷酸二酯酶水平、乳酸脫氫酶(LDH)水平變化,并進行比較。3.統(tǒng)計學方法:采用SPSS21.0版本統(tǒng)計學軟件進行數(shù)據(jù)處理,磷酸二酯酶活性、LDH以(x±s)描述,采用重復測量數(shù)據(jù)的方差分析,組間比較采用t檢驗,以P0.05為差異有統(tǒng)計學意義。結果:1.病例組患者在發(fā)作間期磷酸二酯酶活性與對照組比較無統(tǒng)計學差異(P0.05)。2.病例組患者在發(fā)作后5min、10 min、20min時磷酸二酯酶活性明顯升高,在發(fā)作后20 min時達峰值,之后逐漸下降,至發(fā)作后10 h恢復至發(fā)作間期水平(P0.05);3.全面性發(fā)作患者和部分性發(fā)作患者相比,發(fā)作后5min、10 min、20min時磷酸二酯酶活性明顯升高,在發(fā)作后20 min時達峰值,之后逐漸下降,至發(fā)作后10 h恢復至發(fā)作間期水平(P0.05);4.LDH活性在發(fā)作間期、發(fā)作后不同時間點的變化均無統(tǒng)計學差異(P0.05)。結論:癲癇發(fā)作后磷酸二酯酶活性明顯升高,全面性發(fā)作后磷酸二酯酶活性升高更為明顯,磷酸二酯酶活性增高與ATP水解率密切相關,也進一步證明了癲癇發(fā)作后腺苷酸活性明顯升高,這可能是癲癇發(fā)作終止的一個調(diào)節(jié)機制;全面性發(fā)作后磷酸二酯酶活性增高升高更為明顯,證實腺苷酸活性對全面性發(fā)作的調(diào)節(jié)作用更強。第三部分腺苷A_1受體對杏仁核點燃癲癇大鼠海馬神經(jīng)元損傷作用機制目的:探討腺苷A_1受體活性對點燃癲癇大鼠海馬神經(jīng)元損傷的作用,為癲癇發(fā)作的治療提供理論依據(jù)。方法:1.研究對象:選擇84只SPF級雄性Wistar大鼠,根據(jù)隨機數(shù)字表法將動物分為正常組、致癇組、致癇+腺苷A_1R拮抗劑(8-環(huán)戊-1,3-二丙基黃嘌呤,DPCPX)組、致癇+腺苷A_1R激動劑(2-氯化腺苷,2-CADO)4個分組,每組21只。致癇組、致癇+DPCPX組、致癇+2-CADO組采用電刺激點燃癲癇模型。正常組未進行手術和電刺激致癇等處理;致癇組癲癇模型建立成功前后未注射任何藥物;致癇+DPCPX組大鼠癲癇模型建立成功前1h和成功后1 h尾部靜脈注射0.3mg/kg DPCPX;致癇+2-CADO組大鼠癲癇模型成功前1h和成功后1 h尾部靜脈注射0.6mg/kg 2-CADO。2.觀測指標:采用TUNEL法,觀察各組在癲癇模型建立成功后1天、15天、30天時的海馬CA3區(qū)組織學病理變化及神經(jīng)元凋亡指數(shù)(AI)變化情況。3.統(tǒng)計學方法:符合正態(tài)分布數(shù)據(jù)用(x±s)描述,采用t檢驗,以P0.05為差異有顯著性,統(tǒng)計學軟件選用SPSS21.0版本。結果:1.致癇組、致癇+DPCPX組、致癇+2-CADO組動物在點燃癲癇后1天、15天、30天均出現(xiàn)不同程度的神經(jīng)元細胞排列松散無規(guī)則,輪廓模糊,邊緣欠清晰,胞核萎縮,胞漿空泡等神經(jīng)元結構損害;2.相同時間點,致癇+DPCPX組的神經(jīng)元結構損害程度較致癇組加重,致癇+2-CADO組較致癇組減輕。正常組在不同時間點的AI變化不明顯(P0.05),致癇組、致癇+DPCPX組、致癇+2-CADO組的AI隨著癲癇發(fā)作時間的延長,AI逐漸增加(P0.05);3.在相同時間點,致癇組、致癇+DPCPX組、致癇+2-CADO組的AI均明顯高于正常組(P0.05),致癇+DPCPX組的AI均明顯高于致癇組(P0.05);致癇+2-CADO組的AI明顯低于致癇組和致癇+DPCPX組(P0.05)。結論:癲癇發(fā)作會引起神經(jīng)元損傷和凋亡,腺苷A_1R活性降低,神經(jīng)元損傷和凋亡更為明顯,這可能是癲癇發(fā)作后神經(jīng)元損傷的機制之一;通過增加腺苷A_1R活性可保護神經(jīng)元,降低其損傷,可能是終止癲癇發(fā)作的一個治療方向。
[Abstract]:The research background and current situation of epilepsy is the nervous system is common and easy to recurrent disease, epilepsy, high disability rate, long duration of the disease, the world tens of million of patients with epilepsy, Chinese as a country with a large population, there are about 9000000 patients with epilepsy, seizures caused great psychological burden and economic burden to patients and families with epilepsy is brain. Neurons over temporary central nerve dysfunction caused by the discharge of the basic features of the brain tissue of chronic disease, recurrent, transient, repetitive and stereotyped is four of its clinical characteristics. Recently, many scholars of epilepsy etiology, studied the change and treatment of pathogenesis and pathological methods and made great progress. It is generally believed that synaptic remodeling and epileptogenesis, neurotransmitter receptors, glial cells, ion channels, genetic factors, mossy fiber sprouting and other aspects are closely related, epileptic discharge Electric started with abnormal transmembrane ion movement through synaptic connections and easy to discharge gradually spread, through active suppression and negative feedback to the termination of epileptiform discharge. But the specific mechanism of epileptic seizures is not clear, each specific mechanism of start and end is not clear. Many patients with intractable epilepsy a variety of anti epilepsy drugs had no significant effect, still need to find new targets for pharmacological effects. Therefore, studying the mechanism of epilepsy, pharmacological research of new targets, to improve the prognosis of patients with epilepsy and reduce the death rate has important clinical significance. Many studies indicate that adenosine is anti epilepsy and brain system the important protection systems in the brain. By adenosine and G protein coupled adenosine receptor interaction to inhibition of neuronal activity in the brain tissue of acute seizures after adenosine levels significantly Increased, then werecured, adenosine system known as the "endogenous antiepileptic system", soluble extracellular nucleotides and nucleotide enzyme enzymes produce adenosine in epileptic plays an important regulatory role. At present the relationship between ATPase activities and epilepsy has aroused the attention of medical workers. At present, seizure after the serum ATP, ADP and AMP hydrolysis rate changes and serum soluble phosphodiesterase activity changes in the relevant reports; different seizure types of serum ATP, ADP and AMP hydrolysis rate changes and soluble phosphodiesterase activity changes are the same has not been reported; less research on the relationship between adenosine A_1R and model of hippocampal neurons induced by hand. This paper mainly uses the prospective study included 65 patients with epilepsy (GTCS in 33 cases, partial seizures in 32 cases) and healthy controls were 3 In 5 cases, from two parts: the first part and the second part respectively discusses the types of attacks at different times after serum ATP different seizures, ADP and AMP hydrolysis, different types of seizure onset at different time points before and after the changes of serum soluble phosphodiesterase activity, to explore the relationship between ATPase activities and epileptic seizures and seizure type there is no difference in ATPase activities, to further explore the ATPase activities in the mechanism in the process of epilepsy, and deeply understand the type of ATPase activities sensitivity of different seizures, provide the basis for clinical drug selection; the third part through the establishment of model of amygdala in epileptic rats kindled, analyze and influence lit each time epilepsy rat hippocampal neurons apoptosis and histopathology, adenosine A_1R and model of hippocampal neurons shut The Department, to understand its protective effect on brain nerve, which can be more profound understanding of the relationship between adenosine A_1R and epilepsy, and provide reference for the treatment of epilepsy. The first part of different types of seizure and interictal seizures after serum ATP, the dynamic changes of ADP and the hydrolysis rate of AMP Objective: to investigate the patients with interictal and after seizure serum ATP, ADP and AMP hydrolysis rate changes, analysis of ATP, ADP and AMP and the relationship between the hydrolysis rate of seizures, and analyze the types of epilepsy after ATP seizures, ADP and AMP have no difference in the hydrolysis rate. Methods: 1. subjects: from March 2014 to December 2015 in our hospital treatment of epilepsy patients in 65 cases, including cases (general seizure group 33 cases, 32 cases of complex partial seizures group). Normal group were also collected from the personnel routine health examination in our hospital 35 cases as healthy control group.2. observation index: The ultraviolet absorption spectrophotometry, observe cases after the seizure of 5,10,20,30,60 min and 10 h ATP, ADP and AMP hydrolysis rate changes, compared with the healthy control group; observation group and general seizure patients with complex partial seizure epilepsy after 5,10,20,30,60 min and 10 h ATP, ADP and AMP hydrolysis the rate of change, and compare the.3. statistical method: the data were processed by statistical software SPSS21.0 version, ATP or ADP or AMP on the hydrolysis rate (x + s), using the analysis of variance of repeated measurement data, comparison between groups with t test. Results: 1. cases of patients in the interictal ATP hydrolysis rate. ADP the rate of hydrolysis, the hydrolysis rate of AMP and the control group showed no significant difference (P0.05); 2. 5min after the onset of ATP hydrolysis rate, ADP rate of hydrolysis, the hydrolysis rate of AMP were significantly increased, the hydrolysis rate of ATP after the onset of 20 min reached the peak, then gradually declined to attack After 10 h recovery to interictal levels; the rate of ADP hydrolysis, the hydrolysis rate of AMP after the onset of 5 min reached the peak, then gradually decreased to 60 min after the onset of recovery to interictal levels (P0.05) in patients with.3. after the onset of 5min in serum of patients with ATP the rate of hydrolysis, the hydrolysis rate of ADP, the hydrolysis rate was obviously AMP increased patients ATP hydrolysis rate compared with the control group after the onset of 20 min reached the peak, then gradually declined to 10 h after the onset of recovery to interictal levels; the rate of ADP hydrolysis, the hydrolysis rate of AMP after the onset of 5 min reached the peak, then gradually decreased to 60 min after the onset of recovery to interictal the level of (P0.05).4. general seizure group and partial seizure group compared to 5min after seizure, 20 min serum ATP hydrolysis rate, ADP rate of hydrolysis, the hydrolysis rate of AMP were higher (P0.05). Conclusion: after the seizure of adenylate hydrolysis rate increased significantly, generalized seizures and partial Patients compared to adenylate hydrolysis rate was further up-regulated, suggesting ATPase activity increased may be involved in the termination of regulatory mechanisms associated with seizures. Second different seizure types of relationship between serum soluble phosphodiesterase activity and epilepsy Objective: To investigate the changes of different types of epilepsy patients after the onset of serum soluble phosphodiesterase activity, role understanding the soluble phosphodiesterase activity in epilepsy. Methods: 1. subjects: from March 2014 to December 2015 in our hospital treatment of patients with epilepsy in 65 cases, including cases (general seizure group 33 cases, complex partial seizures group 32 cases). The normal staff also collected the routine physical examination in 35 cases as healthy control group..2. measurements: using ultraviolet absorption spectrophotometry, observation of patients after the onset of 5min, 10 20min and 10 min. H phosphodiesterase levels of lactate dehydrogenase (LDH) levels were compared with the normal control group. The observation group comprehensive seizures and complex partial seizures of epilepsy after 5min group, 10 min 20min and 10 h phosphodiesterase levels, lactate dehydrogenase (LDH) levels, and compare the.3. statistical method: data using SPSS21.0 statistical software, version LDH with phosphodiesterase activity, (x + s), using the analysis of variance of repeated measurement data, were compared by t test, with P0.05 as the difference was statistically significant. Results: 1. cases of patients in the interictal phosphodiesterase activity compared with the control group no significant difference (P0.05).2. patients after the onset of 5min, 10 min, 20min phosphodiesterase activity was significantly increased, and reached a peak in the attack after 20 min, then gradually declined to 10 h after the onset of recovery to interictal water Ping (P0.05); compared with 3. generalized seizures and partial seizures in patients after the onset of 5min, 10 min, 20min phosphodiesterase activity was significantly increased, and reached a peak in the attack after 20 min, then gradually declined to 10 h after the onset of recovery to interictal levels (P0.05); the activity of 4.LDH in interictal. After the onset of changes at different time points were not statistically significant (P0.05). Conclusion: phosphodiesterase activity increased significantly after seizures, generalized seizures after phosphodiesterase activity increased more significantly, increased phosphodiesterase activity is closely related with the hydrolysis rate of ATP, is further evidence that adenosine activity increased significantly after seizures, which may be a regulation the mechanism of seizure termination; general seizure after increased phosphodiesterase activity increased more significantly, with stronger activity of adenylate confirmed on the regulation of general seizure. In the third part, adenosine A_1 Receptor on amygdala kindling injury of hippocampal neurons in epileptic rats Objective: To investigate the mechanism of adenosine A_1 receptor activity of hippocampal neurons in epileptic rats kindled injury, and provide a theoretical basis for the treatment of epilepsy. Methods: 1. subjects: 84 male Wistar SPF rats, then randomly divided into animal normal group, epilepsy group, epilepsy induced by adenosine A_1R antagonist (8- + cyclopent -1,3- two propyl xanthine, DPCPX) group, epileptic (2- + adenosine A_1R agonist adenosine chloride, 2-CADO) 4 groups, 21 rats in each group. Epileptic seizure group + DPCPX group, +2-CADO group with epilepsy electrical kindling model of epilepsy. The normal group did not undergo surgery and electrical stimulation treatment of epileptic seizure groups; epilepsy model was established successfully without any medication before and after injection; epileptic +DPCPX rats epileptic model was established successfully 1H before and after the success of 1 h tail intravenous injection of 0.3mg/kg DPCPX; epilepsy 1 h tail intravenous injection of 0.6mg/kg 2-CADO.2. observed in +2-CADO rats model of epilepsy before and after the success of the success of 1H: the TUNEL method was observed in the epilepsy model was established successfully after 1 days, 15 days, pathological changes and neuronal apoptosis index at 30 days in CA3 area of hippocampus tissue (AI) changes of.3. statistical methods: accord with normal distribution data (x + s), using t test, P0.05 with significant difference, with statistical software SPSS21.0 version. Results: 1. epileptic seizure group, +DPCPX group, +2-CADO group of epileptic animal in kindled seizures after 1 days, 15 days, 30 days there are neurons different degrees of loosely arranged irregular contour, fuzzy edge, less clear, nucleus atrophy, cytoplasmic vacuoles and neuron damage; 2. at the same time, the degree of neuronal damage in +DPCPX group compared with the structure of epileptic seizure groups increased, epileptic + 2-CADO group than in normal group. Epileptic No obvious changes in AI group at different time points (P0.05), epilepsy group, epilepsy group +DPCPX, epilepsy group +2-CADO AI with prolonged seizures, AI gradually increased (P0.05); 3. at the same time, epilepsy group, epilepsy group +DPCPX, epilepsy group +2-CADO AI were significantly higher than normal group (P0.05), epilepsy group +DPCPX AI were significantly higher than that of epilepsy group (P0.05); epilepsy +2-CADO group AI was significantly lower than that of epilepsy group and epilepsy group +DPCPX (P0.05). Conclusion: seizures can cause neuronal injury and apoptosis, reduce the activity of adenosine A_1R injury and apoptosis. Neuronal loss is more obvious, which may be one of the mechanisms of neuronal damage after seizures; by increasing the activity of adenosine A_1R can protect neurons, reduce the damage, may be the termination of a treatment of epilepsy.

【學位授予單位】：鄭州大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R742.1

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