腺苷A2受体活化对缺血性疾病的防治作用研究进展

腺昔,即腺嘌呤核苷,是重要的生物活性物质,大量研究发现腺苷通过激活腺苷受体,参与多种疾病的防治过程。截至目前,腺苷受体已克隆出A1,A2a,A2b和A3四种亚型,他们均可与腺苷结合并启动下游的信号传导机制,对机体产生不同的效应。现综述腺昔A2受体的分布、活化及其在疾病防治中的作用及机制综述。     

动脉粥样硬化发病过程与腺苷三磷酸结合盒转运体A1和肝X受体的作用

目的：分析腺苷三磷酸结合盒转运体A1和肝X受体与动脉粥样硬化的关系。 资料来源：分别以“ABCA1”和“LXR”为检索词，应用计算机在Medline、中文全文数据库CNKI、维普数据库检索2000-01／2005-09期间相关文章。手工检索近期相关文献及书籍。 资料选择：对资料进行初审，选出相关文献，筛除无关文献。纳入标准：①与腺苷三磷酸结合盒转运体A1、肝X受体结构功能有关的文献。②腺苷三磷酸结合盒转运体A1、肝X受体与血脂关系的文献。③腺苷三磷酸结合盒转运体A1、肝X受体多态或突变与血脂关系的文献。④腺苷三磷酸结合盒转运体A2、肝X受体与冠状动脉粥样硬化性心脏病、心肌梗死、脑梗死、动脉粥样硬化相关的文献。⑤腺苷三磷酸结合盒转运体A1、肝X受体多态或突变与冠状动脉粥样硬化性心脏病、心肌梗死、脑梗死、动脉粥样硬化相关的文献。排出标准：①相关文献中内容相似的文献。②与纳入标准不符的文献。 资料提炼：共找出相关文献86篇，并查找全文。选取4篇涉及腺苷三磷酸结合盒转运体A1、肝X受体的结构功能等基础内容；21篇涉及腺苷三磷酸结合盒转运体A1、肝X受体与血脂代谢相关的内容；11篇涉及腺苷三磷酸结合盒转运体A1、肝X受体与动脉粥样硬化相关的内容；4篇涉及肝X受体对腺苷三磷酸结合盒转运体A1调节的内容；2篇与脑卒中有关的内容。共收入42篇文献，其中21篇列为参考文献。 资料综合：分析了腺苷三磷酸结合盒转运体A1、肝X受体的结构和功能的基本情况；文献显示腺苷三磷酸结合盒转运体A1和肝X受体对血脂谱有不同程度的调节；肝X受体对腺苷三磷酸结合盒转运体A1的表达也有调节；两者可能是通过影响血脂谱，或者其他途径对动脉粥样硬化有一定作用。 结论：腺苷三磷酸结合盒转运体A1与肝X受体可能通过调节血脂谱在动脉粥样硬化发病过程中起重要的作用，而且腺苷三磷酸结合盒转运体A1的表达可能受肝X受体的调控，因此它们可能是与动脉粥样硬化密切相关的心脑血管疾病的重要候选基因。     

腺苷受体及其介导的cAMP/PKA/CREB信号通路在高氧致早产大鼠原代Ⅱ型肺泡上皮细胞损伤中的作用

目的 探讨高氧对早产大鼠原代Ⅱ型肺泡上皮细胞(typeⅡalveolar epithelial cells, AECⅡ)腺苷受体及其介导的环磷酸腺苷(cyclic adenosine monophosphate, cAMP)/蛋白激酶A(protein kinase A, PKA)/cAMP反应元件结合蛋白(cAMP-response element binding protein, CREB)信号通路的影响。方法 取早产SD大鼠肺组织分离培养原代AECⅡ,分为常氧组和高氧组,分别在氧气浓度21%和95%条件下培养。采用CCK-8法检测细胞培养6、12、24、48、72 h时AECⅡ增殖的光密度值。分别取培养12、24、48 h时2组原代AECⅡ,采用实时荧光定量PCR法检测细胞腺苷受体A1、A2A、A2B、A3 mRNA相对表达量,采用Western blot法检测细胞腺苷受体A1、A2A、A2B、A3蛋白及p-PKA、p-CREB蛋白相对表达量,采用ELISA法检测细胞cAMP水平。结果 培养6 h时,高氧组原代AECⅡ细胞增殖的光密度值(0.69±0.01)与常氧组(0.68±0...     

动脉粥样硬化发病过程与腺苷三磷酸结合盒转运体A1和肝X受体的作用

目的:分析腺苷三磷酸结合盒转运体A1和肝X受体与动脉粥样硬化的关系。资料来源:分别以“ABCA1”和“LXR”为检索词,应用计算机在Medline、中文全文数据库CNKI、维普数据库检索2000-01/2005-09期间相关文章。手工检索近期相关文献及书籍。资料选择:对资料进行初审,选出相关文献,筛除无关文献。纳入标准:①与腺苷三磷酸结合盒转运体A1、肝X受体结构功能有关的文献。②腺苷三磷酸结合盒转运体A1、肝X受体与血脂关系的文献。③腺苷三磷酸结合盒转运体A1、肝X受体多态或突变与血脂关系的文献。④腺苷三磷酸结合盒转运体A1、肝X受体与冠状动脉粥样硬化性心脏病、心肌梗死、脑梗死、动脉粥样硬化相关的文献。⑤腺苷三磷酸结合盒转运体A1、肝X受体多态或突变与冠状动脉粥样硬化性心脏病、心肌梗死、脑梗死、动脉粥样硬化相关的文献。排出标准:①相关文献中内容相似的文献。②与纳入标准不符的文献。资料提炼:共找出相关文献86篇,并查找全文。选取4篇涉及腺苷三磷酸结合盒转运体A1、肝X受体的结构功能等基础内容;21篇涉及腺苷三磷酸结合盒转运体A1、肝X受体与血脂代谢相关的内容;11篇涉及腺苷三磷酸结合盒转运体A1、肝X受体与动脉粥样硬化相关的内容;4篇涉及肝X受体对腺苷三磷酸结合盒转运体A1调节的内容;2篇与脑卒中有关的内容。共收入42篇文献,其中21篇列为参考文献。资料综合:分析了腺苷三磷酸结合盒转运体A1、肝X受体的结构和功能的基本情况;文献显示腺苷三磷酸结合盒转运体A1和肝X受体对血脂谱有不同程度的调节;肝X受体对腺苷三磷酸结合盒转运体A1的表达也有调节;两者可能是通过影响血脂谱,或者其他途径对动脉粥样硬化有一定作用。结论:腺苷三磷酸结合盒转运体A1与肝X受体可能通过调节血脂谱在动脉粥样硬化发病过程中起重要的作用,而且腺苷三磷酸结合盒转运体A1的表达可能受肝X受体的调控,因此它们可能是与动脉粥样硬化密切相关的心脑血管疾病的重要候选基因。     

腺苷三磷酸结合盒转运蛋白A1在动脉粥样硬化中的作用及其受控特点

目的:分析腺苷三磷酸结合盒转运蛋白A1(ATP binding cassette transport proteion A1,ABCA1)在动脉粥样硬化中的作用及其受控机制。资料来源:以“腺苷三磷酸结合盒转运蛋白A1”为检索词,应用计算机在Pubmed、中文全文数据库CNKI中检索2000-01/2006-11腺苷三磷酸结合盒转运蛋白A1与人有关的期刊文献,前者限定语言种类为英文,后者限定语言种类为中文。资料选择:对英文文献390篇、中文文献58篇初审。纳入标准:①与ABCA1结构及功能有关的文献。②与核受体有关的文献。③与载脂蛋白AⅠ有关的文献。④与ABCA1基因的突变、单核苷酸多态性有关的文献。⑤ABCA1蛋白、核受体、ABCA1基因的突变、单核苷酸多态性与动脉粥样硬化有关的文献。排出标准:①与哮喘、癌症、代谢性疾病有关的文献。②相关文献中内容相似的文献。③综述文献。资料提炼:选取3篇涉及ABCA1结构、功能的基础内容;18篇涉及与核受体的内容;2篇涉及载脂蛋白AⅠ的内容;7篇涉及ABCA1基因的突变、单核苷酸多态性的内容;9篇涉及ABCA1蛋白、核受体、ABCA1基因的突变、单核苷酸与动脉粥样硬化的内容。其中30篇列为参考文献。资料综合:分析了腺苷三磷酸结合盒转运体A1的结构和功能的基本情况;文献显示腺苷三磷酸结合盒转运体A1在动脉粥样硬化发病过程中起重要作用;核受体对腺苷三磷酸结合盒转运体A1的表达有调节,且腺苷三磷酸结合盒转运体A1受基因调控。结论:腺苷三磷酸结合盒转运体A1可能是与动脉粥样硬化密切相关的重要候选基因;深入探讨其机制,有利于开发新药防治动脉粥样硬化。     

腺苷A2A受体敲除小鼠的福尔马林反应减弱同时脊髓NMDA受体结合能力也下降

腺苷是痛觉通路中疼痛反应的调节因子之一。在四种腺苷受体(A1、A2A、A2B、A3)中,腺苷作用于A2A受体被认为有致痛作用,这种作用被认为是刺激了感觉神经末梢的腺苷酸环化酶增加了cAMP水平所致。而腺苷A2A受体缺失的小鼠对热伤害性刺激的反应明显减弱。另外有报道A2A受体的选择性     

腺苷A2A受体基因敲除小鼠瘢痕胶原亚型的变化

背景:作者前期研究发现腺苷受体激动剂可以刺激胶原合成,腺苷受体拮抗剂可以抑制胶原合成,并且可以减轻皮肤胶原纤维增生.腺苷A2A 受体基因敲除小鼠瘢痕转化生长因子β表达降低.目的:利用苦味酸-天狼星红偏振光法观察腺苷A2A 受体基因敲除小鼠瘢痕胶原亚型的变化并探讨其机制.方法:腺苷A2A受体基因敲除小鼠和野生型小鼠制作瘢痕模型,采用苦味酸-天狼星红偏振光法对瘢痕组织中胶原的性质及分布特点进行观察、确定瘢痕组织胶原类型、分布、排列与水平.结果与结论:偏振光显微镜下可见野生型组小鼠增生性瘢痕组织中含有大量的嗜酸性胶原蛋白纤维束,Ⅰ型胶原纤维为红色,呈致密的条束状,显示很强的双折光性,腺苷A2A 受体基因敲除小鼠瘢痕缺乏粗大胶原束,呈稀疏的条束状,排列相对整齐、密度较为均匀,Ⅰ型胶原纤维水平减少(P < 0.01),瘢痕增生显著减轻.提示腺苷A2A 受体参与瘢痕增生,对预防瘢痕增生有积极意义.     

腺苷A2A受体基因敲除小鼠瘢痕胶原亚型的变化

背景：作者前期研究发现腺苷受体激动剂可以刺激胶原合成,腺苷受体拮抗剂可以抑制胶原合成,并且可以减轻皮肤胶原纤维增生。腺苷A2A受体基因敲除小鼠瘢痕转化生长因子β表达降低。目的：利用苦味酸-天狼星红偏振光法观察腺苷A2A受体基因敲除小鼠瘢痕胶原亚型的变化并探讨其机制。方法：腺苷A2A受体基因敲除小鼠和野生型小鼠制作瘢痕模型,采用苦味酸-天狼星红偏振光法对瘢痕组织中胶原的性质及分布特点进行观察、确定瘢痕组织胶原类型、分布、排列与水平。结果与结论：偏振光显微镜下可见野生型组小鼠增生性瘢痕组织中含有大量的嗜酸性胶原蛋白纤维束,Ⅰ型胶原纤维为红色,呈致密的条束状,显示很强的双折光性,腺苷A2A受体基因敲除小鼠瘢痕缺乏粗大胶原束,呈稀疏的条束状,排列相对整齐、密度较为均匀,Ⅰ型胶原纤维水平减少（P〈0.01）,瘢痕增生显著减轻。提示腺苷A2A受体参与瘢痕增生,对预防瘢痕增生有积极意义。     

三种腺苷受体mRNA表达与哮喘发病及第1秒用力呼气值的相关性

目的:通过诱导痰技术检测3种腺苷受体mRNA的表达与哮喘发病及第1秒用力呼气值的相关性。方法:实验于2003-10/2004-06在南京大学医学院附属鼓楼医院中心实验室完成。选择该院呼吸科门诊及住院患者9例(哮喘组),女7例,男2例;均无吸烟史,至少1个月内未用过糖皮质激素类药物。选择南京大学医学院研究生和职工9例为正常组,皆为健康正常人,无吸烟及过敏性疾病史。实验经本院伦理委员会批准,并与受试者签定知情同意书。取两组对象的诱导痰;贴壁法分离和纯化巨噬细胞及炎性细胞,并计算相对构成计数的百分比;利用反转录-多聚酶链反应技术和图像分析半定量法检测诱导痰肺泡巨噬细胞腺苷受体mRNA的表达;计算第1秒用力呼气量占预测值百分比与腺苷受体mRNA的相关性。结果:按意向处理分析,18例均进入结果分析。①哮喘组诱导痰肺泡巨噬细胞表达A1及A2b和A3腺苷受体mRNA吸光度积分扫描相对比值均明显高于正常组(0.44±0.11,0.48±0.07,0.48±0.11;0.29±0.06,0.30±0.10,0.36±0.09,t=2.8,4.63,2.85,P<0.05～0.01)。②哮喘组嗜酸性粒细胞、淋巴细胞相对计数构成比明显高于正常组(P<0.01),而巨噬细胞相对计数构成比明显低于正常组(P<0.01)。③第1秒用力呼气量占预测值百分比在哮喘组与A2b腺苷受体mRNA呈正相关(r=0.49,P<0.05)。而与A1及A3腺苷受体mRNA表达无相关性(P>0.05)。结论:A1,A2b,A3腺苷受体可能参与哮喘发病过程,且在哮喘患者诱导痰巨噬细胞与外周血单核细胞表达均高于正常人。但腺苷受体亚型与第1秒用力呼气量占预测值百分比的相关性并不一致,对气道阻塞程度的影响可能不同,有待于进一步证实。     

基底核中腺苷A_(2A)受体和多巴胺D_2受体调节睡眠-觉醒作用机制

越来越多的研究关注基底核(basal ganglia,BG)对睡眠-觉醒的调节作用,其中纹状体和苍白球可能是控制睡眠和觉醒的关键结构。腺苷A2A受体与多巴胺D2受体在基底核中均高度共表达,特别是在纹状体。腺苷是目前为止发现的最强的内源性促眠物质之一,可通过激活A1和A2A受体诱导睡眠。而多巴胺D2受体对于觉醒的维持有着重要作用。这些研究成果均提示基底核中A2A受体和D2受体调节睡眠-觉醒,腺苷作用于兴奋性的A2A受体,增加伏隔核中抑制性GABA能神经元活性,抑制主要觉醒系统,促进睡眠;抑制性多巴胺D2受体系统则发挥了相反的作用。本文综述基底核中腺苷A2A受体和多巴胺D2受体调节睡眠-觉醒机制。     

Adenosinergic cardioprotection: multiple receptors, multiple pathways

Adenosine, formed primarily via hydrolysis of 5'-AMP, has been historically dubbed a "retaliatory" metabolite due to enhanced local release and beneficial actions during cellular/metabolic stress. From a cardiovascular perspective, evidence indicates the adenosinergic system is essential in mediation of intrinsic protection (e.g., pre- and postconditioning) and determining myocardial resistance to insult. Modulation of adenosine and its receptors thus remains a promising, though as yet not well-realized, approach to amelioration of injury in ischemic-reperfused myocardium. Adenosine exerts effects through A(1), A(2A), A(2B), and A(3) adenosine receptor subtypes (A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR), which are all expressed in myocardial and vascular cells, and couple to G proteins to trigger a range of responses (generally, but not always, beneficial). Adenosine can also enhance tolerance to injurious stimuli via receptor-independent metabolic effects. Given adenosines contribution to preconditioning, it is no surprise that postreceptor signaling typically mimics that associated with preconditioning. This involves activation/translocation of PKC, PI3 kinase, and MAPKs, with ultimate effects at the level of mitochondrial targets-the mitochondrial K(ATP) channel and/or the mitochondrial permeability transition pore (mPTP). Nonetheless, differences in cytoprotective signaling and actions of the different adenosine receptor subtypes have been recently revealed. Our understanding of adenosinergic cytoprotection continues to evolve, with roles for the A(2) subtypes emerging, together with evidence of essential receptor "cross-talk" in mediation of protection. This review focuses on current research into adenosine-mediated cardioprotection, highlighting recent findings which, together with a wealth of prior knowledge, may ultimately facilitate adenosinergic approaches to clinical cardiac protection.     

Progress in the pursuit of therapeutic adenosine receptor antagonists

Ever since the discovery of the hypotensive and bradycardiac effects of adenosine, adenosine receptors continue to represent promising drug targets. First, this is due to the fact that the receptors are expressed in a large variety of tissues. In particular, the actions of adenosine (or methylxanthine antagonists) in the central nervous system, in the circulation, on immune cells, and on other tissues can be beneficial in certain disorders. Second, there exists a large number of ligands, which have been generated by introducing several modifications in the structure of the lead compounds (adenosine and methylxanthine), some of them highly specific. Four adenosine receptor subtypes (A1, A2A, A2B, and A3) have been cloned and pharmacologically characterized, all of which are G protein-coupled receptors. Adenosine receptors can be distinguished according to their preferred mechanism of signal transduction: A1 and A3 receptors interact with pertussis toxin-sensitive G proteins of the Gi and Go family; the canonical signaling mechanism of the A2A and of the A2B receptors is stimulation of adenylyl cyclase via Gs proteins. In addition to the coupling to adenylyl cyclase, all four subtypes may positively couple to phospholipase C via different G protein subunits. The development of new ligands, in particular, potent and selective antagonists, for all subtypes of adenosine receptors has so far been directed by traditional medicinal chemistry. The availability of genetic information promises to facilitate understanding of the drug-receptor interaction leading to the rational design of a potentially therapeutically important class of drugs. Moreover, molecular modeling may further rationalize observed interactions between the receptors and their ligands. In this review, we will summarize the most relevant progress in developing new therapeutic adenosine receptor antagonists.     

Adenosine receptor-mediated cardioprotection: are all 4 subtypes required or redundant?

Adenosine is a purine nucleoside, which is produced primarily through the metabolism of adenosine triphosphate (ATP), therefore its levels increase during stressful situations when ATP utilization increases. Adenosine exerts potent cardioprotective effects on the ischemic/reperfused heart, reducing reversible and irreversible myocardial injury. Adenosine receptors (ARs) are G-protein-coupled receptors, and 4 subtypes exist--A(1), A(2A), A(2B), and A(3), all of which have been shown to be cardioprotective. Adenosine receptors are expressed on multiple cardiac cells, including fibroblasts, endothelial cells, smooth muscle cells, and myocytes. Activation of both A(1) and A(3) receptors prior to ischemia has been shown in multiple experimental models to reduce ischemia/reperfusion-induced cardiac injury. Additionally, activation of the A(2A) receptor at the onset of reperfusion has been shown to reduce injury. Most recently, there is evidence that the A(2B) receptor has cardioprotective effects upon its activation. However, controversy remains regarding the precise timing of activation of these receptors required to induce cardioprotection, as well as their involvement in ischemic preconditioning and postconditioning. Adenosine receptors have been suggested to reduce cell death through actions at the mitochondrial ATP-dependent potassium (K(ATP)) channel, as well as protein kinase C and mitogen-activated protein kinase (MAPK) signaling. Additionally, the ability of ARs to interact has been documented, and several recent reports suggest that these interactions play a role in AR-mediated cardioprotection. This review summarizes the current knowledge of the cardioprotective effects of each AR subtype, as well as the proposed mechanisms of AR cardioprotection. Additionally, the role of AR interactions in cardioprotection is discussed.     

Purinergic receptors: new targets for the treatment of gout and fibrosis

Adenosine triphosphate is involved in many metabolic reactions, but it has also a role as a cellular danger signal transmitted through purinergic receptors (PRs). Indeed, adenosine 5′‐triphosphate (ATP) can bind to PRs which are found in the membrane of many cell types, although the relative proportions of the receptor subtypes differ. PRs are classified according to genetic and pharmacological criteria and especially their affinities for agonists and their transduction mechanism (i.e. as metabotropic P2YRs or ionotropic P2XRs). Extracellular ATP release by activated or necrotic cells may activate various PRs and especially P2X7R, the best‐characterized PR, on immune cells. P2X7R is known to regulate the activation of the Nod‐like receptor (NLR)‐family protein, NLRP3 inflammasome, which permit the release of IL‐1β, a potent pro‐inflammatory cytokine. The P2X7R/NLRP3 pathway is involved in many inflammatory diseases, such as gout, and in fibrosis diseases associated with inflammatory process, liver or lung fibrosis. Some authors imaging also a real promising therapeutic potential of P2X7R blockage. Thus, several pharmaceutical companies have developed P2X7R antagonists as novel anti‐inflammatory drug candidates. Clinical trials of the efficacy of these antagonists are now underway. A better understanding of the P2X7R/NLRP3 signalling pathways permits the identification of targets and the development of a new class of drugs able to inhibit the fibrogenesis process and collagen deposition.     

Further evidence that propentofylline (HWA 285) influences both adenosine receptors and adenosine transport

We have examined the actions of a novel xanthine derivative, propentofylline (HWA 285), that has been shown to protect against ischemic brain damage in rats and gerbils, on adenosine receptors (A1 and A2), and on adenosine transporters using several techniques, cells and tissues. Propentofylline and its hydroxylated metabolite A 72 0287 were about 20 times less potent than theophylline in displacing A1-agonist binding to membranes from rat cortex, and A1-antagonist binding to whole DDT, MF-2 smooth muscle cells. A1-agonist binding to adenosine A1-receptors in several brain structures was inhibited in a concentration-dependent manner by A 72 0287 and propentofylline as judged by quantitative autoradiography (IC50-values 300-600 microM in eg striatum and in cortex layer IV). In two functional assays, A1-receptor mediated effects were blocked by propentofylline. A1-receptor-mediated inhibition of cyclic AMP accumulation was virtually abolished by 100 microM propentofylline. The A1-receptor-mediated inhibition of evoked acetylcholine release was also reduced by propentofylline, but in this case the effect is not due exclusively to adenosine receptor antagonism but also to another action since the presynaptic inhibitory effect of carbachol was also inhibited. Adenosine A2-receptors were also antagonized by propentofylline as judged by a concentration-dependent antagonism of A2-agonist-induced cAMP accumulation in human T-leukemia cells (possessing putative A2b-receptors; pA2-value 180 microM compared to 0.26 microM for 8-cpt), and in PC-12 cells (possessing putative A2a-receptors, Ki-value 365 microM). Finally, adenosine transporters were affected by propentofylline and A 72 0287. Thus, [3H]-nitrobenzylthioinosine-binding to guinea-pig cardiac membranes was blocked by propentofylline or A 72 0287 (Ki 270 microM). The present results show that propentofylline and its hydroxylated metabolite can influence adenosine mechanisms in a multitude of ways. How these different actions may contribute to the ability of propentofylline to reduce the magnitude of ischemic damage is discussed.     

Desensitization of adenosine and dopamine receptors in rat brain after treatment with adenosine analogs

Maximally tolerated doses of N6-[(R)-1-methyl-2-phenylethyl] adenosine (0.50 nmol/hr/2 wk), 5'-N-ethylcarboxamide adenosine (NECA, 0.04 nmol/hr/2 wk) or deoxycoformycin (5 nmol/hr/1 wk) were administered i.c.v. to rats using mini-osmotic pumps. Adenosine receptor function was subsequently assayed using both ligand binding and adenylate cyclase assays. Binding to A1 receptors was quantitated using [3H]N6-[(R)-1-methyl-2-phenylethyl]adenosine, a selective agonist ligand at A1 receptors. Differences in the binding of this ligand and that of [3H]NECA, which binds to A1 and A2 receptors with similar affinities, were used to quantitate A2 receptors. None of the treatments affected A1 receptor function as assessed by both ligand binding and adenylate cyclase assays. A2 receptor binding and A2 receptor-mediated stimulation of adenylate cyclase were blunted in striatal membranes from NECA- and deoxycoformycin-treated rats but unaffected in striatal membranes from N6-[(R]-1-methyl-2-phenylethyl]adenosine-treated rats. All three pretreatments attenuated D1 dopamine receptor-mediated stimulation of adenylate cyclase in striatal membranes. These results suggest that 1) the A2 adenosine receptor system is susceptible to desensitization and 2) different mechanisms are involved in the NECA- and deoxycoformycin-induced desensitization of A2 adenosine receptor and D1 dopamine receptor systems. It is suggested that the D1 dopamine receptor desensitization is, in fact, due to the tonic stimulation of adenosine A1 receptors.     

Autophagy may protect the brain against prolonged consequences of headache attacks: A narrative/hypothesis review

Objective

To assess the potential of autophagy in migraine pathogenesis.

Background

The interplay between neurons and microglial cells is important in migraine pathogenesis. Migraine-related effects, such as cortical spreading depolarization and release of calcitonin gene–related peptide, may initiate adenosine triphosphate (ATP)-mediating pro-nociceptive signaling in the meninges causing headaches. Such signaling may be induced by the interaction of ATP with purinergic receptor P2X 7 (P2X7R) on microglial cells leading to a Ca²⁺-mediated pH increase in lysosomes and release of autolysosome-like vehicles from microglial cells indicating autophagy impairment.

Methods

A search in PubMed was conducted with the use of the terms “migraine,” “autophagy,” “microglia,” and “degradation” in different combinations.

Results

Impaired autophagy in microglia may activate secretory autophagy and release of specific proteins, including brain-derived neurotrophic factor (BDNF), which can be also released through the pores induced by P2X7R activation in microglial cells. BDNF may be likewise released from microglial cells upon ATP- and Ca²⁺-mediated activation of another purinergic receptor, P2X4R. BDNF released from microglia might induce autophagy in neurons to clear cellular debris produced by oxidative stress, which is induced in the brain as the response to migraine-related energy deficit. Therefore, migraine-related signaling may impair degradative autophagy, stimulate secretory autophagy in microglia, and degradative autophagy in neurons. These effects are mediated by purinergic receptors P2X4R and P2X7R, BDNF, ATP, and Ca²⁺.

Conclusion

Different effects of migraine-related events on degradative autophagy in microglia and neurons may prevent prolonged changes in the brain related to headache attacks.     

Stimulation of adenosine A2A receptor inhibits LPS-induced expression of intercellular adhesion molecule 1 and production of TNF-alpha in human peripheral blood mononuclear cells

LPS stimulates CD14/Toll-like receptor (TLR) 4, leading to induce TNF-alpha production. Cell-to-cell interaction through the engagement between intercellular adhesion molecule (ICAM) 1 on monocytes and its ligand on T cells has been suggested to play a role in the TNF-alpha production by LPS-treated human peripheral blood mononuclear cells (PBMCs). Adenosine is reported to inhibit LPS-induced TNF-alpha production. However, little is known about the mechanism of the inhibitory effects induced by adenosine on the LPS-induced immune responses. We found that adenosine inhibited the expression of ICAM-1 and the production of TNF-alpha by human PBMC via adenosine A2A receptor in the presence of LPS. However, the stimulation of A1R or A3R enhanced the actions of adenosine. Adenosine had no effect on the expression of CD14 and TLR-4, suggesting that the inhibitory effects of adenosine on the LPS actions might be independent of the expression of CD14 and TLR-4. Thus, adenosine differentially regulates the expression of ICAM-1 and the production of TNF-alpha through plural subtypes of receptors.     

Modulation of hippocampal glutamatergic transmission by ATP is dependent on adenosine a(1) receptors

Excitatory glutamatergic synapses in the hippocampal CA1 region of rats are potently inhibited by purines, including adenosine, ATP, and ATP analogs. Adenosine A(1) receptors are known to mediate at least part of the response to adenine nucleotides, either because adenine nucleotides activate A(1) receptors directly, or activate them secondarily upon the nucleotides' conversion to adenosine. In the present studies, the inhibitory effects of adenosine, ATP, the purportedly stable ATP analog adenosine-5'-O-(3-thio)triphosphate (ATPgammaS), and cyclic AMP were examined in mice with a null mutation in the adenosine A(1) receptor gene. ATPgammaS displaced the binding of A(1)-selective ligands to intact brain sections and brain homogenates from adenosine A(1) receptor wild-type animals. In homogenates, but not in intact brain sections, this displacement was abolished by adenosine deaminase. In hippocampal slices from wild-type mice, purines abolished synaptic responses, but slices from mice lacking functional A(1) receptors showed no synaptic modulation by adenosine, ATP, cAMP, or ATPgammaS. In slices from heterozygous mice the dose-response curve for both adenosine and ATP was shifted to the right. In all cases, inhibition of synaptic responses by purines could be blocked by prior treatment with the competitive adenosine A(1) receptor antagonist 8-cyclopentyltheophylline. Taken together, these results show that even supposedly stable adenine nucleotides are rapidly converted to adenosine at sites close to the A(1) receptor, and that inhibition of synaptic transmission by purine nucleotides is mediated exclusively by A(1) receptors.     

Dopamine-mediated disinhibition in the CA1 region of rat hippocampus via D3 receptor activation

The hippocampal formation is thought to contribute to both addictive behaviors and to psychotic disorders, and the actions of the neurotransmitter dopamine are intimately involved with these disease states. We have used both whole-cell and extracellular recording techniques in hippocampal slices to investigate the actions of both cocaine and dopamine receptor agonists in the CA1 region. In the presence of cocaine (10 microM), endogenously released dopamine decreased monosynaptic inhibitory postsynaptic currents (IPSCs) evoked from stratum radiatum but not from stratum oriens. This effect of cocaine was not blocked by the D(1/5) antagonist SCH 23390 ({R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine}) (3 microM), whereas several D(2)-like dopamine receptor antagonists prevented the cocaine-induced decrease in the IPSC. The most selective of the effective antagonists tested was the D(3) antagonist, U 99194 ({5,6-dimethoxy-indan-2-yl dipropylamine}) maleate (1 microM). An exogenously applied D(3)-selective dopamine receptor agonist, PD 128907 ({(+)-(4aR, 10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano-[4,3-b]-1,4-oxazin-9-ol}) (1 microM), also significantly inhibited the IPSC, providing further evidence that the activation of the D(3) subtype of dopamine receptor by endogenously released dopamine can modulate inhibition in the CA1 region. This disinhibitory action on pyramidal cells also increased synaptic excitability following Schaffer collateral stimulation, as demonstrated by either a decrease in paired-pulse inhibition of the population spike response or by an increase in the excitatory component of the mixed synaptic response evoked from stratum radiatum. These actions indicate that the activation of D(3) receptors by endogenously released dopamine, especially under conditions of transporter blockade, may significantly impact the processing of synaptic information through the stratum radiatum layer of the hippocampus.