胆碱能抗炎通路α7烟碱型乙酰胆碱受体的最新研究进展

α7nAChR(α7 nicotinic acetylcholine receptor)属于烟碱型乙酰胆碱受体（nAChRs）,是机体胆碱能抗炎通路的关键受体,在免疫系统的神经调控中发挥重要作用。近期研究发现,α7nAChR还参与调节免疫以外的多种生理病理过程,如非酒精性脂肪肝、血管新生、保护心脏等。此外,α7nAChR在神经退行性疾病等与能量代谢紧密关联。本文综述α7nAChR在治疗炎症、改善能量代谢中发挥的作用,以及α7nAChR参与治疗的新方向。     

a7烟碱型乙酰胆碱受体与炎症的调节作用

在神经系统和非神经胆碱能系统（NNAS）中,d7烟碱型乙酰胆碱受体（a7nAChR）表现出良好的稳定性和丰富性,是典型N受体,属于典型介导神经抗炎通路的关键分子。适量的促炎因子有利于激活免疫系统清除病原体,并可促进组织修复;过量的促炎因子则可造成组织损伤。胆碱能神经抗炎通路对炎性反应的调节越来越受到人们的重视,本文主要综述Ⅸ7nAChR在胆碱能抗炎途径、免疫活性细胞抗炎作用及血管内皮细胞上及抗炎作用。     

非可兴奋性内皮细胞α7受体与血管新生

烟碱受体α7亚型 (α7nicotinicacetylcholinereceptor,α7nAChR)广泛分布于中枢和外周神经系统 ,是中枢神经系统重要神经递质受体 ,参与神经通路形成、维持和多种生理功能调节。近年来研究发现内皮细胞、血管平滑肌细胞、肺上皮细胞、皮肤角质细胞等非神经元细胞表达α7受体 ,并参与细胞有丝分裂、分化、细胞骨架形成、细胞间联接、运动和迁移等细胞机制调节。体外、体内试验表明α7受体参与内皮细胞多种生物活性物质的分泌和释放 ,参与内皮细胞与其它细胞间信号转导 ,参与内皮细胞血管新生调节。尤其是内皮细胞α7受体与血管新生关系的研究 ,揭示了内皮细胞存在调节血管新生药物作用新靶标。     

儿茶酚抑素与高血压

儿茶酚抑素作用于内源性烟碱型乙酰胆碱受体(nAChR)可抑制儿茶酚胺释放,具有扩血管、降血压、降低心肌收缩力和促进血管生成作用.本文综述儿茶酚抑素对血压的调节作用及其异构体在高血压治疗中的研究进展.     

烟碱乙酰胆碱受体结构的研究进展

烟碱型乙酰胆碱受体（nAChR）是离子通道型受体,属于Cys-loop受体的超级家族,通过配体门控离子通道介导许多生理活动,是治疗精神类疾病的重要靶点。nAChR包括肌肉型和神经型两种。nAChR是由五个亚基组成的具有中心孔道的五聚体,本文简要介绍了近年来烟碱乙酰胆碱受体结构的研究进展。     

血小板衍生生长因子与糖尿病血管病变的关系

血小板衍生生长因子（PDGF）是一种主要由血小板分泌产生的重要促细胞生长因子。其主要的生理作用是促进细胞分裂增生及细胞外基质（ECM）积聚。糖尿病时,在高血糖、终末期糖基化产物（AGEs）及脂质代谢紊乱等刺激下,PDGF及其受体（PDGFR）在血管表达水平升高。PDGF通过ECM积聚,引起血管内皮功能的异常,最终导致动脉粥样硬化及血管内皮损伤损伤,在糖尿病血管病变的发生和发展中起重要的作用。     

鸢尾素Irisin抑制PDGF-BB诱导的血管干细胞向血管平滑肌细胞分化并影响p38信号通路表达

目的 探讨鸢尾素（Irisin）对血管中膜干细胞（MVSCs）向血管平滑肌细胞（VSMCs）分化的作用及其机制。方法 原代培养大鼠MVSCs,PDGF-BB诱导其分化,加入适量Irisin,荧光定量PCR法检测VSMCs相关标记α-SMA、CNN1、SM22α等,蛋白印迹法（Western blot）检测VSMCs相关标记α-SMA、CNN1、SM22α等,以及p38等信号通路。结果 Irisin抑制PDGF-BB诱导的MVSCs向VSMCs分化,Irisin抑制p38的磷酸化。结论 Irisin通过调节p38信号通路抑制PDGF-BB诱导的血管干细胞向平滑肌细胞的分化,从而在动脉粥样硬化的防治中发挥重要作用。     

大鼠颈上神经节培养神经元烟碱电流及美加明的使用依赖性阻滞

比较几种烟碱型乙酰胆碱受体(nAChR)激动剂及拮抗剂对颈上神经节(SCG)培养神经元nAChR的作用和SCG培养神经元nAChR的药理特征.方法:用全细胞膜片钳技术结合局部压力喷射给药观察培养的新生大鼠SCG神经元对胆碱能药物的反应.结果:所测试的交感神经元均可被nAChR激动剂所激动,激动剂在相同浓度下诱发的电流峰值分别为:乙酰胆碱(ACh),443±183 pA;烟碱,1175±377 pA;碘化1,1-二甲基-4-苯基哌嗪(DMPP),2946±358 pA.在几种nAChR拮抗剂中,美加明(Mec),六烃季胺,箭毒在相同浓度下拮抗DMPP引起的全细胞电流的峰值分别为:435±154 pA,725±320 pA,887±214 pA,但α-银环蛇毒对之无影响.Mec对DMPP电流的拮抗具有使用依赖性.当Mec 1 μmol·L~(-1)与DMPP 100 μmol·L~(-1)混合向SCG神经元压力喷射时,前6次电流分别为第一次的％:100,64±3,50±3,41±4,36±4,32±3％.结论:SCG神经元的nAChR与骨胳肌及中枢nAChR有不同的药理特征.     

α7烟碱型乙酰胆碱受体与炎症的调节作用

在神经系统和非神经胆碱能系统(NNAS)中,α7烟碱型乙酰胆碱受体(α7nAChR)表现出良好的稳定性和丰富性,是典型N受体,属于典型介导神经抗炎通路的关键分子。适量的促炎因子有利于激活免疫系统清除病原体,并可促进组织修复;过量的促炎因子则可造成组织损伤。胆碱能神经抗炎通路对炎性反应的调节越来越受到人们的重视,本文主要综述α7nAChR在胆碱能抗炎途径、免疫活性细胞抗炎作用及血管内皮细胞上及抗炎作用。     

动脉粥样硬化的血管内皮细胞功能异常及治疗

动脉粥样硬化（ＡＳ）是一个复杂的过程，其特征是氧修饰的低密度脂蛋白（ＬＤＬ）积累，局部炎症免疫反应及动脉壁内一氧化氮（ＮＯ）生物活性下降。这些病理生理及生物化学方面的改变导致内皮依赖性血管舒缩功能障碍，平滑肌细胞（ＳＭＣ）增殖，粥样斑块脆性的增加及临床症状的发生（如稳定型心绞痛和急性冠脉综合征）。在这些改变中血管内皮细胞起着关键性作用，内皮细胞通过ＮＯ合成来影响血管紧张度，ＡＳ及其他常见的危险性因     

Subtypes of nicotinic acetylcholine receptors in nicotine reward, dependence, and withdrawal: evidence from genetically modified mice

Neuronal nicotinic acetylcholine receptors (nAChRs) can regulate the activity of many neurotransmitter pathways throughout the central nervous system and are considered to be important modulators of cognition and emotion. nAChRs are also the primary site of action in the brain for nicotine, the major addictive component of tobacco smoke. nAChRs consist of five membrane-spanning subunits (alpha and beta isoforms) that can associate in various combinations to form functional nAChR ion channels. Owing to a dearth of nAChR subtype-selective ligands, the precise subunit composition of the nAChRs that regulate the rewarding effects of nicotine and the development of nicotine dependence are unknown. The advent of mice with genetic nAChR subunit modifications, however, has provided a useful experimental approach to assess the contribution of individual subunits in vivo. Here, we review data generated from nAChR subunit knockout and genetically modified mice supporting a role for discrete nAChR subunits in nicotine reinforcement and dependence processes. Importantly, the rates of tobacco dependence are far higher in patients suffering from comorbid psychiatric illnesses compared with the general population, which may at least partly reflect disease-associated alterations in nAChR signaling. An understanding of the role of nAChRs in psychiatric disorders associated with high rates of tobacco addiction, therefore, may reveal novel insights into mechanisms of nicotine dependence. Thus, we also briefly review data generated from genetically modified mice to support a role for discrete nAChR subunits in anxiety disorders, depression, and schizophrenia.     

The α7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca dependent mechanism

Neuronal nicotinic acetylcholine receptors (nAChR) have been suggested to play a role in a variety of modulatory and regulatory processes, including neuroprotection. Here we have characterized the neuroprotective effects of nicotine against an excitotoxic insult in primary hippocampal cultures. Exposure of hippocampal neurons to 200 μM NMDA for 1 h decreased cell viability by 25±5%, an effect blocked by NMDA receptor antagonists. Nicotine (10 μM) counteracted the NMDA-induced cell death when co-incubated with NMDA or when present subsequent to the NMDA treatment. Nicotine protection was prevented by 1μM MLA, confirming that it was mediated by nAChR, and by 1 μM α-bungarotoxin, demonstrating that the α7 nAChR subtype was responsible. Both the NMDA evoked neurotoxicity and nicotine neuroprotection were Ca²⁺-dependent. In Fura-2-loaded hippocampal neurons, nicotine (10 μM) and NMDA (200 μM) acutely increased intracellular resting Ca²⁺ from 70 nM to 200 and 500 nM, respectively. Responses to NMDA were unaffected by the presence of nicotine. ⁴⁵Ca²⁺ uptake after a 1 h exposure to nicotine or NMDA also demonstrated quantitative differences between the two drugs. This study demonstrates that the α7 subtype of nAChR can support neuronal survival after an excitotoxic stimulus, through a Ca²⁺ dependent mechanism that operates downstream of NMDA receptor activation.     

Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to mainstream cigarette smoke or α4β2 receptors to nicotine

Smokers are reported to have a higher density of central nicotinic acetylcholine receptors (nAChRs) that non-smokers at autopsy. Whether this increased receptor density is a response to smoking or a result of genetic variability is not known. While sub-chronic treatment of rats and mice with nicotine results in upregulation of central nAChRs, changes in receptor density in response to cigarette smoke have not been studied previously. In this study, male Sprague-Dawley rats were exposed nose-only for 13 weeks to mainstream cigarette smoke followed by assessment of [³H]nicotine binding in five brain regions of smoke- and sham-exposed animals. In smoke-exposed animals, there was a significant increase in nAChR density in the cortex, striatum, and cerebellum (35, 25, and 31% increases, respectively), while there was no significant change in receptor density in the thalamus and hippocampus. Smoke exposure did not alter markedly the affinity of the receptor for nicotine in these brain regions. Furthermore, up-regulation of nAChRs did not alter the biphasic binding properties by which nicotine binds to its receptor. There were no changes in the association (fast phase) or isomerization (slow phase) rate constants, and the percent contribution of slow and fast phase binding to nAChRs was not altered in the up-regulated receptor population compared with control. Similar results were observed following chronic nicotine exposure of cultured cortical cells from fetal rat brain or cells transfected with the α4β2 nAChR subtype. These results show that the up-regulation following smoke exposure in the rat is phenomenologically similar to that observed in vitro. These data provide preliminary evidence for a relationship between cigarette smoking and nAChR up-regulation in vivo and suggest that similar mechanisms of upregulation may underlie chronic smoke exposure of live animals and nicotine exposure of artificially expressed α4β2 receptors in vitro.     

α7 nicotinic acetylcholine receptor subunit in angiogenesis and epithelial to mesenchymal transition

Cigarette smoking is strongly correlated with many diseases like cancer, cardiovascular disease and macular degeneration. Nicotine, the main active and addictive component of tobacco smoke has recently been shown to enhance angiogenesis in many experimental systems and animal models. The pro-angiogenic activity of nicotine is mediated by nicotinic acetylcholine receptors, particularly the alpha 7 subunit, that are expressed on a variety of non-neuronal cells including those in the vasculature such as endothelial cells and smooth muscle cells. The present review focuses on the role of α7nAChR in mediating the pro-angiogenic effects of nicotine and describes the molecular mechanisms involved in nicotine-induced angiogenesis as well as epithelial to mesenchymal transition. These observations on nicotine function highlight the therapeutic potential of α7nAChR agonists and antagonists for combating angiogenesis related diseases.     

The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration

In the last five years there has been a rapid explosion of publications reporting that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in neurodegenerative disorders. Furthermore, there is a well-established loss of nAChRs in post-mortem brains from patients with Alzheimer's disease, Parkinson's disease and a range of other disorders. In the present review we discuss the evidence that nicotine and subtype selective nAChR ligands can provide neuroprotection in in vitro cell culture systems and in in vivo studies in animal models of such disorders. Whilst in vitro data pertaining to a protective effect of nicotine against nigral neurotoxins like MPTP is less robust, most studies agree that nicotine is protective against glutamate and beta-amyloid toxicity in various culture systems. This effect appears to be mediated by alpha7 subtype nAChRs since the protection is blocked by alpha-bungarotoxin and is mimicked by alpha7 selective agonists. In vivo studies indicate that alpha7 receptors play a critical role in protection from cholinergic lesions and enhancing cognitive function. The exact subtype involved in the neuroprotectant effects seen in animal models of Parkinson's disease is not clear, but in general broad spectrum nAChR agonists appear to provide protection, while alpha4beta2 receptors appear to mediate symptomatic improvements. Evidence favouring a protectant effect of nicotine against acute degenerative conditions is less strong, though some protection has been observed with nicotine pre-treatment in global ischaemia models. A variety of cellular mechanisms ranging from the production of growth factors through to inactivation of toxins and antioxidant actions of nicotine have been proposed to underlie the nAChR-mediated neuroprotection in vitro and in vivo. In summary, although the lack of subtype selective ligands has hampered progress, it is clear that in the future neuronal nAChR agonists could provide functional improvements and slow or halt the progress of several crippling degenerative diseases.     

Multiple CNS nicotinic receptors mediate l-dopa-induced dyskinesias: Studies with parkinsonian nicotinic receptor knockout mice

Accumulating evidence supports the idea that drugs acting at nicotinic acetylcholine receptors (nAChRs) may be beneficial for Parkinson's disease, a neurodegenerative movement disorder characterized by a loss of nigrostriatal dopaminergic neurons. Nicotine administration to parkinsonian animals protects against nigrostriatal damage. In addition, nicotine and nAChR drugs improve l-dopa-induced dyskinesias, a debilitating side effect of l-dopa therapy which remains the gold-standard treatment for Parkinson's disease. Nicotine exerts its antidyskinetic effect by interacting with multiple nAChRs. One approach to identify the subtypes specifically involved in l-dopa-induced dyskinesias is through the use of nAChR subunit null mutant mice. Previous work with β2 and α6 nAChR knockout mice has shown that α6β2* nAChRs were necessary for the development/maintenance of l-dopa-induced abnormal involuntary movements (AIMs). The present results in parkinsonian α4 nAChR knockout mice indicate that α4β2* nAChRs also play an essential role since nicotine did not reduce l-dopa-induced AIMs in such mice. Combined analyses of the data from α4 and α6 knockout mice suggest that the α6α4β2β3 subtype may be critical. In contrast to the studies with α4 and α6 knockout mice, nicotine treatment did reduce l-dopa-induced AIMs in parkinsonian α7 nAChR knockout mice. However, α7 nAChR subunit deletion alone increased baseline AIMs, suggesting that α7 receptors exert an inhibitory influence on l-dopa-induced AIMs. In conclusion, α6β2*, α4β2* and α7 nAChRs all modulate l-dopa-induced AIMs, although their mode of regulation varies. Thus drugs targeting one or multiple nAChRs may be optimal for reducing l-dopa-induced dyskinesias in Parkinson's disease.     

Cytisine derivatives as ligands for neuronal nicotine receptors and with various pharmacological activities

Neuronal nicotinic acetylcholine receptors (nAChRs) form a family of ACh-gated cation channels made up of different subtypes. They are widely distributed in peripheral and central nervous systems and are involved in complex cerebral processes as learning, memory, nociception, movement, etc. The possibility that subtype-selective ligands be used in the treatment of CNS disorders promoted the synthesis of a large number of structural analogues of nicotine and epibatidine, two very potent nAChR agonists. Pursuing our long standing research on the structural modification of quinolizidine alkaloids, we devoted our attention to cytisine, another very potent ligand for many nAChR subtypes. Thus a systematic structural modification of cytisine was undertaken in order to obtain compounds of potential therapeutic interest at peripheral as well as central level, with a particular concern for achieving nAChR subtype selective ligands. Up to the present more than 80 cytisine derivatives, mainly of N-substitution and a few by modifying the pyridone ring, have been prepared. The biological results, which concern so far about an half of the prepared compounds, indicate that the introduction of a nitro group in position 3 of the pyridone nucleus further enhances the high affinity of cytisine, while the introduction of substituents on the basic nitrogen, though reducing in different degrees the affinity, gives rise to compounds with a higher selectivity for central (alpha(4)beta(2)) versus gangliar (alpha(3)-containing) receptor subtype. On the other hand, the analgesic, antihypertensive and inotropic activities found in some N-substituted cytisines, represent an attractive starting point for the development of more active compounds.     

Genetic matters: Thirty years of progress using mouse models in nicotinic research

This research update summarizes thirty years of studies on genetic influences on responses to the acute or chronic administration of nicotine. Early studies established that various inbred mice are differentially sensitive to the effects of the drug. Classical genetic analyses confirmed that nicotine effects on locomotion, body temperature and seizures are heritable. A significant inverse correlation between the locomotor and hypothermic effects and the density of nicotine binding sites suggested that differential expression α4β2-neuronal nicotinic acetylcholine receptor (nAChR) mediated some of this genetic variability. Subsequent studies with α4 and β2 nAChR null (decreased sensitivity) and gain of function mutants (increased sensitivity) supports the role of the α4β2*nAChR subtype. However, null mutant mice still respond to nicotine, indicating that other nAChR subtypes also mediate these responses. Mice differing in initial sensitivity to nicotine also differ in tolerance development following chronic treatment: those mice that are initially more sensitive to nicotine develop tolerance at lower treatment doses than less sensitive mice, indicating that tolerance is an adaptive response to the effects of nicotine. In contrast, the sensitivity of mice to pre-pulse inhibition of acoustic startle response is correlated with the expression of α7-nAChR. While genetic variability in nAChR expression and function is an important factor contributing to differences in response to nicotine, the observations that altered activity of opioid, glutamate, and cannabinoid receptors among others also change nicotine sensitivity reinforces the proposal that the genetics of nicotine response is more complex than differences in nAChRs.     

Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation-conducting transmembrane channels from the cys-loop receptor superfamily. The neuronal subtypes of these receptors (e.g. the α7 and α4β2 subtypes) are involved in neurobehavioral processes such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and a number of cognitive functions like learning and memory. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders, and behavioral studies in animals are useful models to assess the effects of compounds that act on these receptors. Allosteric modulators are ligands that bind to the receptors at sites other than the orthosteric site where acetylcholine, the endogenous agonist for the nAChRs, binds. While conventional ligands for the neuronal nAChRs have been studied for their behavioral effects in animals, allosteric modulators for these receptors have only recently gained attention, and research on their behavioral effects is growing rapidly. Here we will discuss the behavioral effects of allosteric modulators of the neuronal nAChRs.