羽扇豆醇对人高转移肝癌HCCLM3增殖影响的机制研究

摘 要 目的： 研究羽扇豆醇（Lupeol）在人高转移肝癌细胞系HCCLM3中的抗增殖作用机制。方法: 运用CCK 8法检测不同浓度Lupeol在12-48 h对HCCLM3细胞活力的影响及相关Caspase参与Lupeol（20～100 μmol·L^-1）诱导的细胞凋亡类型;运用Realtime PCR评价Lupeol对细胞内Caspase家族及Bcl 2相关基因的mRNA表达的影响;同时运用流式细胞术检测Lupeol对细胞周期分布的影响。结果:Lupeol在24～48 h能够抑制HCCLM3的细胞增殖,并呈现浓度依赖性,在24 h处理细胞的IC₅₀为93 μmol·L^-1;运用60～100 μmol·L^-1的Lupeol能够使HCCLM3细胞在G2/M期细胞数增加1倍;Lupeol能够活化Caspase通路,与对照组相比Lupeol处理后细胞内Caspase 3的mRNA表达量增加50%～150%,同时100 μmol·L^-1的Lupeol处理细胞后使胞内p53及Bax的mRNA表达量分别上调1倍以上,并显著降低Bcl 2及PARP的mRNA水平(P<0.05或P<0.01)。结论: Lupeol具有抑制肝癌细胞增殖能力,对肝癌预防及治疗可能具有一定的协同作用。     

羽扇豆醇抑制人肝癌Huh-7细胞增殖机制研究

摘 要 目的：研究羽扇豆醇（lupeol）对人肝癌Huh-7细胞增殖的影响。方法: 运用CCK-8法检测lupeol（10~150 μmol·L^-1）对T24细胞活力的影响;运用caspase抑制剂确证凋亡相关蛋白caspase是否与lupeol对细胞增殖抑制作用有关;运用western blot检测lupeol对c-Jun蛋白表达的影响;运用real time PCR评价lupeol对miR-21、MMP-2、MMP-9基因mRNA表达的影响;运用pGL3 Basic荧光素酶报告系统研究lupeol对MMP-9启动子活性的影响。结果: Lupeol在72 h能够抑制Huh-7细胞增殖,该抑制作用具有剂量依赖性;lupeol处理细胞72 h后半抑制浓度（IC50）为80 μmol·L^-1;与对照组相比,运用lupeol能够使Huh-7细胞中c-Jun蛋白表达下调;lupeol能够降低miR-21表达水平;与对照组相比,lupeol处理Huh-7细胞降低MMP-9的mRNA表达,并使MMP-9基因启动子活性下调40%;以上结果与对照组比较差异均有统计学意义（P<0.05）。结论: Lupeol能够抑制人肝癌Huh-7细胞增殖,该作用与抑制miR-21/c-Jun/MMP-9信号通路有关。     

青蒿琥酯对人源肝星状细胞中Akt/GSK-3β/β-catenin信号通路的影响研究

摘 要 目的：探讨青蒿琥酯（Art）对Akt/GSK 3β/β catenin信号通路的影响。方法: 不同浓度（0,12.5,25,50 μg·mL^-1）Art作用于人源肝星状细胞（LX 2）,采用CCK 8法检测细胞增殖情况,并确定给药浓度;给予不同浓度Akt抑制药MK 2206 0～8 μmol·L^-1,Western blot法确定其最佳抑制浓度;给予Art、MK 2206、MK 2206+Art,采用Western blot法检测各组Akt、p Akt、GSK 3β、p GSK 3β、β catenin蛋白表达情况。结果: CCK 8法检测细胞存活率,当选用25 μg·mL^-1Art作用于LX 2细胞24h时细胞存活率约80%,Western blot法确定当MK 2206浓度为6 μmol·L^-1时,可有效抑制p Akt的表达;Art组（25 μg·mL^-1）、MK 2206组（6 μmol·L^-1）、MK 2206（6 μmol·L^-1）+Art（25 μg·mL^-1）组与对照组相比,Akt、p Akt、p GSK 3β、β catenin蛋白表达均有显著差异（P<0.05）,MK 2206（6 μmol·L^-1）+Art（25 μg·mL^-1）组分别与Art（25 μg·mL^-1）组、MK 2206（6 μmol·L^-1）组比较,GSK 3β、Akt蛋白表达无显著差异（P>0.05）,p Akt、p GSK 3β、β catenin蛋白表达显著降低（P<0.01）。结论: Art可通过Akt因子对Wnt/β catenin信号通路中相关因子产生影响,进而抑制细胞增殖,缓解肝纤维发展进程。     

黄芩苷联合奥沙利铂调控miR-433-3p/SRC对胃癌细胞增殖和侵袭的影响

目的 探究黄芩苷联合奥沙利铂调控miR-433-3p/SRC对胃癌细胞增殖和侵袭的影响。方法 将SGC-7901细胞分为对照组、黄芩苷（100、200、300 μmol·L^-1）组、奥沙利铂（33 μmol·L^-1）组,联合用药（300 μmol·L^-1黄芩苷+33 μmol·L^-1奥沙利铂）组,miR-433-3p组、miR-NC组、anti-miR-433-3p组、anti-miR-NC组、pcDNA-SRC组、si-SRC组,miR-433-3p+联合用药组、anti-miR-433-3p+联合用药组、pcDNA-SRC+联合用药组、si-SRC+联合用药组、miR-433-3p+pcDNASRC+联合用药组。CCK-8检测细胞增殖能力;Transwell小室法检测细胞侵袭能力;流式细胞仪检测细胞凋亡率;实时荧光定量PCR （qRT-PCR）检测细胞中miR-433-3p表达;双荧光素酶报告检测miR-433-3p和SRC的靶向关系;Westernblotting检测细胞中SRC蛋白表达。结果 与对照组相比,黄芩苷（100、200、300 μmol·L^-1）组、奥沙利铂组、联合用药组细胞增殖抑制率、凋亡率和miR-433-3p表达显著增加（P<0.05）,细胞侵袭数目、SRC蛋白表达显著减少（P<0.05）;与黄芩苷300 μmol·L^-1组、奥沙利铂组相比,联合用药组细胞增殖抑制率、凋亡率显著增加,细胞侵袭数目显著减少;与黄芩苷300 μmol·L^-1组比较,miR-433-3p表达显著增加（P<0.05）;与奥沙利铂组比较,SRC蛋白表达显著减少（P<0.05）。与对照组比较,miR-433-3p组细胞中miR-433-3p表达显著升高,SRC蛋白表达显著降低,anti-miR-433-3p组细胞中miR-433-3p表达显著降低,SRC蛋白表达显著升高（P<0.05）;miR-433-3p+联合用药组细胞增殖抑制率和凋亡率显著高于联合用药组,细胞侵袭数目显著少于联合用药组（P<0.05）,anti-miR-433-3p+联合用药组细胞增殖抑制率和凋亡率显著低于联合用药组,细胞侵袭数目显著多于联合用药组（P<0.05）。miR-433-3p组SRC-WT荧光素酶活性显著低于miR-NC组（P<0.05）。si-SRC组细胞中SRC蛋白表达显著低于对照组（P<0.05）,pcDNA-SRC组细胞中SRC蛋白表达显著高于对照组（P<0.05）;与pcDNA-SRC组相比,miR-433-3p+pcDNA-SRC组细胞中SRC蛋白表达显著降低（P<0.05）。si-SRC+联合用药组细胞增殖抑制率和凋亡率显著高于联合用药组,细胞侵袭数目显著少于联合用药组（P<0.05）,pcDNA-SRC+联合用药组细胞增殖抑制率和凋亡率显著低于联合用药组,细胞侵袭数显著高于联合用药组（P<0.05）。与pcDNA-SRC+联合用药组相比,miR-433-3p+pcDNA-SRC+联合用药组细胞增殖抑制率和凋亡率显著降低（P<0.05）,细胞侵袭数目显著升高（P<0.05）。结论 黄芩苷联合奥沙利铂可通过miR-433-3p靶向调控SRC抑制胃癌细胞的增殖和侵袭,诱导胃癌细胞凋亡。     

miR-199a-5p和miR-206靶向调控SULF1并抑制卵巢上皮细胞对顺铂的敏感性★

目的 SULF1是硫酸酯酶家族成员之一，主要发挥肿瘤抑制因子的作用，在多种肿瘤中低表达，本研究旨在筛选直接靶向SULF1的microRNAs，并验证候选microRNAs对SULF1表达的负调控作用。方法 利用TargetScanHuman 7.2、miRDB、DIANA和RNAhybrid数据库预测调控SULF1的microRNAs。利用实时荧光定量PCR和Western blotting实验探索microRNAs对SULF1表达的影响。双荧光素酶报告基因实验探究microRNAs和SULF1基因的直接结合能力。CCK-8实验验证microRNAs对铂类药物敏感性的影响。结果 利用数据库预测到两个microRNAs：miR-199a-5p和miR-206，二者均可靶向SULF1的3''-UTR区域。实时荧光定量PCR结果显示，与IOSE80细胞中的阴性对照相比，miR-199a-5p和miR-206对应的模拟物（mimics）分别使SULF1的mRNA表达水平降低至23.07%和20.11%，而它们的抑制剂（inhibitors）则分别使SULF1的mRNA表达水平升高3.62倍和3.09倍。Western blotting结果表明，miR-199a-5p和miR-206也可降低SULF1蛋白表达水平。双荧光素酶报告基因实验表明，miR-206和miR-199a-5p均可直接结合SULF1的3''-UTR，且miR-206具有更强的调控作用。CCK-8实验结果表明，降低miR-199a-5p和miR-206的表达水平可显著增强IOSE80细胞对顺铂的敏感性（IC₅₀： 9.287 μmol·L^-1/11.32 μmol·L^-1 vs. 16.75 μmol·L^-1），相反，二者过表达可显著降低IOSE80细胞对顺铂的敏感性。结论 miR-199a-5p和miR-206均可直接与SULF1的3''-UTR结合，下调SULF1表达，降低卵巢细胞对顺铂的敏感性。     

吉马酮通过HBXIP/p53信号通路诱导A549、CNE-1、HepG2细胞凋亡

目的 研究吉马酮诱导肺癌 A549、 鼻咽癌 CNE-1、 肝癌 HepG2 细胞凋亡的机制 。 方法 50、 150、 200、250、300 μmol·L^-1的吉马酮处理肝癌 HepG2、肺癌 A549、鼻咽癌 CNE-1、结肠癌 Caco-2 细胞 24、48、72 h 后,MTT 实验检测细胞的存活率的变化。100、150、200 μmol·L^-1的吉马酮分别处理 A549、HepG2、CNE-1细胞 48 h后采用流式细胞术检测细胞凋亡的变化;Western blotting 实验检测细胞凋亡标志蛋白 cleaved-Caspase-3、Caspase-3 的变化,检测乙型肝炎 X相互作用蛋白（HBXIP）、p53蛋白的表达量变化。分别在 A549、HepG2、CNE-1细胞中应用 siRNA 敲低 HBXIP,Westernblotting实验检测 HBXIP的敲低效果及 p53蛋白表达变化;MTT实验检测敲低 HBXIP对吉马酮诱导的细胞增殖抑制作用的影响。结果 吉马酮对鼻咽癌CNE-1、肝癌HepG2细胞增殖抑制作用较强,与溶剂对照组比较,200、250、300 μmol·L^-1组细胞存活率显著下降（P＜0.05）;在高浓度时对肺癌A549细胞增殖抑制效果较强,与溶剂对照组比较,250、300 μmol·L^-1组细胞存活率显著下降（P＜0.05）;对结肠癌Caco-2细胞作用相对较弱。与对照组比较,100、150、200 μmol·L^-1吉马酮处理A549、HepG2、CNE-1细胞 48 h后,凋亡率显著升高（P＜0.05）,cleaved-Caspase-3、p53蛋白表达显著上升（P＜0.05）;以 150、200 μmol·L^-1吉马酮处理A549、HepG2、CNE-1细胞48 h后,HBXIP的蛋白表达显著降低（P＜0.05）。siRNA-HBXIP处理48 h后,与对照组比较,HBXIP的蛋白表达量显著下降（P＜0.05）,p53蛋白表达量显著上升（P＜0.05）。与单独使用的相同浓度的吉马酮相比,沉默HBXIP后A549、HepG2、CNE-1细胞对吉马酮的敏感度明显提高,150、200、250 μmol·L^-1组均差异显著（P＜0.05）。结论 吉马酮可以抑制A549、HepG2、CNE-1细胞增殖、诱导细胞凋亡,作用机制可能与调控HBXIP/p53信号通路相关。     

联苯双酯对大鼠肝星状细胞增殖和凋亡及PPARγ表达的影响

摘 要 目的： 探讨联苯双酯(dimethyl dicarboxylate biphenyl,DDB)对大鼠肝星状细胞HSC-T6增殖和凋亡及过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma, PPARγ)表达的影响。方法: 接种HSC T6细胞于96孔板和6孔板中,分别用CCK 8法和流式细胞术测定不同浓度联苯双酯作用于细胞24 h后对细胞增殖和凋亡的影响;实时荧光定量PCR（Quantitative Real time PCR,Q-PCR）和Western blotting分别检测药物对HSC-T6细胞PPARγ mRNA和蛋白的表达的影响。结果: 相比于对照组（0 μmol·L^-1）,DDB在实验浓度（8～64 μmol·L^-1）能明显抑制HSC T6的增殖（P<0.05),促进HSC T6的凋亡（P<0.05);药物处理过的HSC T6细胞PPARγ mRNA及其蛋白表达均有显著提高。结论:DDB可通过上调HSC T6细胞中PPARγ的表达抑制细胞的增殖,促进细胞的凋亡。     

青蒿琥酯对人白血病K562，K562 /ADM细胞凋亡的作用及对NF-κB p65表达的影响

摘 要 目的:观察青蒿琥酯对人白血病K562、K562 /ADM细胞凋亡以及对p65表达的影响。方法: 采用流式细胞仪检测青蒿琥酯在不同浓度和不同时间段对K562、K562 /ADM细胞凋亡的影响,采用Western blot法检测15 μmol·L^-1青蒿琥酯在不同时间对K562细胞NF-κB p65表达的影响。结果 青蒿琥酯对K562细胞凋亡影响不明显,但对阿霉素耐药K562 /ADM细胞影响较大,青蒿琥浓度为7.5 μmol·L^-1和15 μmol·L^-1时,K562 /ADM细胞的调亡率明显高于K562细胞（P<0.01）,15 μmol·L^-1青蒿琥酯作用后4 h后,K562 /ADM细胞的调亡率明显增加（P<0.01）;经15 μmol·L^-1青蒿琥酯作用后, p65表达随时间的增加而明显降低（P<0.01）。结论 青蒿琥酯通过下调P65的表达而诱导白血病细胞凋亡。     

EPA、DHA对脂多糖诱导大鼠系膜细胞增殖及PPARγ表达的影响

目的 观察二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）对脂多糖（LPS）诱导大鼠肾小球系膜细胞（GMCs）增殖及过氧化物酶体增殖物激活受体γ（PPARγ）表达的影响。方法 用脂多糖(15 mg·L^-1)刺激大鼠肾小球系膜细胞,二十碳五烯酸和二十二碳六烯酸(10、100 μmol·L^-1)分别培养48 h后,采用噻唑蓝（MTT）方法检测肾小球系膜细胞的增殖情况;采用实时定量PCR方法检测过氧化物酶体增殖物激活受体γ mRNA的表达;采用Western Blot方法检测过氧化物酶体增殖物激活受体γ 蛋白的表达。结果 二十碳五烯酸和二十二碳六烯酸显著抑制脂多糖诱导的肾小球系膜细胞增殖,增加过氧化物酶体增殖物激活受体γ mRNA和蛋白的表达。结论 二十碳五烯酸和二十二碳六烯酸对受损肾小球系膜细胞的保护作用可能与抑制肾小球系膜细胞增殖,激活潜在的抗炎因子过氧化物酶体增殖物激活受体γ有关。     

槲皮素诱导人结肠癌细胞HT-29凋亡的机制研究

目的 探讨槲皮素在体外对人结肠癌HT-29细胞凋亡的影响,并对其诱导机制进行研究。方法 体外常规培养HT-29细胞,随机设定对照组和高、中、低剂量（32,16,8 μg·mL^-1）槲皮素组,药物干预24 h后,采用CCK-8试剂盒检测槲皮素对HT-29细胞增殖的影响,倒置显微镜观察细胞形态变化,蛋白免疫印迹法检测MKK3/6/p38信号通路蛋白表达,并同时检测凋亡相关蛋白Caspase 8、Caspase 3、Bax及Bcl-2的表达水平。结果 槲皮素干扰HT-29细胞24 h后,CCK-8实验发现槲皮素可明显抑制细胞的增殖;形态学观察发现细胞密度明显减小、细胞体积变小;免疫印迹实验发现槲皮素可诱导MKK3/6及p38的磷酸化,进而促进促凋亡蛋白Caspase8、Caspase3及Bax的表达,抑制了抗凋亡蛋白Bcl-2的表达。结论 槲皮素可诱导人结肠癌HT-29细胞凋亡,其作用机制可能与激活MKK3/6/p38信号通路有关。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

---

Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.