Muscle relaxant action of excitatory amino acid antagonists

Antagonists of neuronal excitation induced by dicarboxylic amino acids were tested in genetically spastic rats of the Han-Wistar strain. These animals exhibit an increased muscle tone which can be measured as a spontaneous tonic activity in the electromyogram of the gastrocnemius-soleus muscle. Compounds that block excitation due to N-methyl-D-aspartic acid reduced the spontaneous activity measured in the electromyogram in a dose-related manner. The most potent compounds, 2-amino-7-phosphonoheptanoic and kynurenic acids were effective muscle relaxants when given either intraperitoneally or intracerebroventricularly. 2-Amino-5-phosphonopentanoic acid possessed much weaker muscle relaxant activity, while L-glutamic acid diethylester was inactive by either route. The results suggest that blockade of N-methyl-D-aspartic acid receptors results in a myorelaxant effect. Specific antagonists of excitation at N-methyl-D-aspartic acid receptors may provide a new class of muscle relaxants.     

D-aspartate binding to the glutamate uptake site in human brain tissue — effects of leucotomy

Summary Binding of [3 H]D-aspartate, as an indicator of glutamate uptake sites, was investigated in post-mortem human brain tissue by use of a centrifugation assay to separate free and bound ligand. Binding was displaceable, apparently saturable and to a single site, with mean K_D and Bmax values of 2.3 M and 40.3 nmol/g tissue in the frontal cortex. The method was applied to the study of tissue from frontal and temporal cortices and the caudate nucleus of five psychiatric patients who had undergone a frontal leucotomy. The effects of this neurosurgical procedure were to diminish by almost 50% the density of D-aspartate binding sites in the frontal cortex and caudate nucleus, while the temporal cortex was less affected. It is concluded that the method provides a potentially useful correlate of glutamatergic innervation in human brain tissue.     

腺苷A1受体和NMDA受体在海马齿状回突触传递活动中的关系

目的　探讨腺苷A1受体阻断剂对海马齿状回 (DG)突触传递活动的影响及其与NMDA受体的关系。方法采用在体记录麻醉大鼠LTP的电生理学方法 ,观察腺苷A1受体特异性阻断剂 8 环戊 1,3 二丙基黄嘌呤 (DPCPX)与NMDA受体激动剂、阻断剂在海马DG基础突触传递活动和高频刺激诱导的LTP中作用的相关性。结果　DPCPX(6mg·L- 1,5μL ,icv)或NMDA(0 2mg·L- 1,5μL ,icv)不影响大鼠海马DG突触传递活动 ,DPCPX对icvNMDA后高频刺激诱导已形成的LTP维持也无影响 ;预先给予DPCPX后则可显著增强NMDA的海马DG基础突触传递活动和LTP ;AP5(0 5mg·L- 1,5μL)阻断NMDA受体后对LTP的抑制作用不受DPCPX的影响 ,但预先给予DPCPX则可取消AP5 对LTP的抑制作用。结论　DPCPX不影响海马DG突触传递活动 ,但可影响NMDA受体的效应 ,增强NMDA受体在海马DG突触传递活动中的作用     

N-甲基-4-苯氧基吡啶-2-甲酰胺衍生物的合成及其抗肿瘤活性研究

目的设计并合成结构新颖的N-甲基-4-苯氧基吡啶-2-甲酰胺衍生物,并对其抗肿瘤活性进行初步评价。方法通过分析索拉菲尼与B-Raf激酶的共结晶模型,在保留其药效团的基础上,设计了16个目标化合物,以吡啶甲酸为原料,经氯代、酯化、取代、还原、氨解及与取代的氨基甲酸苯酯反应制得9个目标化合物;经氯代、氨解、取代及与取代的氨基甲酸苯酯反应得到7个目标化合物;以索拉菲尼为阳性对照,采用MTT法,评价目标化合物对人肺癌细胞株H460、人结肠癌细胞株HT-29和人胃癌细胞株MKN-45增殖的抑制活性。结果与结论部分目标化合物显示出较好的抗肿瘤活性,活性优于或与索拉菲尼相当,其中化合物9b和12f的活性突出。初步构效关系研究表明,末端苯环上取代基的电性效应和取代位置对化合物的活性具有显著影响。     

Sustained Release of Minocycline From Minocycline-Calcium-Dextran Sulfate Complex Microparticles for Periodontitis Treatment

It is important to address the periodontitis-associated bacteria in the residual subgingival plaque after scaling and root planing to successfully treat periodontitis. In this study, we explored the possibility of exploiting the ion pairing/complexation of minocycline, Ca²⁺, and sulfate/sulfonate-bearing biopolymers to develop an intrapocket delivery system of minocycline as an adjunct to scaling and root planing. Minocycline-calcium-dextran sulfate complex microparticles were synthesized from minocycline, CaCl₂, and dextran sulfate. They were characterized using Fourier-transform infrared spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. An in vitro release study was conducted to evaluate the release kinetics of minocycline from these microparticles. Agar disk diffusion assays and biofilm-grown bacteria assays were used to assess antibacterial capability. High loading efficiency (96.98% ± 0.12%) and high loading content (44.69% ± 0.03%) for minocycline were observed for these complex microparticles. Mino-Ca-DS microparticles achieved sustained release of minocycline for at least 9 days at pH 7.4 and 18 days at pH 6.4 in phosphate-buffered saline, respectively. They also demonstrated potent antimicrobial effects against Streptococcus mutans and Aggregatibacter actinomycetemcomitans in agar disk diffusion and biofilm assays. These results suggested that the ion pairing/complexation of minocycline, Ca²⁺, and sulfonate/sulfate-bearing biopolymers can be exploited to develop complex microparticles as local delivery systems for periodontitis treatment.     

中药治疗中风的分子靶点

“中风”是中医学对急性脑血管疾病的统称,具有极高的死亡率和致残率。中医药治疗中风有着悠久的历史,临床实验也证实了其疗效。然而由于中药常常需要多味药物联合使用,其有效成分很难明确,对其有效性评价具有挑战性,因此很难将中药制剂推向世界。综述中药治疗中风的分子靶点作用,列举了一些可能起效的天然化学物质,调查结果表明多成分多靶点的中药理论具有科学性。现代分子医学和传统中医理论的结合能促进医学界的广泛交流,值得深入探讨。     

糠醛—油,N—甲基—2—吡咯烷酮—油汽液平衡和虚拟组分法研究

用改进的Ｅｌｌｉｓ平衡釜，采用化学分析、微型萃取和气相色谱模拟实沸点蒸馏相结合的方法，测定了糠醛－提余油，糠醛－抽出油，Ｎ－甲基－２－吡咯烷酮提余油，Ｎ－甲基－２－吡咯烷酮－抽出油四个系统在常压下的汽液平衡数据。应用虚拟组分法，采用Ｃｈａｏ－Ｓｅａｄｅｒ混合模型对实验数据进行了关联，取得了较好结果。     

东风桔化学成分的研究

从东风桔根中分离到一种新的吖啶酮类生物硷。根据紫外,红外,核磁共振谱和质谱等证明其结构为N-甲基-1,4,5-三羟基-3,6-二甲氧基吖啶酮-9,命名为东风桔碱B。     

Neurotoxic effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the cat. Tyrosine hydroxylase immunohistochemistry

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces substantia nigra pars compacta (SNc) cell death in several species including the mouse, dog and monkey. MPTP is presently shown to cause apparent nigral cell death in the SNc of the cat as noted by a long-lasting decrease in tyrosine-hydroxylase (TH)-like cell staining. A transient loss of TH-like staining is also observed in the ventral tegmental area, locus coeruleus and retrorubral area. These latter areas appear normal 1.5-5.0 months after MPTP administration. The caudate nucleus (CD) showed a greater TH depletion than the nucleus accumbens (ACC) and only recovered slightly over time. After 7 days of MPTP, an apparent axonopathy, characterized by lightly staining fibers with large TH-positive varicosities, is seen in the CD and to a lesser extent, in the ACC. These findings demonstrate that MPTP is toxic to the cat's nigrostriatal dopaminergic system and suggests that the cat is a good intermediate species in which to study the responses of dopaminergic neurons to MPTP.     

NMDA和非NMDA受体参与介导猫脊髓内脏伤害性信息传递(英文)

目的:研究NMDA(N-methyl-D-aspartic acid)和非NMDA受体在介导脊髓内脏痛传入中的作用,方法:气球膨胀(3-15 kPa,20 s)麻醉猫结-直肠诱发脊髓背角痛敏神经元发放,结果:1)扩张结-直肠引起神经元发放增加的为兴奋性型:17个SLA型(短潜伏期突然增加);11个SLS型(短潜伏期渐增);9个LL型(长潜伏期),15个神经元属于抑制性的Inh型,2)67.6％,78.4％和59.5％的膨胀肠诱发兴奋的神经元,分别被微电泳NMDA、使君子酸(QA)和海人藻酸(KA)激活;60％,86.7％和53.3％的Inh神经元也分别被3个酸激活.3)微电泳NMDA受体拮抗剂d,l-2-amino-5-phosphonovalemte(APV)和非NMDA受体拮抗剂6,7-dinitro-quinoxaline-2,3-dione(DNQX),分别使兴奋性反应减少35％±10％和65％±14％,DNQX明显强于APV(P<0.05).DNQX使3/7个Inh神经元抑制翻转30％-50％,而APV无效,结论:NMDA和非NMDA受体均参与介导脊髓内脏伤害性信息传递,而非NMDA受体的作用更强。 (责任编辑 李颖)