锰神经毒性机制研究进展

过量锰暴露可能会损害中枢神经系统,产生不可逆转的神经毒性,导致严重的神经退行性疾病.锰的神经毒性机制可能与转运稳态失调、氧化应激与线粒体损伤、自噬、蛋白质折叠错误、细胞凋亡、神经炎症有关,其中蛋白质错误折叠、线粒体损伤和神经炎症等又称锰神经毒性的3种主要损伤机制.本文对上述研究进展予以综述,以期为锰中毒防治提供科学依据...     

神经刺激器定位神经阻滞109例分析

目的观察神经刺激器定位神经阻滞的手术实用范围及麻醉效果。方法先据解剖用探笔模式测到体表相应位置,再用刺激针模式直至要探寻的神经所支配的肌肉群发生有节律的颤搐,调小电流至接近神经。定位准确后,回抽注射器无回血、液体和气泡即注入局麻药。结果 109例使用神经刺激器定位神经阻滞,无痛率(95/109)为88%,轻微疼痛率(11/109)为10%,无痛与轻微疼痛两者达98%。结论神经刺激器引导的神经阻滞,神经定位指标明确、客观,绝大多数患者效果确实。     

骨间前神经旋前方肌支转位修复鱼际肌支和尺神经深支的解剖学观察和临床应用

目的了解有关应用骨间前神经旋前方肌支转位修复正中神经鱼际肌支和尺神经深支的解剖,总结应用此方法的临床效果。方法观察6具成人上肢标本,测量其旋前方肌支、正中神经鱼际肌支和尺神经深支的横径,以及正中神经鱼际肌支起始处、尺神经深支起始处至旋前方肌上缘的距离。1996年4月～1997年3月,临床应用5例。旋前方肌支转位修复陈旧性尺神经损伤3例,陈旧性正中神经损伤1例,急性正中神经损伤1例,其中3例需游离神经移植。结果骨间前神经旋前方肌支在旋前方肌上缘处、正中神经鱼际肌支起始处、尺神经深支起始处,神经干横径分别为1.3～1.9、1.5～2.3、1.8～2.3mm。正中神经鱼际肌支起始处、尺神经深支起始处至旋前方肌上缘的距离分别是75.2～84.8mm、53.5～74.0mm。临床应用经12～23个月随访,4例手内在肌功能恢复M3～M4级,1例未见恢复。结论骨间前神经旋前方肌支转位修复正中神经鱼际肌支和尺神经深支可达到肌支-肌支修复的设想,缩短再生距离和时间,有利于手内在肌的功能恢复。     

SD大鼠神经干细胞评价药物神经毒性模型研究

目的：应用SD大鼠神经干细胞评价药物的神经毒性,为新药早期筛选和临床前安全性评价提供体外替代方法。方法：体外培养SD大鼠神经干细胞,传代后得到稳定的第二代神经球。以已知具有神经毒性的长春新碱、顺铂、瑞芬太尼、丙泊酚注射液、丙戊酸钠、苯妥英钠、丙烯酰胺、乙醇、氧化铁纳米粒子作为神经毒性阳性物质,以培养基作为神经毒性空白对照品;以没有神经毒性且具有促进神经细胞生长的神经生长因子作为检测模型的敏感性;以验证SD大鼠神经干细胞模型对神经毒性药物的检出能力。结果：长春新碱、顺铂、丙泊酚注射液、苯妥英钠、丙烯酰胺、氧化铁纳米粒子可引起全部或部分神经球解离破碎,神经干细胞坏死。顺铂、丙戊酸钠和苯妥英钠可见显著性的抑制神经球聚集。长春新碱、顺铂、瑞芬太尼、氧化铁纳米粒子、丙泊酚注射液、丙戊酸钠、苯妥英钠、丙烯酰胺、乙醇均表现剂量相关性的神经干细胞增殖毒性作用。神经生长因子可见促进神经球聚集及神经干细胞增殖。结论：本文以SD大鼠神经干细胞模型,以神经干细胞体外生长发育指标,验证了已知神经毒性抗肿瘤药物、麻醉剂、抗癫痫药物等的神经毒性特征。评价结果与这些药物已知的神经毒性作用特点一致,该评价方法可作为药物神经毒性临床前安全性评价研究的体外替代试验。     

糖尿病周围神经病患者的神经传导速度分析

目的 探讨糖尿病周围神经病患者周围神经传导速度(NCV)改变的特征.方法 运用肌电诱发电位仪对在本院就诊的62例糖尿病周围神经病患者,根据临床症状及体征分组:单纯感觉异常组38例,感觉运动异常组24例,并与20例健康者对照,对神经传导速度(NCV)进行检测.结果 健康对照组正中神经、尺神经、腓肠神经的感觉传导速度分别为:(63.2±4.9)、(61.0±4.6)、(55.5±3.1)m/s;正中神经、尺神经、胫神经、腓总神经运动传导速度分别为:(56.6±4.7)、(55.4±4.7)、(45.9±3.9)、(48.3±3.2)m/s.糖尿病周围神经病患者单纯感觉异常组上述神经的感觉传导速度分别为:(43.1±8.6)、(46.2±7.9)、(34.8±5.7)m/s;上述神经运动传导速度分别为:(42.1±8.5)、(43.8±8.1)、(32.3±7.3)、(34.2±5.6)m/s.糖尿病周围神经病感觉运动异常组上述神经的感觉传导速度分别为:(38.3±9.3)、(37.7±9.5)、(26.7±6.6)m/s;上述神经运动传导速度分别为:(39.1±7.3)、(40.9±6.5)、(22.9±6.8)、(29.1±4.6)m/s.糖尿病周围神经病患者四肢的周围神经传导速度较健康者减慢;糖尿病周围神经病患者中有症状者的神经传导速度慢于无症状者.结论 糖尿病周围神经病患者周围神经受损范围广泛,上下肢均可受累,存在亚临床性运动神经损害,周围神经NCV检测可用于早期糖尿病周围神经病的诊断和发现糖尿病周围神经病的亚临床病变.     

经神经刺激仪引导肌间沟臂丛神经阻滞的临床疗效

目的探讨在神经刺激仪引导下行肌间沟臂丛神经阻滞麻醉的临床疗效。方法选择2012年1月—2013年1月该院收治的拟行肌间沟臂丛神经阻滞的患者60例,分为实验组和对照组各30例,实验组采用神经刺激仪辅助定位,对照组采用传统异感定位,比较两组患者麻醉效果。结果实验组麻醉起效时间及阻滞操作时间均较对照组缩短;实验组麻醉成功率达93．3％,而对照组麻醉成功率71．1％,实验组麻醉效果明显优于对照组,实验组患者并发症发生率少于对照患者,差异均有统计学意义（P〈0．05）。结论在神经刺激仪引导下进行肌间沟臂丛神经阻滞,操作简单、定位准确率高、麻醉效果好、并发症少,值得临床推广应用。     

颈丛联合臂丛神经阻滞麻醉效果的研究

基于肩部及上肢神经分布的特点，单纯应用颈丛或臂丛神经阻滞，容易发生阻滞不全的情况。本研究采取颈丛、臂丛神经联合阻滞的方法，取得了满意的效果。     

神经刺激仪辅助下垂直锁骨下臂丛神经阻滞的临床体会

目的比较神经刺激仪引导下垂直锁骨下臂丛神经阻滞与传统方法臂丛神经阻滞效果。方法选择我院前臂及手部手术患者58例,其中男42例,女16例,随机分为2组：即神经刺激定位组（Ⅰ组）、传统方法组（Ⅱ组）,记录麻醉操作时间、神经阻滞的起效时间：即局麻药注毕至可以开始手术时间,及镇痛持续时间。观察手术开始前患者正中神经、尺神经、桡神经和肌皮神经支配区域的感觉阻滞情况,评定每组麻醉阻滞效果及术中情况和有无并发症。结果 I组患者麻醉起效时间、桡神经及肌皮神经阻滞满意率明显高于Ⅱ组,差异有非常显著性;而麻醉操作时间、正中神经及尺神经阻滞满意率、术后镇痛持续时间差异无显著性。操作过程中2组均无严重并发症发生。结论神经刺激仪引导下垂直锁骨下臂丛神经阻滞定位方便、麻醉起效快,阻滞成功率高、不良反应少,经培训后操作时间与传统臂丛阻滞无明显差异,可代替传统腋路臂丛阻滞用于临床麻醉。     

去分化肌肉干细胞神经分化潜能的探讨

目的探讨去分化肌肉干细胞经条件培养诱导,具有神经干细胞性质并分化为终末神经细胞的潜能。方法依次用神经干细胞增殖及神经细胞分化条件培养基,对去分化肌肉干细胞进行体外诱导,促使其向神经干细胞转变以及向终末神经细胞分化,并通过形态学、免疫细胞化学、RT-PCR等实验手段研究其性质并加以鉴定。结果 (1)去分化肌肉干细胞在神经干细胞增殖条件培养基诱导下,可形成神经球,EdU标记阳性,抗Nestin、Neurofilament-m(NFm)、GFAP、CNPase阳性;Myogenin表达水平下调,而Nestin、Sca-1表达上调;(2)经神经细胞分化条件培养基诱导,神经球细胞可分化为形态学上典型的、抗NFm阳性神经元,以及抗GFAP、CNPase阳性神经胶质细胞。结论去分化肌肉干细胞具有神经系的多分化潜能。     

神经传导检测和肌电图检查在平山病中的诊断价值

目的探讨神经传导检测和肌电图检查在平山病中的诊断价值。方法选取福鼎市医院2016年8月-2018年8月收治的平山病患者25例为观察组,并选取本院同期体检健康者29例为对照组。两组均行神经传导检测和肌电图检查。(1)比较两组尺神经和正中神经的神经传导检测结果,包括感觉神经动作电位、感觉神经传导速度、拇短展肌复合肌肉动作电位以及远端运动潜伏期等。(2)观察观察组肌电图异常情况,包括平均电压增高、平均时限延长、多相电位增多以及自发电位等。结果观察组尺神经和正中神经的远端动作潜伏期高于对照组,拇短展肌复合肌肉动作电位低于对照组(P<0.05)。两组尺神经正中神经的感觉神经动作电位和感觉神经传导速度比较,差异无统计学意义(P>0.05)。观察组患肢远端肌平均电压增高、平均时限延长、多相电位增多以及自发电位发生率均高于对侧近端肌、对侧远端肌以及患肢近端肌(P<0.05)。患肢近端肌平均时限延长、自发电位、平均电压增高以及多相电位增多的发生率均高于对侧近端肌和对侧远端肌(P<0.05)。对侧近端肌和对侧远端肌的肌电图异常发生率比较,差异无统计意义(P>0.05)。结论神经传导检测和肌电图检查肌电图检查在平山病诊断中的应用价值较高,可较准确地判断病情严重程度。     

Classes of sigma2 (σ2) receptor ligands: structure affinity relationship (SAfiR) studies and antiproliferative activity

Although several pieces of information are still missing about sigma-2 (σ2) receptor, the production of high affinity 2 receptor ligands allowed important acquisitions. Morphans such as CB64D and CB184 were the first truly σ2-selective ligands synthesized, and their use in cell cultures highlighted the relationship between σ2 receptors and cell proliferation, shedding light on important diagnostic and therapeutic potentials with which σ2 ligands are endowed. The most significant classes of compounds are herein discussed. The design and Structure-Affinity Relationship studies (SAfiR) of σ2 receptor ligands belonging to the classes of morphans, indoles (siramesine analogues), granatanes, flexible benzamides and N-cyclohexylpiperazines are reported, together with the biological results which these compounds provided giving a crucial contribution to the 2 receptor research. The pharmacophore models which were generated on the basis of different classes of the σ2 ligands and the attempts for σ2 receptor purification are briefly described.     

Targeting the cannabinoid CB2 receptor: modelling and structural determinants of CB2 selective ligands

Recent developments indicate that CB2 receptor ligands have the potential to become therapeutically important. To explore this potential, it is necessary to develop compounds with high affinity for the CB2 receptor and little affinity for the CB1 receptor. This review will discuss structure-activity relations at both receptors for classical cannabinoids and cannabimimetic indoles. Examples of CB2 selective ligands from both classes of compounds are presented and the structural features leading to selectivity are described. Two approaches, receptor mutations and molecular modelling, have been employed to investigate the interaction of ligands with both cannabinoid receptors. These results obtained from these techniques are discussed.     

Enhancement of aqueous solubility and stability employing a trans acetate axis in trans planar amine platinum compounds while maintaining the biological profile

A general approach to solubilization and possible in vivo activation of the transplatinum geometry is presented. The synthesis and characterization of new water-soluble cytotoxic transplatinum compounds are described. Use of acetate ligands (and carboxylate ligands in general) in trans-[Pt(OAc)(2)(L)(L')] results in significantly enhanced aqueous solubility and chemical stability in comparison to the parent dichlorides. The new compounds are the first cytotoxic transplatinum compounds containing an N(2)O(2) donor set, similar to carboplatin and oxaliplatin.     

Coordination Complexes of Copper in Mass Exchange of Biologically Active Substances

Special features of the interaction of copper with organic compounds containing groups (ligands) susceptible to the formation of coordination complexes are considered. Some general properties of copper-containing compounds are described, which determine the main physicochemical characteristics of such complexes. The behavior of coordination complexes of copper with said ligands in chromatographic systems is analogous to the behavior of coordination complexes of silver with olefinic compounds.__________Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 2, pp. 45 – 48, February, 2005.     

Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring

A series of chiral analogues of bicalutamide bearing electrophilic groups (isothiocyanate, N-chloroacetyl, and N-bromoacetyl) on aromatic ring B of the parent molecule were synthesized. These compounds were designed as affinity ligands for the androgen receptor (AR). We prepared the (R)- and (S)-optical isomers of these compounds as pure enantiomers. The AR binding affinities of these compounds were measured in a competitive binding assay with the radiolabeled high-affinity AR ligand, [(3)H]mibolerone. In accordance with our previous results for the enantiomers of bicalutamide, we found that all (R)-isomers demonstrated much higher binding affinity to the AR as compared to their corresponding (S)-isomers. The para-substituted affinity ligands in ring B bound the AR with higher affinities than the corresponding meta-substituted analogues. Oxidation of thioester affinity ligands to their sulfonyl analogues for the para-substituted compounds decreased AR binding affinities and similar modification increased binding affinities for corresponding meta-analogues. The least potent para-substituted sulfonyl compounds had higher AR binding affinities than the most potent meta-substituted sulfonyl compounds. Overall, the para-substituted unoxidized molecules demonstrated the highest AR binding affinity. Subsequent research using AR exchange assays and Scatchard analyses showed that the isothiocyanate affinity ligands (R)-7, (R)-9, and (R)-10 reported herein are the first specific chemoaffinity ligands for the AR.     

Medicinal chemistry of indolylglyoxylamide TSPO high affinity ligands with anxiolytic-like effects

The mitochondrial translocator protein (TSPO) mediates the synthesis of neurosteroids in the CNS, which have been demonstrated to enhance the neurotransmitter GABA response, exhibiting related behavioural properties. Selective TSPO ligands are able to stimulate steroidogenesis with great efficacy, thus representing potential anxiolytic agents. This review describes the development of a class of high affinity ligands to TSPO, N,N-dialkylindol-3-ylglyoxylamides (IGA), from the initial stages of design to the pharmacological characterization of selected compounds for their anxiolytic activity. Affinity data and SARs of the new class of ligands are discussed; the potential applications of compounds characterized by the indolylglyoxylyl scaffold in diagnostic imaging are also pointed out.     

The concept of selectivity in 5-HT receptor research

Since the demonstration that serotonin (5-hydroxytryptamine, 5-HT) interacts with different (sub)types of membrane receptors, several compounds have been proposed as potent and selective ligands for one of these 5-HT subtypes. Unfortunately, specific and highly selective ligands (selectivity ratios greater than or equal to 1000) for the majority of 5-HT subtypes are still lacking. A few compounds are selective (ratios greater than or equal to 100), but most of the reputed 'selective' tools display affinities for other 5-HT subtypes and/or other (neuro-) transmitter receptors. Mainly due to different interpretations of the concept of selectivity, many of these nonselective compounds are still used to characterize 5-HT receptors. In this paper, we present the affinities (obtained by radioligand binding studies) of the most selective tools known today for each of the 5-HT subtypes and discuss the structure-activity relationships of some interesting series. The potential use of several of these selective ligands as pharmacological tools and therapeutics will be briefly reviewed.     

Synthesis and preliminary evaluation of affinity to retinoic acid receptors for new organosilicon-based retinoids

Facile synthetic routes to new silicon-containing ligands (1–4) for retinoic acid receptors (RARs) are reported. The design of these RAR ligands is based on a pharmacophoric model that divides the molecules into three regions (A, B, and C). The series of ligands is unique in region A due to their acyclic nature and the presence of alkyl-substituted silicon at the core. Substituted silyl groups that are generally viewed as protecting groups are used to fulfill pharmacophore requirements. Various alkyl substituents available on the silicon starting materials afford an opportunity to explore steric effects on binding. In region B of ligands 1–4, a cinnamate moiety maintains some degree of conjugation and planarity in the molecules. A biaryl group used in region B of another series of compounds is reported to lead to RARb selectivity. Finally, region C of the ligands contains a carboxylate group, a well know pharmacophore requirement for RAR ligands. The compounds prepared in this work were found to have micromolar to nanomolar affinity for these medically relevant target receptors. The proposed silane-containing ligands ‘represent a new series of siloacetylenic aryl acids that are worth of further investigation. They may serve as leads for the development of higher-affinity, more receptor-selective agents.