Neurochemical neutralization of amphetamine-type stimulants in rat brain by the indatraline analog (−)-HY038

Amphetamine-type stimulants are substrates for the proteins that serve as transporters for the biogenic amines dopamine (DA), serotonin (5HT), and norepinephrine (NE) and release these neurotransmitters from neurons located in the peripheral and central nervous system. Using indatraline as a lead compound, we sought to develop a long-acting depot medication that would neutralize the deleterious effects of amphetamine-type stimulants. Our first efforts produced (±)-HY038, and its two stereoisomers, which are hydroxy-substituted analog of indatraline. The K_i values for [³H]DA reuptake inhibition by (−)-HY038 and (+)-HY038 were 3.2 ± 0.1 and 32 ± 1 nM. Similar results were obtained for [³H]5HT reuptake inhibition. (−)-HY038 and (+)-HY038 were slightly less potent at inhibiting [³H]NE reuptake (K_i values of 20 ± 2 and 159 ± 12 nM). Low doses of (−)-HY038 blunted the ability of AMPH to release [³H]DA by shifting the AMPH dose-response curve to the right in a dose-dependent manner. (−)-HY038 also inhibited the ability of (+)-methamphetamine and (±)-3,4-methylenedioxymethamphetamine ((±)-MDMA) to release [³H]DA. Low doses of (−)-HY038 blunted the ability of these stimulants to release [³H]NE and [³H]5HT by shifting their dose-response curves to the right in a manner similar to that seen for inhibition of [³H]DA release. These data indicate that (−)-HY038 inhibits the ability of AMPH, (+)-methamphetamine and (±)-MDMA to release DA, NE, and 5HT and therefore might have the potential to neutralize the neurotoxic and cardiovascular side-effects of substrate-type stimulants.     

导痰汤合菖蒲郁金汤对卒中后抑郁症的实验研究

目的观察导痰汤合菖蒲郁金汤对卒中后抑郁症(PSD)大鼠模型行为学能力及脑内神经递质含量的影响。方法将80只大鼠随机分为4组,即模型组、导痰汤合菖蒲郁金汤组(中药组)、氟西汀组及假手术组,每组20只。模型组、中药组、氟西汀组采用双侧颈总动脉永久性结扎后行为限制法制备大鼠PSD模型,假手术组仅做颈正中切口即缝合。造模成功后第2d模型组、假手术组均予0.9%氯化钠注射液灌胃,中药组予导痰汤合菖蒲郁金汤灌胃,氟西汀组予盐酸氟西汀水溶液灌胃,均连续给药28d。测定大鼠海马区5-羟色胺(5-HT)、去甲肾上腺素(NE)、多巴胺(DA)、5-羟基吲哚乙酸(5-HIAA)含量的变化,并进行糖水消耗试验。结果假手术组、中药组及氟西汀组糖水消耗量均高于模型组(P0.05),纯水消耗量均低于模型组(P0.05);假手术组、中药组及氟西汀组NE、DA、5-HT及5-HIAA含量均高于模型组(P0.05);中药组NE、5-HT及5-HIAA含量均低于假手术组(P0.05);氟西汀组NE、DA含量均低于假手术组(P0.05)。结论导痰汤合菖蒲郁金汤可以改善PSD大鼠的行为及脑内单胺类神经递质的含量。     

术后谵妄病理生理机制的研究现状

术后谵妄是各类外科术后常见的一种严重并发症。然而,关于术后谵妄的病理生理机制尚未清楚。多种机制共同参与了术后谵妄的发生发展。目前,可能涉及的机制包括缺血性脑损伤、神经递质失调和神经炎症。理解其病理生理机制有助于积极预防和治疗该并发症。本文对术后谵妄的最新机制研究进行综述,以期为临床实践和研究提供必要的参考依据。关键词:术后谵妄;缺血性脑损伤;神经递质失调;神经炎症     

The binding sites for benztropines and dopamine in the dopamine transporter overlap

Analogs of benztropines (BZTs) are potent inhibitors of the dopamine transporter (DAT) but are less effective than cocaine as behavioral stimulants. As a result, there have been efforts to evaluate these compounds as leads for potential medication for cocaine addiction. Here we use computational modeling together with site-directed mutagenesis to characterize the binding site for BZTs in DAT. Docking into molecular models based on the structure of the bacterial homolog LeuT supported a BZT binding site that overlaps with the substrate-binding pocket. In agreement, mutations of residues within the pocket, including² Val152^3.46 to Ala or Ile, Ser422^8.60 to Ala and Asn157^3.51 to Cys or Ala, resulted in decreased affinity for BZT and the analog JHW007, as assessed in [³H]dopamine uptake inhibition assays and/or [³H]CFT competition binding assay. A putative polar interaction of one of the phenyl ring fluorine substituents in JHW007 with Asn157^3.51 was used as a criterion for determining likely binding poses and establish a structural context for the mutagenesis findings. The analysis positioned the other fluorine-substituted phenyl ring of JHW007 in close proximity to Ala479^10.51/Ala480^10.52 in transmembrane segment (TM) 10. The lack of such an interaction for BZT led to a more tilted orientation, as compared to JHW007, bringing one of the phenyl rings even closer to Ala479^10.51/Ala480^10.52. Mutation of Ala479^10.51 and Ala480^10.52 to valines supported these predictions with a larger decrease in the affinity for BZT than for JHW007. Summarized, our data suggest that BZTs display a classical competitive binding mode with binding sites overlapping those of cocaine and dopamine.     

胆管癌周围神经浸润的研究进展

胆管癌是一种破坏力极强的恶性肿瘤,具有低诊断率和高病死率的特点,手术是其唯一的根治方法,然而患者就诊往往在进展期,所以目前胆管癌的根治率很低,且手术复发率很高.胆管癌沿周围神经浸润是胆管癌发生发展过程中特别是在早期具有的非常重要的特性,且与术后复发率和预后密切相关.因此,如果了解胆管癌周围神经浸润的相关机制,早期对其进行干预,必将大大提高患者的手术切除率及预后.本文重点就目前胆管癌神经浸润研究最热门的几个可能的分子及其可能的相关机制进行综述.     

T-type channels-secretion coupling: evidence for a fast low-threshold exocytosis

T-type channels are transient low-voltage-activated (LVA) Ca²⁺ channels that control Ca²⁺ entry in excitable cells during small depolarizations around resting potential. Studies in the past 20 years focused on the biophysical, physiological, and molecular characterization of T-type channels in most tissues. This led to a well-defined picture of the functional role of LVA channels in controlling low-threshold spikes, oscillatory cell activity, muscle contraction, hormone release, cell growth and differentiation. So far, little attention has been devoted to the role of T-type channels in transmitter release, which mainly involves channel types belonging to the high-voltage-activated (HVA) Ca²⁺ channel family. However, evidence is accumulating in favor of a unique participation of T-type channels in fast transmitter release. Clear data are now reported in reciprocal synapses of the retina and olfactory bulb, synaptic contacts between primary afferent and second order nociceptive neurons, rhythmic inhibitory interneurons of invertebrates and clonal cell lines transfected with recombinant α₁ channel subunits. T-type channels also regulate the large dense-core vesicle release of neuroendocrine cells where Ca²⁺ dependence, rate of vesicle release, and size of readily releasable pool appear comparable to those associated to HVA channels. This suggests that when sufficiently expressed and properly located near the release zones, T-type channels can trigger fast low-threshold secretion. In this study, we will review the main findings that assign a specific task to T-type channels in fast exocytosis, discussing their possible involvement in the control of the Ca²⁺-dependent processes regulating exocytosis like vesicle depletion and vesicle recycling.     

美金刚联合多奈哌齐对阿尔茨海默病患者认知功能及神经递质的影响

目的 探讨美金刚联合多奈哌齐对阿尔茨海默病(AD)患者认知功能及神经递质的影响.方法 选取北京航天总医院收治的AD患者100例,随机分为试验组(n=50)、对照组(n=50),对照组予以多奈哌齐治疗,试验组在此基础上予以盐酸美金刚治疗,比较2组临床疗效、AD评定量表的认知分量表(ADAS-Cog)评分、神经精神科问卷(...     

同性恋者及其性取向的生物学研究进展

本文就近些年来有关同性恋的性取向及其影响因素的研究进展做一综述,旨在不仅以心理学角度关心同性恋者,更重要的是从遗传学、神经生物学方面揭示同性恋的成因,以使其得到社会的理解和认同,创造宽松和谐的环境,使他们不再感到孤独.     

安神补心胶囊对小鼠大脑内神经递质影响

目的:观察安神补心胶囊对小鼠大脑神经递质5-羟色胺(5-HT)及γ-氨基丁酸(GABA)含量的影响,初步探讨安神补心胶囊改善睡眠作用机制,为临床研究提供实验理论依据。方法:将昆明小鼠随机为空白对照组、地西泮对照组、安神补心胶囊组,分别灌相应药物:0.9%氯化钠注射液、地西泮水溶液(0.1 mg/mL)及安神补心胶囊水溶液(0.1 g药丸/mL),每天灌胃给药1次(0.1 mL/10 g),连续灌胃8 d,末次给药后,用酶联免疫吸附测定法测定小鼠大脑5-HT及GABA含量。结果:空白对照组、地西泮对照组、安神补心胶囊组5-HT含量分别为(604.56±31.35)ng/mL、(468.42±30.33)ng/mL、(518.21±31.20)ng/mL;GABA含量分别为(10.77±1.04)μmol/L、(14.58±0.75)μmol/L(12.07±0.88)μmol/L。与空白对照组相比,安神补心胶囊组能明显降低小鼠大脑5-HT含量及提高小鼠大脑GABA含量,差异有统计学意义(P0.05),与地西泮对照组比较,差异亦具有统计学意义(P0.05)。结论:安神补心胶囊具有良好的改善睡眠作用,其作用机制可能与抑制减少大脑5-HT的合成及刺激增加大脑GABA的分泌有关。