K—ATP通道：“神经元-胶质保护”的理想靶标

近十多年来，人们发现了许多所谓的“神经保护剂”，但是，在临床应用过程中大多未获得理想的疗效。新近的研究表明，这些神经保护剂之所以未获得实际的临床疗效，主要原因在于大多药物仅局限于针对神经元损伤的某一特定机制、长期忽略了占据大部分脑体积的神经胶质细胞（包括星形胶质细胞和小胶质细胞等）的作用，因此，提出兼具神经元和神经胶质细胞保护作用（neuro-glial protection）的保护剂是今后发展的方向。鉴于我们认识较为深刻的神经递质的受体大多不能普遍表达于神经元和神经胶质细胞，因此，通过发展受体的配基成为理想的临床保护药几无可能，探索理想的“神经元-胶质保护”的靶标已经显得尤为必要。     

神经元钙通道及钙拮抗剂的抗脑缺血作用

目的综述中枢神经系统内钙通道在脑缺血方面的作用及钙拮抗剂的抗脑缺血作用。方法根据近年国内外公开发表的有关文献,从神经元钙通道的分型及功能、胞内Ca2+与缺血性神经元损伤以及各类钙拮抗剂对脑缺血及其所致神经元损伤的影响等方面,阐述神经元钙通道及钙拮抗剂的抗脑缺血作用。结果至少有6种形式的电压依赖性钙通道,在不同部位的分布与特定功能相关,对调节神经元的兴奋性、神经递质的合成与释放、神经元的营养和发育起重要作用。脑缺血时脑细胞的损伤与L-电压依赖性钙通道开放致Ca2+内流有关,NMDA受体和L-电压依赖性钙通道是脑缺血时神经元Ca2+增多从而致细胞死亡的源头。结论深入认识中枢神经系统钙通道各亚型及其在脑缺血时神经元的信号转导过程中的作用,有助于钙拮抗剂的开发,为神经保护剂的研发提供了可能。     

神经元钙传感蛋白的研究进展及其在脑缺血中的作用

神经元钙传感蛋白NCS-1(neuronal calcium sensor-1,NCS-1)是一种具有较强的钙离子结合能力的蛋白质。NCS-1可以结合、传导细微的钙离子浓度变化;而当钙离子浓度超过微摩尔/升数量级时(即生理浓度),其结合能力即达到饱和,这也是它与钙调素(可感受较高浓度的钙离子变化)等其它钙结合蛋白的重要区别之一。它在脑缺血损伤中的作用,还未引起足够的重视,但是根据现有报道,NCS-1极有可能是脑缺血损伤的一个重要的保护因子。另外有研究显示,NCS-1还与神经细胞金属沉积性疾病的发生有关,可以明显增加神经元突触的传导功能。     

小檗碱对神经元保护作用机制的研究进展

小檗碱是一种异喹啉生物碱,具有多种药理作用。研究表明小檗碱可以通过影响多种途径发挥神经保护作用,包括PI3K/Akt/Bcl-2、Akt/Nrf-2/HO-1、GSK-3、MAPK、AMPK、阿尔茨海默病-β-淀粉样蛋白、NMDA受体和MMP-9途径。总结小檗碱在脑缺血、阿尔茨海默病和实验性自身免疫性脑脊髓炎等神经元疾病模型中的作用机制,了解更多关于小檗碱如何介导这些途径,为未来对神经疾病的临床治疗提供参考。     

糖尿病心肌病中离子通道研究进展

糖尿病心肌病是一个日益严重的公共健康问题，患者心脏会出现功能和结构的改变。心脏中钾通道、钠通道、钙通道及TRPM7通道与该疾病息息相关，本综述分析了相关心脏离子通道，以了解其在糖尿病心肌病的病理生理和发病机制中的潜在作用。     

新鲜分离的新生大鼠皮层神经元的钙振荡

目的:研究新鲜分离的新生大鼠皮层神经元胞内钙离子浓度([Ca~(2 )]_i)发生振荡的机制。方法:采用酶解结合机械分离法从6—7日龄大鼠分离皮层神经元,用M40钙离子测量系统(PTI)测量细胞内钙离子浓度的变化。用Fura-2作为钙离子指示剂。结果:在观察到的82个神经元细胞中,47个产生了自发钙振荡。自发钙振荡依赖于胞外钙离子浓度。去除外钙后自发钙振荡立即停止。四乙铵1mmol/L引起钙振荡振幅增大,频率变快。CsCl 1mmol/L主要引起频率增加。BaCl_2 1mmol/L可使振幅、频率增高,并有明显的高台样基线增加。结论:皮层神经元在无突触联系的情况下具有产生自发[Ca~(2 )]_i振荡的特性,K~ 通道在决定钙振荡的幅值和频率方面起重要作用。     

过氧化氢对培养大鼠海马神经元瞬时外向钾电流的影响

目的　研究过氧化氢对海马神经元上瞬时外向钾电流的影响。方法　采用全细胞膜片钳技术记录培养大鼠海马神经元瞬时外向钾电流的变化。结果　 3 0 μmol·L-1H2 O2 孵育 12h后 (1)明显抑制IA,电流密度由 (5 3 8±15 8) pA·pF-1变为 (18 5± 6 2 ) pA·pF-1(n =10 ,P <0 0 1) ;(2 )明显抑制IA 激活作用 ,半数最大激活电压由 (-15 2± 3 6)mV左移至 (- 18 2± 2 7)mV(n =10 ,P <0 0 1) ;(3 )明显抑制IA 失活作用 ,失活常数由 (42 2± 10 1)ms变为 (81 9± 3 5 0 )ms(n =10 ,P <0 0 5 ) ,半数最大灭活膜电位V1/ 2 由 (- 87 5± 12 6)mV变为 (- 99 8± 2 1)mV(n =10 ,P <0 0 1) ;(4)明显抑制IA 电流失活后复活作用 ;恢复时间常数由 (2 7 9± 14 1)ms变为 (5 8 6± 10 0 )ms(n=10～ 11,P <0 0 1) ;(5 )降低静息膜电位 ,由 (- 64 9±9 4)mV变为 (- 46 0± 12 8)mV(n =6～ 11,P <0 0 1) ,延长动作电位时程 ,由 (8 7± 3 4)ms增至 (16 0± 6 2 )ms(n =6～ 11,P <0 0 5 )。结论　H2 O2 对IA 的抑制作用可能参与其对神经元的氧化应激损伤毒性     

SOD模拟化合物的研究进展

超氧化物歧化酶 (ｓｕｐｅｒｏｘｉｄｅｄｉｓｍｕｔａｓｅ ,ＳＯＤ) ,是生物体内普遍存在的一种金属蛋白酶 ,按国际标准命名为ＥＣ 1.15 .1.1。它在血浆中的半衰期仅 5～ 8ｍｉｎ ,其保存的稳定性 ,与生物膜的亲和性 ,病灶趋向性及抗原性等问题均是临床应用的难点[1] 。为此用化学手段合成与表征具有相关结构铜、锰、铁甚至钴等金属离子的配合物来模拟ＳＯＤ[2～ 14 ] ,将为进一步认识ＳＯＤ的结构与功能的相关规律性和开发研制新型ＳＯＤ制剂 ,提供重要的理论依据。　　通过Ｘ 射线衍射分析、红外光谱、核磁共振谱、顺磁共振谱、穆斯堡尔…     

抗糖尿病药物研究进展

糖尿病是一种慢性进行性病 ,病人主要表现为高血糖及糖尿。持续的高血糖会导致许多并发症的产生 ,如视网膜、肾脏、神经系统病变及血管并发症。血管并发症是糖尿病患者致死致残的主要原因。因此保持接近正常范围的血糖水平对于预防糖尿病并发症十分重要。　　临床将糖尿病分为两型。 1型糖尿病 (胰岛素依赖型 )是由于胰岛 β细胞损害引起胰岛素分泌水平极低而致高血糖 ,约占糖尿病人的 10 %。其治疗只能依赖于外源性给予胰岛素。另一大类为 2型(非胰岛素依赖型 ) ,是胰岛素分泌的相对不足及胰岛素作用环节不健全而致血糖水平升高[1] 。对 2…     

肽核酸研究进展

序列选择性作用于核酸的试剂在分子生物学和药物化学领域有重要意义,因为它们有望成为定靶于基因的诊断和治疗药物。其中,寡核苷酸（ＯＮｓ）有最好的识别特异性和亲和性,它通过ＷａｔｓｏｎＣｒｉｃｋ碱基配对与含互补序列的单链核酸结合形成双螺旋结构,或以Ｈｏｏ...     

细胞因子小分子模拟物研究进

细胞因子通过与靶细胞表面特定受体相互作用,在细胞间及细胞与环境之间扮演传递信息的重要角色.细胞因子在许多重要的生物过程(如调控细胞和体液免疫反应、血细胞生成作用、炎症反应、伤口愈合和细胞程序性死亡)中起关键作用.     

异亚丙基莽草酸抗血栓作用的实验研究

目的研究异亚丙基莽草酸(ISA)对大鼠动静脉环路血栓、大脑中动脉栓塞及血小板聚集的对抗作用及机制。方法用动静脉环路血栓及三氯化铁致大脑中动脉栓塞(MCAT)模型观察药物作用;并研究了ISA体内、外给药对血小板聚集的影响。结果ISA 25,50,100及200 mg·kg^-1 ig均可显著降低大鼠体外血栓重量;ISA 50,100,200 mg·kg^-1 ig可明显改善MCAT模型大鼠神经症状;ISA 100及200 mg·kg^-1 ig MCAT模型大鼠脑梗塞范围分别下降27.8%和31.6%;另外,ISA体内、外给药对ADP和胶原诱导的血小板聚集有明显的抑制作用。结论ISA可能通过抗血小板聚集作用抑制血栓的形成。     

EFFECTS OF BKCa CHANNELS ON THE REDUCTION OF CYTOSOLIC Ca2+ IN cGMP-INDUCED RELAXATION OF GUINEAPIG TRACHEA

1. In order to examine the mechanisms of cGMP-induced relaxation in airway smooth muscle, the effects of atrial natriuretic peptide (ANP) and 8-brom cGMP on muscle tone were studied by measuring isometric tension, while the effects on cytosolic Ca²⁺ concentrations were studied by measuring the spectra of fura-2 loaded in guinea-pig tracheal strips. 2. Atrial natriuretic peptide and 8-brom cGMP caused a concentration-dependent inhibition of spontaneous tone in the guinea-pig trachea. The relaxant effects of these agents on spontaneous tone were markedly suppressed in the presence of iberiotoxin (IbTX), a selective inhibitor of large-conductance Ca²⁺-activated K⁺ (BKca) channels. Iberiotoxin (30 nmol/L) markedly affected the maximal effect induced by ANP and 8-brom cGMP and augmented EC₇₀ values for ANP and EC₅₀values for 8-brom cGMP approximately 27- and 17-fold, respectively. The inhibitory effects of IbTX on relaxation induced by these agents were diminished in the presence of 1 μmol/L nifedipine, an antagonist of voltage-operated Ca²⁺channels (VOCC). 3. The inhibitory action of ANP and 8-brom cGMP on spontaneous tone was not affected by the presence of 10 μmol/L glibenclamide, an inhibitor of ATP-sensitive K⁺ channels, and 100 nmol/L apamin, an inhibitor of small-conductance Ca²+-activated K⁺ channels. When these agents were applied to tissues precontracted by high (40mmol/L) K⁺, the relaxant effects of these agents markedly diminished. 4. The extracellular Ca²⁺-dependent contraction was inhibited in the presence of 0.3 μmoI/L ANP or 0.1 mmol/L 8-brom cGMP. Concentration—response curves to extracellular Ca²⁺ (0.03—2.4 mmol/L) were markedly diminished by exposure to these agents. The maximal effect induced by extracellular Ca²⁺ was affected by these agents. 5. Atrial natriuretic peptide caused an inhibition of spontaneous tone accompanied by a reduction in the intracellular Ca²⁺ concentration. In the presence of IbTX, the elimination of both muscle tone and cytosolic Ca²⁺ by ANP was suppressed. 6. We conclude that ANP and 8-brom cGMP activate BKca channels and that the inhibition of Ca²⁺ influx through VOCC, mediated by BKca channel activation, may be involved in cGMP-dependent bronchodilation.     

DIFFERENTIAL EFFECTS OF ANTIARRHYTHMIC AGENTS ON POST-PAUSE REPOLARIZATION IN CARDIAC PURKINJE FIBRES

1. Marked action potential duration (APD) prolongation with agents such as quinidine is often a precursor of early afterdepolarizations and triggered activity, thought to be the underlying mechanism of torsade de pointes. Episodes of torsade de pointes commonly occur following a pause. 2. We recently demonstrated that quinidine, but not disopyramide, produced marked further prolongation of APD immediately following pauses of 2-10s interpolated into a basic drive train in canine Purkinje fibres. 3. We report here experiments aimed at further elucidating the mechanisms of this phenomenon. 4. We used standard microelectrode techniques to record action potentials from canine Purkinje fibres driven at a baseline interstimulus interval (ISI) of 1000 ms. 5. We were able to reproduce the phenomenon of postpause prolongation of APD with amitriptyline, which blocks both sodium and potassium channels, as does quinidine. Furthermore, we showed that the kinetics of interaction of amitriptyline, with the sodium channel, are similar to those known to exist for quinidine (time constant of recovery from blockade 2.3±0.6s). 6. In contrast, we were unable to reproduce post-pause prolongation of APD with three pure class III antiarrhythmic agents, d -sotalol, clofilium and dofetilide. 7. We propose that quinidine and amitriptyline behave similarly, in that they both produce two separate, opposing effects on APD. During a pause, the sodium channel-blocking action of these compounds diminishes exponentially, allowing the potassium channel blocking effect to become manifest as post-pause prolongation of APD. None of d sotalol, clofilium or dofetilide exhibits significant sodium channel blockade and, thus, these agents do not manifest post-pause prolongation of repolarization. Disopyramide does produce sodium channel blockade, but recovery from this effect is much slower than for quinidine or amitriptyline (time constant 12-50s). Thus, we propose insufficient recovery occurs during the intervals under study to uncover the action potential-prolonging effect of the unopposed potassium channel blockade for disopyramide.     

α-芋螺毒素的研究现况

α-芋螺毒素是近年来研究得较多的一种海洋生物神经毒素，它特异性竞争结合烟碱型乙酰胆碱受体，化学结构独特。本文介绍有关α-芋螺毒素的种类、结构特征、生物学活性和制备方法等方面的研究进展及其在生物化学、生物学以及新药开发等方面的应用前景。     

EFFECTS OF BRADYKININ ON [3H]-NOREPINEPHRINE RELEASE IN RAT HYPOTHALAMUS

• 1 We examined the regulatory actions of bradykinin on norepinephrine release in the hypo-thalamus of rats.
• 2 Bradykinin increased the stimulation-evoked [³H]-norepinephrine release from hypothalamic slices of Sprague-Dawley rats in a dose-dependent manner (1 Hz: S2/S1 ratio, mean ± s.e.m., control 0.868±0.016, n= 6; bradykinin 1±10^–6mol/L 1.039±0.018, n= 6, P<0.05;bradykinin3.3 ×10^–6 mol/L 1.130 ± 0.064, n= 6, P<0.05). The basal release of [³H]-norepinephrine was not affected by the peptide.
• 3 Bay K 8644, a dihydropyridine-sensitive calcium channel agonist, significantly potentiated the facilitatory effect of bradykinin on norepinephrine release, although Bay K 8644 by itself had no significant effect. By contrast, nicardipine, a dihydropyridine-sensitive calcium channel blocker, reversed the increase in norepinephrine release induced by bradykinin and Bay K 8644.
• 4 These results indicate that bradykinin may increase norepinephrine release in rat hypo-thalamus, partially mediated by interactions with dihydropyridine-sensitive calcium channels.