槲皮素修复铅致大鼠海马突触可塑性损伤及Natratoxin神经毒素抑制背根神经节A型钾电流作用的研究
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摘要
铅是最重要的环境神经毒物之一。现已证实儿童在发育过程中的慢性铅暴露能够引起学习记忆功能和神经行为等认知功能的损伤。海马是与学习记忆功能密切相关的一个重要脑区,海马神经元活性依赖的突触可塑性被认为是学习和记忆功能的细胞与分子基础。研究结果表明,在发育过程中的慢性铅暴露损伤了大鼠海马的突触可塑性,这可能是慢性铅暴露损伤学习和记忆功能和神经行为等认知功能的机制之一。铅作用的毒理机制是复杂的,除了引起神经元突触可塑性损伤外,铅暴露导致的生物体氧化应激被认为是其发挥毒性作用的一个重要途径。黄酮类化合物在自然界的植物中广泛存在,在水果、种子、茶叶和红酒中含量十分丰富,其中槲皮素是含量最丰富的黄酮类化合物之一,并且作为饮食的一部分被人体摄取。槲皮素的抗氧化性被认为比维生素C、维生素E和β-胡萝卜素要高出一个摩尔级别;此外,槲皮素是典型的多酚类化合物,具有很强的金属离子螯合能力和自由基清除能力。本实验中,新生的Wistar大鼠自出生起至成年通过引用0.2%醋酸铅溶液(1090 ppm)接受慢性铅暴露。槲皮素处理组从实验开始前一周接受治疗,以30 mg/kg体重/天的剂量对铅暴露组以腹腔注射的方式给药,持续7天。治疗结束后,进行大鼠海马DG区的PP-DG通路上的在位电生理记录,包括输入/输出功能,双脉冲响应和长时程增强等参数。结果显示,慢性铅暴露明显降低DG区诱导的EPSP和PS的LTP幅度:而在铅+槲皮素处理组,其LTP幅度则明显高于铅暴露组。同时,我们还应用电感耦合等离子体质谱仪检测了不同处理组动物的海马铅水平,结果表明铅+槲皮素处理组的海马铅浓度显著低于铅暴露组。以上结果提供了一个直接的电生理水平的证掘证明槲皮素能够减轻慢性铅暴露引起大鼠DG区的突触可塑性损伤,表明槲皮素有可能成为治疗铅导致认知损伤的一个潜在药物。
Natratoxin是一种从Naja atra venom眼镜蛇中分离纯化的新型小分子蛇毒分泌型磷脂酶A2(sPLA2s)神经毒素,其神经毒理作用尚未深入了解。背根神经节(DRG)神经元是一类具有假单极结构特征的初级感觉神经元;A型钾电流(I_A)对调节神经元的动作电位发放频率和复极化有着重要意义,其改变对神经元的兴奋性产生重要影响。本文应用全细胞膜片钳技术根据动力学和药理学特性分离鉴定急性分离的大鼠背根神经节神经元上A型钾电流,研究Natratoxin对DRG神经元细胞I_A的效应,并初步探讨其作用机理。观察到Natratoxin以浓度依赖性方式抑制I_A;并且使I_A的稳态激活曲线向超极化方向移动,其中10μM Natratoxin使半数激活电压V_(1/2)和斜率因子K分别由对照的-5.0±2.8 mV和18.3±2.8 mV减少为-13.5±2.2 mV(P＜0.05)和15.4±2.0 mV(P＜0.05);Natratoxin同时也使稳态失活曲线向超极化方向移动,其中10μM Natratoxin使半数激活电压V_(1/2)由对照的-80.5±0.9mV减少到-93.0±2.6 mV(P＜0.01),斜率因子k由对照的9.3±0.9 mV增加到11.6±1.8 mV(P＜0.05)。此外,我们还发现这种抑制作用是酶活性非依赖的。我们得出结论:Natratoxin以浓度依赖性的和酶活性非依赖的方式抑制DRG神经元A型钾电流,并且改变了通道的一系列动力学性质,导致神经元的兴奋性增加,这可能是其发挥对外周的神经毒理作用和影响外周痛觉过程的作用机理之一。
Lead (Pb~(2+)) is one of the most important neurotoxic metals in the environment. It has now been well established that chronic Pb~(2+) exposure in development produces deficits of learning and memory, cognitive deficits and neurobehavioral dysfunction in children and in a lot of animal species. Hippocampus is an important brain region which plays a key role in learning and memory. Long-term potentiation (LTP) in hippocampus is an activity-dependent synaptic plasticity that is believed to form the cellular basis for learning and memory. Chronic Pb~(2+) exposure in development induces impairments of synaptic plasticity in rat hippocampus. It was suggested that such deficits in LTP may underlie cognitive impairments associated with Pb~(2+) exposure. Recent studies suggest that Pb~(2+) produces impairments partly through oxidative stress. Flavonoids are a group of naturally occurring compounds widely distributed in most plants. Quercetin is the representative natural flavonoid molecule that has a long history of consumption as part of normal human diet, such as fruits, vegetables, wine and tea. As a strong antioxidant and radical scavenger, quercetin is mort potent that vitamin C, vitamin E, andβ-carotene on a molar basis. In addition, quercetin can chelate metal ions due to its catechol function site. To determine whether quercetin treatment could rescue impairments of synaptic plasticity induced by chronic Pb~(2+) exposure, we investigated the input/output functions (I/O), paired-pulse reactions (PPR) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anaesthetized rat in vivo by stimulating the lateral perforant path and recording field potentials. The results showed that the depressed I/O, PPR and long-term potentiation (LTP) of chronic Pb~(2+)-exposed group were significantly increased by quercetin treatment. In addition, hippocampal Pb~(2+) concentrations of different treatment groups were measured by PlasmaQuad 3 inductive coupled plasma mass spectroscopy. The results showed that hippocampal Pb~(2+) concentration was partially reduced after quercetin treatment. These findings suggest that quercetin treatment could relieve chronic Pb exposure-induced himpairment of synaptic plasticity and might be a potential therapeutic intervention to cure cognitive deficits induced by Pb~(2+).
Snake venom secretory phospholipaseA2s (sPLA2s) have a lot of neurotoxic and pathological functions which are still not clearly revealed. Here we investigated the inhibitory effect of Natratoxin, a newly purified snake venom secretory phospholipaseA2s (sPLA2s) from Naja atra venom, on A-type potassium currents in media-sized (35-40 mm) neurons from acutely dissociated rat dorsal root ganglia (DRG) by conventional whole-cell voltage-clamp method. The inhibitory effect was dose dependent. For the normalized activation curves fitted by a single Boltzmann equation, there was an obvious shift to more hyperpolarized voltages with increasing concentrations of Natratoxin. The V_(1/2) and the slope factor k decreased from -5.0±2.8 mV and 18.3±2.8 mV under control condition to -13.5±2.2 mV (P<0.05) and 15.4±2.0 mV (P<.05) by 10μM Natratoxin, respectively. For the normalized steady-state inactivation curves, the V_(1/2) decreased from -80.5±0.9 mV under control condition to -93.0±2.6 mV (P<0.01) and the k increased from 9.3±0.9 mV under control condition to 11.6±1.8 mV (P<0.05) by 10μM Natratoxin, respectively. The curves were shifted to more hyperpolarized voltages by Natratoxin, indicating that channels were easier to be inactivated at higher concentrations of Natratoxin at any given potential. In addition, we found that the inhibitory effects of Natratoxin on A-type K~+ currents were independent of its enzymatic activities. In conclusion, our results showed that Natratoxin caused the alteration of properties of A-type potassium currents in rat DRG neurons. These may contribute to the peripheral neurotoxic effects and nociceptive effects of snake venom sPLA2s observed in human snakebite envenomations.
Natratoxin是一种从Naja atra venom眼镜蛇中分离纯化的新型小分子蛇毒分泌型磷脂酶A2(sPLA2s)神经毒素,其神经毒理作用尚未深入了解。背根神经节(DRG)神经元是一类具有假单极结构特征的初级感觉神经元;A型钾电流(I_A)对调节神经元的动作电位发放频率和复极化有着重要意义,其改变对神经元的兴奋性产生重要影响。本文应用全细胞膜片钳技术根据动力学和药理学特性分离鉴定急性分离的大鼠背根神经节神经元上A型钾电流,研究Natratoxin对DRG神经元细胞I_A的效应,并初步探讨其作用机理。观察到Natratoxin以浓度依赖性方式抑制I_A;并且使I_A的稳态激活曲线向超极化方向移动,其中10μM Natratoxin使半数激活电压V_(1/2)和斜率因子K分别由对照的-5.0±2.8 mV和18.3±2.8 mV减少为-13.5±2.2 mV(P＜0.05)和15.4±2.0 mV(P＜0.05);Natratoxin同时也使稳态失活曲线向超极化方向移动,其中10μM Natratoxin使半数激活电压V_(1/2)由对照的-80.5±0.9mV减少到-93.0±2.6 mV(P＜0.01),斜率因子k由对照的9.3±0.9 mV增加到11.6±1.8 mV(P＜0.05)。此外,我们还发现这种抑制作用是酶活性非依赖的。我们得出结论:Natratoxin以浓度依赖性的和酶活性非依赖的方式抑制DRG神经元A型钾电流,并且改变了通道的一系列动力学性质,导致神经元的兴奋性增加,这可能是其发挥对外周的神经毒理作用和影响外周痛觉过程的作用机理之一。
Lead (Pb~(2+)) is one of the most important neurotoxic metals in the environment. It has now been well established that chronic Pb~(2+) exposure in development produces deficits of learning and memory, cognitive deficits and neurobehavioral dysfunction in children and in a lot of animal species. Hippocampus is an important brain region which plays a key role in learning and memory. Long-term potentiation (LTP) in hippocampus is an activity-dependent synaptic plasticity that is believed to form the cellular basis for learning and memory. Chronic Pb~(2+) exposure in development induces impairments of synaptic plasticity in rat hippocampus. It was suggested that such deficits in LTP may underlie cognitive impairments associated with Pb~(2+) exposure. Recent studies suggest that Pb~(2+) produces impairments partly through oxidative stress. Flavonoids are a group of naturally occurring compounds widely distributed in most plants. Quercetin is the representative natural flavonoid molecule that has a long history of consumption as part of normal human diet, such as fruits, vegetables, wine and tea. As a strong antioxidant and radical scavenger, quercetin is mort potent that vitamin C, vitamin E, andβ-carotene on a molar basis. In addition, quercetin can chelate metal ions due to its catechol function site. To determine whether quercetin treatment could rescue impairments of synaptic plasticity induced by chronic Pb~(2+) exposure, we investigated the input/output functions (I/O), paired-pulse reactions (PPR) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anaesthetized rat in vivo by stimulating the lateral perforant path and recording field potentials. The results showed that the depressed I/O, PPR and long-term potentiation (LTP) of chronic Pb~(2+)-exposed group were significantly increased by quercetin treatment. In addition, hippocampal Pb~(2+) concentrations of different treatment groups were measured by PlasmaQuad 3 inductive coupled plasma mass spectroscopy. The results showed that hippocampal Pb~(2+) concentration was partially reduced after quercetin treatment. These findings suggest that quercetin treatment could relieve chronic Pb exposure-induced himpairment of synaptic plasticity and might be a potential therapeutic intervention to cure cognitive deficits induced by Pb~(2+).
Snake venom secretory phospholipaseA2s (sPLA2s) have a lot of neurotoxic and pathological functions which are still not clearly revealed. Here we investigated the inhibitory effect of Natratoxin, a newly purified snake venom secretory phospholipaseA2s (sPLA2s) from Naja atra venom, on A-type potassium currents in media-sized (35-40 mm) neurons from acutely dissociated rat dorsal root ganglia (DRG) by conventional whole-cell voltage-clamp method. The inhibitory effect was dose dependent. For the normalized activation curves fitted by a single Boltzmann equation, there was an obvious shift to more hyperpolarized voltages with increasing concentrations of Natratoxin. The V_(1/2) and the slope factor k decreased from -5.0±2.8 mV and 18.3±2.8 mV under control condition to -13.5±2.2 mV (P<0.05) and 15.4±2.0 mV (P<.05) by 10μM Natratoxin, respectively. For the normalized steady-state inactivation curves, the V_(1/2) decreased from -80.5±0.9 mV under control condition to -93.0±2.6 mV (P<0.01) and the k increased from 9.3±0.9 mV under control condition to 11.6±1.8 mV (P<0.05) by 10μM Natratoxin, respectively. The curves were shifted to more hyperpolarized voltages by Natratoxin, indicating that channels were easier to be inactivated at higher concentrations of Natratoxin at any given potential. In addition, we found that the inhibitory effects of Natratoxin on A-type K~+ currents were independent of its enzymatic activities. In conclusion, our results showed that Natratoxin caused the alteration of properties of A-type potassium currents in rat DRG neurons. These may contribute to the peripheral neurotoxic effects and nociceptive effects of snake venom sPLA2s observed in human snakebite envenomations.
引文
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