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首页> 外文学位 >Biological applications of boronate optical probes, neurotoxins and antioxidants in neuronal cell culture.
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Biological applications of boronate optical probes, neurotoxins and antioxidants in neuronal cell culture.

机译：硼酸盐光学探针，神经毒素和抗氧化剂在神经元细胞培养中的生物学应用。

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摘要

The neurochemistry of hydrogen peroxide (H2O2) in living systems has received increased attention owing to its contributions as a marker for oxidative stress and damage events associated with neurodegeneration. H2O2 is a major reactive oxygen species (ROS) in living organisms, yet its production, accumulation and trafficking within neuronal cells is poorly understood. Using the H2O2 selective optical probe Peroxyfluor-1 (PF1), we determined its ability to operate within neuronal cell lines (RN46A-B14 and SKNSH) and primary cortical neurons.;In collaboration with Professor Bryan K Yamamoto at the BU Medical Campus, we used PF1 to study the role of H2O2 in serotonin (5-HT) neurons in the presence of the well-known neurotoxin and drug of abuse, 3,4methylenedioxymethamphetamine (MDMA). We found that MDMA creates the pro-oxidant environment to non-enzymatically hydroxylate L-tyrosine in the 5-HT cell line RN46A-B14. Dopamine (DA) is formed by endogenous amino acid decarboxylase (AADC) and is further metabolized by monoamine oxidase B (MAO-B) to produce H2O2 as a by-product.;Next, we investigated oxidative stress in a dopaminergic cell line (SKNSH). We found significant increases in H2O2 formation upon treatment with the current drug therapy for Parkinson's disease (PD), L-3,4 dihydroxyphenylalanine (L-dopa). L-dopa results in the AADC conversion of L-dopa to DA in the brain. A replenishment of DA in the surviving neurons temporarily alleviates symptoms of the disease; however, the therapy is not curative, and dopaminergic cells continue to die in PD patients receiving L-dopa. The proposed mechanism for L-dopa induced cell death is by autoxidation into ROS and toxic quinones. We found that resveratrol and flavonoid antioxidants reduced L-dopa-induced H2O2 formation and cytotoxicity.;We also synthesized boronate polyphenols that resemble the antioxidant scaffolds with which we had great success as neuroprotectants. We envisioned that placing a boronate ester functionality on the antioxidant backbone would increase solubility, cell permeability and decrease H2O2-induced cell death in SKNSH cells. Of the boronate coumarins, stilbenes and flavones we synthesized, we found that 7-boronatecoumarin and to a lesser extent (E)-3,5-dihydroxy, 4'-boronatestilbene were water soluble, cell permeable and preserved SKNSH cell viability in the presence of H2O2.
机译：生命系统中的过氧化氢（H2O2）的神经化学因其作为氧化应激和与神经变性相关的损伤事件的标志物而受到关注。 H2O2是活生物体中的主要活性氧（ROS），但人们对其在神经元细胞内的产生，积累和运输的了解却很少。使用H2O2选择性光学探针Peroxyfluor-1（PF1），我们确定了它在神经元细胞系（RN46A-B14和SKNSH）和原代皮层神经元中的运作能力。；与BU Medical Campus的Bryan K Yamamoto教授合作，我们为了研究过氧化氢在5-HT神经元中5-羟色胺（5-HT）神经元中的作用，在已知的神经毒素和滥用药物3，4-亚甲基二氧基甲基苯丙胺（MDMA）存在的情况下，使用PF1进行了研究。我们发现，MDMA在5-HT细胞系RN46A-B14中创造了非氧化剂羟基化L-酪氨酸的促氧化剂环境。多巴胺（DA）由内源性氨基酸脱羧酶（AADC）形成，并进一步被单胺氧化酶B（MAO-B）代谢，产生副产物H2O2。接下来，我们研究了多巴胺能细胞系（SKNSH）的氧化应激）。我们发现，目前的帕金森氏病（PD），L-3,4二羟基苯丙氨酸（L-dopa）药物治疗后，H2O2的形成显着增加。 L-多巴导致大脑中L-多巴ADA转化为DA。存活神经元中DA的补充暂时缓解了疾病的症状。然而，该疗法不是治愈性的，多巴胺能细胞继续在接受左旋多巴的PD患者中死亡。左旋多巴诱导的细胞死亡的拟议机制是通过自氧化成ROS和有毒醌。我们发现白藜芦醇和类黄酮抗氧化剂减少了L-多巴诱导的H2O2形成和细胞毒性。我们还合成了类似于抗氧化剂支架的硼酸多酚，作为抗神经保护剂，我们取得了巨大的成功。我们设想将硼酸酯官能团置于抗氧化剂骨架上会增加溶解度，细胞通透性并减少HNS2细胞中H2O2诱导的细胞死亡。在我们合成的硼酸香豆素，丁苯醚和黄酮中，我们发现7-硼酸香豆素和较小程度的（E）-3,5-二羟基，4'-硼酸二苯乙烯都是水溶性的，细胞可渗透的，并且在存在SKNSH细胞时保持活力H2O2。

著录项

  • 作者

    Peritore, Carina S.;

  • 作者单位

    Boston University.;

  • 授予单位 Boston University.;
  • 学科 Biology Neurobiology.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 170 p.
  • 总页数 170
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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