Mathylglyoxal - Effects on Nociceptive NeuronsMechanisms of Sensitization, Hyperexcitability and Inaktivation

糖尿病是西方世界多发性神经病的常见原因。糖尿病神经病变（DN）的特征在于阳性和阴性症状同时发生。阴性症状即涉及自主神经系统胃轻瘫和躯体感觉系统中的温冷辨别障碍。阳性症状是自发性疼痛，最常见的是烧灼感和/或感觉异常。这一方面表明敏化和过度兴奋，另一方面表明外周伤害感受器和自主神经元的脱敏或变性。我们证明，甲基乙二醛（MG），一种内源性代谢产物，主要在疼痛性糖尿病神经病变患者的血浆中发现较高的量。我们还发现MG通过翻译后修饰激活化学和冷敏感离子通道TRPA 1。我们还发现MG通过翻译后修饰激活化学和冷敏感离子通道TRPA 1。它还增加了钠通道亚型1.8的激活，并减少了亚型1.7的激活。这些修饰可以解释神经元的激活、敏化和过度兴奋以及它们的脱敏，从而解释DN患者的阳性和阴性症状。我们预期，人类伤害感受器，特别是“沉默”伤害感受器（CMi）变得过度兴奋，而不表达钠通道亚型1.8和TRPA 1的自主神经元变得低兴奋。一段时间以前，在MG被描述为糖尿病神经调节剂之前，我们已经使用显微神经造影术来证明CMi在DN患者中是自发活性和致敏的。在我们目前的项目中，我们计划研究MG对周围神经元的影响，特别是通过细胞水平上的电生理技术，动物模型，以及通过人类健康受试者和DN患者的显微神经成像。我们将使用受体或离子通道缺陷小鼠以及组成性高MG血浆水平的小鼠来研究MG对感觉神经元的影响。这些结果将与在人体中进行的相应实验的结果进行比较和关联。人类心理生理学实验将进一步研究MG的致痛和致敏作用的翻译方面。该项目的另一个目的是阐明其他糖尿病和炎症介质和MG的协同作用。该项目旨在揭示从实验室到旁边的转化方法中的机制，这有助于人类糖尿病神经病变的症状。

Diabetes is a common cause for polyneuropathy in the western world. Diabetic neuropathy (DN) is characterized by the simultaneous incidence of positive and negative symptoms. Negative symptoms are i.e. concerning the autonomous nervous system gastroparesis and in the somatosensory system an impairment of warm-cold discrimination. Positive symptoms are spontaneous pain, most often of a burning character and/or paresthesia. This indicates sensitization and hyperexcitability on one hand and de-sensitization or degeneration of peripheral nociceptors and autonomous neurons on the other. We demonstrated that Methylglyoxal (MG), an endogenous metabolite, is found in higher quantities mainly in the plasma of patients with painful diabetic neuropathy. We also found that MG activates the chemo- and cold sensitive ion channel TRPA1 by posttranslational modification. We also found that MG activates the chemo- and cold sensitive ion channel TRPA1 by posttranslational modification. It also increases the activation of the sodium channel subtype 1.8 and decreases activation of the subtype 1.7. These modifications could account for activation, sensitization and hyperexcitability of neurons as well as for their desensitization and thus for the positive and negative symptoms of the patients with DN. We expect, that human nociceptors, especially "silent" nociceptors (CMi) become hyperexcitable, whereas autonomous neurons that do not express sodium channel subtype 1.8 and TRPA1 become hypoexcitable. Some time ago, before MG was described as a diabetic neuromodulator, we already used microeurography to demonstrate that CMi are spontaneously active and sensitized in patients with DN. In our current project we plan to investigate MG effects on peripheral neurons especially by electrophysiological techniques on cellular level, animal models and also via mircroneurography in human healthy subjects and patients with DN. We will use receptor- or ion channel deficient mice as well as mice with constitutively high MG plasma level to investigate MG effects on sensory neurons. These results will be compared and correlated to the findings from corresponding experiments done in human. Human psychophysiological experiments will further investigate the translational aspects of the algogenic and sensitizing actions of MG. Another aim of the project is to elucidate synergistic effects of other diabetic and inflammatory mediators and MG.This project aims to uncover mechanisms in a translational approach form bench to beside, which contribute to the symptoms of diabetic neuropathy in humans.