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Neuroprotection in platinum-induced neurotoxicity

铂引起的神经毒性的神经保护

基本信息

批准号：
290546143
负责人：
Professor Dr. Tim Hagenacker
金额：
--
依托单位：
Klinik für Neurologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/290546143?language=en
关键词：
Neuroprotection platinum induced neurotoxicity

项目摘要

Neurotoxic side effects of platinum-based chemotherapy are frequent and often associated with permanent neurologic deficits resulting in immobility and refractory pain in tumor patients. While the cytostatic, kidney- and hematotoxic mechanisms of these drugs are well known, mechanisms of neurotoxicity mostly unknown. Current preventive strategies are furthermore not successful, but is has been suggested that several mechanisms are significantly involved in neurotoxicity and polyneuropathy. Especially dysfunction of the neuronal calcium-homeostasis have been suggested as a cause of neurotoxicity. The accumulation of calcium leads to excitotoxic effects, activation of pro-apoptotic proteins and inhibits the repair of platin-DNA adducts resulting in a neuronal cell death and neuropathy. The following study follows the hypothesis that a targeted inhibition of calcium accumulation in dorsal root ganglion neurons have neuroprotective effects and can prevent neuropathy in a model of platin-induced polyneuropathy. It is planned to identify the main calcium carrying membran-bound proteins after administration platinum-based chemotherapy by isolation of subtypes of voltage-gated caIcium channels and thermoreceptors using electrophysiological and molecular methods. Afterwards, it is planned to prevent neuropathy in a rodent model of platinum-based chemotherapy by targeted inhibition of the prior identified calcium channels and subsequent reduction of DNA-adducts in dorsal root ganglions. The study is designed to evaluate new mechanism based neuroprotection against chemotherapy-induced polyneuropathy.

以铂为基础的化疗的神经毒性副作用很常见，并经常与永久性神经功能障碍有关，导致肿瘤患者行动不便和顽固性疼痛。虽然这些药物的细胞抑制、肾脏和血液毒性机制是众所周知的，但神经毒性的机制大多不清楚。此外，目前的预防策略并不成功，但已提出几种机制与神经毒性和多发性神经病密切相关。尤其是神经元钙稳态功能障碍被认为是神经毒性的原因之一。钙的积累导致兴奋毒性效应，激活促凋亡蛋白，抑制铂-DNA加合物的修复，导致神经细胞死亡和神经病变。下面的研究遵循这样的假设：在铂诱导的多发性神经病模型中，有针对性地抑制背根神经节神经元中钙的积累具有神经保护作用，并可以预防神经病变。我们计划通过电生理和分子方法分离电压门控钙通道和热感受器亚型来鉴定给药后主要携带钙离子的膜结合蛋白。之后，计划通过靶向抑制先前发现的钙通道并随后减少背根神经节中的DNA加合物来预防以铂为基础的化疗的啮齿动物模型的神经病变。这项研究旨在评估基于新机制的神经保护，以对抗化疗所致的多发性神经病。