Neuroprotection in platinum-induced neurotoxicity

以铂为基础的化疗的神经毒性副作用是常见的，通常与永久性神经功能缺损相关，导致肿瘤患者不活动和难治性疼痛。虽然这些药物的细胞抑制，肾和血液毒性机制是众所周知的，但神经毒性机制大多未知。目前的预防策略也不成功，但已经提出了几个机制显著参与神经毒性和多神经病变。特别是神经元钙稳态功能障碍已被认为是神经毒性的一个原因。钙的积累导致兴奋毒性作用，激活促凋亡蛋白，抑制铂- dna加合物的修复，导致神经元细胞死亡和神经病变。下面的研究假设靶向抑制背根神经节神经元钙积累具有神经保护作用，可以预防铂诱导的多发性神经病模型的神经病变。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，鉴定给药铂基化疗后主要的载钙膜结合蛋白。随后，计划通过靶向抑制先前确定的钙通道和随后减少背根神经节dna加合物来预防铂基化疗啮齿动物模型中的神经病变。该研究旨在评估基于神经保护的新机制，以对抗化疗诱导的多发性神经病变。

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.