Neuroprotection in platinum-induced neurotoxicity

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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.