Effects of dichloroacetate on transcriptional networks in rat Schwann cells and primary sensory neurons

Peripheral neuropathy (PN) is a debilitating side effect of many pharmaceutical agents and is among the most common reasons why patients stop their treatment early. Dichloroacetate (DCA) is a therapeutic drug that inhibits the pyruvate dehydrogenase complex (PDC), thereby modulating metabolic flux in cells. Despite success in improving outcomes of disease, reversible PN has been the single factor limiting the therapeutic potential for DCA. As a result, clinical trials for the drug have been halted prematurely. Establishing toxicity pathways in cells of the peripheral nervous system (PNS) that are involved in DCA-induced PN would provide new opportunities to intervene and mitigate adverse side effects associated with DCA. We investigated the molecular mechanisms underlying DCA-induced injury to both glial and neuronal cells. It was hypothesized that SCs would show activated transcriptional responses associated with oxidative damage and apoptosis at therapeutic doses while these responses will be absent or reduced in DRGs. Experiments were expected to pinpoint molecular mechanisms underlying DCA-induced neurotoxicity, and to reveal the window of therapeutic intervention to reduce side effects associated with DCA in clinical settings.周围神经病（Peripheral neuropathy, PN）是众多药物制剂引发的致残性不良反应，亦是导致患者提前终止治疗的最常见诱因之一。二氯乙酸盐（Dichloroacetate, DCA）作为一种治疗性药物，可通过抑制丙酮酸脱氢酶复合物（pyruvate dehydrogenase complex, PDC）调控细胞代谢流。尽管其在改善疾病转归方面成效显著，但可逆性周围神经病成为制约其治疗潜力的唯一因素，致使该药物的临床试验被迫提前终止。明确诱发二氯乙酸盐相关周围神经病的周围神经系统（Peripheral nervous system, PNS）细胞毒性通路，将为干预并缓解二氯乙酸盐相关不良副作用提供全新契机。本研究探究了二氯乙酸盐对胶质细胞与神经元细胞造成损伤的潜在分子机制。研究假设：在治疗剂量下，施万细胞会呈现出与氧化损伤及细胞凋亡相关的激活转录反应，而背根神经节（Dorsal Root Ganglia, DRG）中则不会出现此类反应或反应程度有所减弱。本研究旨在精准阐明二氯乙酸盐诱导神经毒性的潜在分子机制，并揭示临床场景中降低二氯乙酸盐相关副作用的治疗干预窗口。