Niemann-Pick Disease Type C (NP-C) is a fatal lysosomal storage disorder with progressive neurodegeneration. In addition to the characteristic cholesterol and lipid overload phenotype, we previously found that altered metal homeostasis is also a pathological feature. Increased brain iron in the Npc1-/- mouse model of NP-C may potentially contribute to neurodegeneration, similar to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Deferiprone (DFP) is a brain penetrating iron chelator that has demonstrated effectiveness in preventing neurological deterioration in Parkinson's disease clinical trials. Therefore, we hypothesized that DFP treatment, targeting brain iron overload, may have therapeutic benefits for NP-C. Npc1-/- mice were assigned to four experimental groups: (1) pre-symptomatic (P15) + 75 mg/kg DFP; (2) pre-symptomatic (P15) + 150 mg/kg DFP; (3) symptomatic (P49) + 75 mg/kg DFP; (4) symptomatic (P49) + 150 mg/kg DFP. Our study found that in Npc1-/- mice, DFP treatment did not offer any improvement over the expected disease trajectory and median lifespan. Moreover, earlier treatment and higher dose of DFP resulted in adverse effects on body weight and onset of ataxia. The outcome of our study indicated that, despite increased brain iron, Npc1-/- mice were vulnerable to pharmacological iron depletion, especially in early life. Therefore, based on the current model, iron chelation therapy is not a suitable treatment option for NP-C.

中文翻译：

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去铁酮对铁的螯合不能挽救尼曼-皮克病C1型小鼠模型。

C型尼曼-皮克病（NP-C）是一种致命的溶酶体贮积病，伴有进行性神经变性。除了特征性的胆固醇和脂质超负荷表型外，我们先前还发现，金属稳态的改变也是一种病理特征。NP-C的Npc1-/-小鼠模型中脑铁的增加可能会导致神经退行性变，类似于神经退行性疾病，例如阿尔茨海默氏病和帕金森氏病。Deferiprone（DFP）是一种脑穿透铁螯合剂，在帕金森氏病临床试验中已证明可有效预防神经系统恶化。因此，我们假设针对脑铁超负荷的DFP治疗可能对NP-C具有治疗益处。将Npc1-/-小鼠分为四个实验组：（1）症状前（P15）+ 75 mg / kg DFP；（2）有症状的（P15）+ 150 mg / kg DFP；（3）有症状（P49）+ 75 mg / kg DFP；（4）有症状（P49）+ 150 mg / kg DFP。我们的研究发现，在Npc1-/-小鼠中，DFP疗法对预期的疾病轨迹和中位寿命没有任何改善。此外，较早的治疗和较高的DFP剂量会对体重和共济失调的发作产生不利影响。我们的研究结果表明，尽管脑铁增加，但Npc1-/-小鼠仍易受到药理性铁耗竭的影响，尤其是在早期。因此，根据当前模型，铁螯合疗法不是NP-C的合适治疗选择。DFP疗法在预期的疾病轨迹和中位寿命方面没有任何改善。此外，较早的治疗和较高的DFP剂量会对体重和共济失调的发作产生不利影响。我们的研究结果表明，尽管脑铁增加，但Npc1-/-小鼠仍易受到药理性铁耗竭的影响，尤其是在早期。因此，根据当前模型，铁螯合疗法不是NP-C的合适治疗选择。DFP疗法在预期的疾病轨迹和中位寿命方面没有任何改善。此外，较早的治疗和较高的DFP剂量会对体重和共济失调的发作产生不利影响。我们的研究结果表明，尽管脑铁增加，但Npc1-/-小鼠仍易受到药理性铁耗竭的影响，尤其是在早期。因此，根据当前模型，铁螯合疗法不是NP-C的合适治疗选择。