Neurosteroids in health and disease

神经类固醇在健康和疾病中的作用

• 批准号: 6918923
• 负责人: SYNTHIA H MELLON
• 金额: $ 43.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918923
• 关键词: Neurosteroids; health; disease

DESCRIPTION (provided by applicant): Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood-on set neurodegenerative disorder for which there is no treatment. It is a lysosomal lipid storage disease characterized by defective trafficking of intracellular cholesterol, and lysosomal accumulation of unesterified cholesterol, gangliosides, and other lipids. Neurosteroids, synthesized from cholesterol in the nervous system, affect growth and differentiation of neurons. Our recently published data show that post-embryonic neurosteroid synthesis is altered in a time- and region- specific fashion in the BALB/c NP-C mouse, and that neurons and glia expressing steroidogenic enzymes are lost in the NP-C mouse. In particular, the synthesis of the GABA-ergic neurosteroid allopregnanolone (ALLO) is substantially diminished at birth when the rodent brain is still undergoing maturation, and decreases further over time. We hypothesize that these alterations in neurosteroidogenesis may contribute to the clinical phenotype. Our data show that appropriately timed treatment of NP-C mice with ALLO increases the lifespan of NP-C mice and delays the onset of neurological impairments that are hallmarks of this disease in mice - tremor, ataxia, and hindlimb dysfunction. Furthermore, ALLO treatment of NP-C mice significantly increases cerebellar Purkinje and granule cell survival and substantially reduces accumulation of cortical gangliosides GM1, GM2 and GM3. As a prerequisite for submission of an IND to the FDA for future clinical trials in children with NP-C, we propose to establish the.pharmacokinetics and pharmacodynamics of ALLO in wild type and NP-C mice, optimize ALLO treatment in NP-C mice, and generate toxicology safety data in animals. The use of neuro-active steroids in the treatment of degenerative brain diseases has not been described previously. We believe it is very possible that other brain diseases, including, but not limited to congenital storage diseases, may benefit from similar treatments with neuro-active steroids. Thus this proposal is directed toward the treatment of a broad group of disorders with a novel class of drugs, with NP-C as the model disease.

描述（由申请人提供）： 尼曼-匹克 C 型 (NP-C) 疾病是一种致命的常染色体隐性遗传、儿童期发病的神经退行性疾病，目前尚无治疗方法。它是一种溶酶体脂质贮积病，其特征是细胞内胆固醇运输缺陷以及未酯化胆固醇、神经节苷脂和其他脂质的溶酶体积累。神经类固醇由神经系统中的胆固醇合成，影响神经元的生长和分化。我们最近发表的数据表明，BALB/c NP-C 小鼠中胚胎后神经类固醇合成以时间和区域特异性方式发生改变，并且表达类固醇生成酶的神经元和神经胶质细胞在 NP-C 小鼠中丢失。特别是，当啮齿动物大脑仍在成熟时，GABA 能神经类固醇四氢孕酮 (ALLO) 的合成在出生时大幅减少，并且随着时间的推移进一步减少。我们假设神经类固醇生成的这些改变可能有助于临床表型。我们的数据表明，对 NP-C 小鼠进行适当的 ALLO 治疗可以延长 NP-C 小鼠的寿命，并延缓神经损伤的发生，而神经损伤是该疾病的标志，即震颤、共济失调和后肢功能障碍。此外，对 NP-C 小鼠进行 ALLO 治疗可显着增加小脑浦肯野细胞和颗粒细胞的存活率，并显着减少皮质神经节苷脂 GM1、GM2 和 GM3 的积累。作为向 FDA 提交 IND 进行未来 NP-C 儿童临床试验的先决条件，我们建议在野生型和 NP-C 小鼠中建立 ALLO 的药代动力学和药效学，优化 NP-C 小鼠中的 ALLO 治疗，并生成动物毒理学安全数据。以前没有描述过使用神经活性类固醇治疗退行性脑疾病。我们相信其他脑部疾病，包括但不限于先天性脑储存疾病，很可能受益于神经活性类固醇的类似治疗。因此，该提案旨在用一类新型药物治疗广泛的疾病，以 NP-C 作为模型疾病。