Neurosteroids in health and disease

神经类固醇在健康和疾病中的作用

• 批准号: 7073430
• 负责人: SYNTHIA H MELLON
• 金额: $ 49.87万
• 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/7073430
• 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）： Niemann-Pick型C（NP-C）疾病是一种致命的，常染色体隐性的，儿童期神经退行性疾病，没有治疗。这是一种溶酶体脂质储存疾病，其特征是流量的细胞内胆固醇和未酯化胆固醇，神经节剂和其他脂质的溶酶体积累。神经蛋白酶是由神经系统中胆固醇合成的，会影响神经元的生长和分化。我们最近发表的数据表明，在BALB/C NP-C小鼠中以时间和区域特异性方式改变了胚胎后神经固醇的合成，并且在NP-C小鼠中丢失了表达类固醇激素酶的神经元和神经元。特别是，当啮齿动物大脑仍在成熟时，出生时GABA-凝胶神经类固醇（Allo）的合成大大减少，并且随着时间的推移进一步降低。我们假设神经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，适当定时治疗NP-C小鼠的Allo会增加NP-C小鼠的寿命，并延迟神经系统障碍的发作，这些神经系统障碍是该疾病的标志 - Tremor，ataxia和Hindlimb功能障碍。此外，NP-C小鼠的Allo治疗显着增加了小脑Purkinje和颗粒细胞的存活，并大大降低了皮质神经节神经节苷脂GM1，GM2和GM3的积累。作为NP-C儿童未来临床试验的IND提交IDS的先决条件，我们建议在野生型和NP-C小鼠中建立Allo的Pharmacokinetics和Allo的药物学，优化NP-C小鼠中的Allo治疗，并在动物中为动物中的毒理学安全数据提供。先前尚未描述神经活性类固醇在退化性脑疾病治疗中的使用。我们认为，包括但不限于先天性储存疾病在内的其他脑部疾病很可能受益于神经活性类固醇的类似治疗方法。因此，该提案针对用新型药物，NP-C作为模型疾病来治疗一组广泛的疾病。