Neurosteroids in health and disease

神经类固醇在健康和疾病中的作用

• 批准号: 7693708
• 负责人: SYNTHIA H MELLON
• 金额: $ 72.73万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693708
• 关键词: Adolescent; Adult; Affect; Age; Age-Years; Allopregnanolone; Animals; Ataxia; Biological Assay; Birth; Brain; Brain Diseases; Cell Survival; Cerebellum; Child; Childhood; Cholesterol; Clinical; Clinical Trials; Collaborations; Data; Defect; Diagnosis; Differentiation and Growth; Disease; Disease model; Dose; Drug Kinetics; Early treatment; Embryo; Enzymes; Functional disorder; Future; Gangliosides; Health; Hindlimb; Impairment; In Vitro; Inbred BALB C Mice; International; Life; Lipids; Longevity; Measures; Mus; Neonatal; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Plasma; Production; Publishing; Research Personnel; Rodent; Route; Safety; Steroids; Subcutaneous Injections; Supraoptic Vertical Ophthalmoplegia; Time; Tissues; Toxic effect; Toxicology; Treatment Protocols; Tremor; Weaning; cholesterol trafficking; clinical phenotype; drinking water; effective therapy; gamma-Aminobutyric Acid; granule cell; meetings; neuronal survival; neurosteroids; novel; postnatal; programs; response; trafficking

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）：

项目成果

Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS).

• DOI: 10.1016/j.yfrne.2008.11.002
• 发表时间: 2009-01
• 期刊: FRONTIERS IN NEUROENDOCRINOLOGY
• 影响因子: 7.4
• 作者: Maninger, Nicole;Wolkowitz, Owen M.;Reus, Victor I.;Epel, Elissa S.;Mellon, Synthia H.
• 通讯作者: Mellon, Synthia H.