Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis

详细信息    查看全文

• 作者：James P. Bennett Jr.^a ; ^b ; ^c ; ^d ; ^{jim@neurodegenerationtherapeutics.comcastbiz.net" class="auth_mail" title="E-mail the corresponding author} ; ; Laura C. O&rsquo ; Brien^a ; ^b ; David G. Brohawn^a ; ^e
• 关键词：Microneurotrophin ; ALS ; iPSC-derived motor neuron ; RNA-sequencing ; Gene ontology
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：117
• 期：Complete
• 页码：68-77
• 全文大小：1199 K

文摘

Microneurotrophins (MNT’s) are small molecule derivatives of dehydroepiandrosterone (DHEA) and do not have significant interactions with sex steroid receptors. MNT’s retain high-affinity binding to protein tyrosine kinase (Trk) receptors and can mimic many pleiotropic actions of neurotrophin (NT) proteins on neurons. MNT’s offer therapeutic potential for diseases such as amyotrophic lateral sclerosis (ALS) where motor neurons (MN) degenerate.

MNT’s cross artificial membranes mimicking the blood–brain barrier, are not major substrates for ABC (ATP-binding cassette) transporters and are metabolized rapidly by mouse but more slowly by human hepatocytes. A lead MNT (BNN27) and its mono-oxidation metabolites enter mouse brain rapidly. RNA-sequencing measured gene expression profiles of human H9eSC-(embryonic stem cell)-derived or CTL (control) subject iPSC-(induced pluripotential stem cell)-derived MN’s exposed to NT proteins or MNT molecules. Expression ratios (relative to DMSO (dimethylsulfoxide) vehicle) were calculated, and the resulting top 500 gene lists were analyzed for Gene Ontology (GO) grouping using DAVID (Database for Annotation, Visualization and Integrated Discovery). The MNT’s BNN20, BNN23, and BNN27 showed overlap of GO terms with NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor) in the H9eSC-derived MN’s. In the iPSC-derived MN’s two (BNN20, BNN27) showed overlap of GO terms with NGF or BDNF. Each NT protein had GO terms that did not overlap with any MNT in the MN cell lines.