Dexpramipexole is ineffective in two models of ALS related neurodegeneration
| Autor: | Alan Gill, Steven Perrin, Fernando G. Vieira, Kenneth Thompson, Andy J. Moreno, Steven Finkbeiner, Beth Levine, Joshua D. Kidd, Eva S. LaDow |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Mutant
lcsh:Medicine Bioinformatics Biochemistry Antioxidants Motor Neuron Diseases Mice Pramipexole Superoxide Dismutase-1 0302 clinical medicine Nucleic Acids Molecular Cell Biology Drug Discovery Medicine and Health Sciences Amyotrophic lateral sclerosis lcsh:Science Cells Cultured Cellular Stress Responses Neurons 0303 health sciences Multidisciplinary Cell Death Neuronal Morphology Neurodegeneration Neurodegenerative Diseases Animal Models Transfection DNA-Binding Proteins Neuroprotective Agents Neurology Cell Processes Dexpramipexole Research Article medicine.drug Drug Research and Development Mouse Models Context (language use) Research and Analysis Methods 03 medical and health sciences Model Organisms medicine Animals Humans Rats Long-Evans Benzothiazoles 030304 developmental biology Pharmacology Biology and life sciences Superoxide Dismutase business.industry Amyotrophic Lateral Sclerosis lcsh:R Cell Biology medicine.disease Rats Mice Inbred C57BL Clinical trial RNA processing Cellular Neuroscience RNA lcsh:Q Clinical Medicine business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE, Vol 9, Iss 12, p e91608 (2014) PLoS ONE Finkbeiner, Steven; Vieira, FG; LaDow, E; Moreno, A; Kidd, JD; Levine, B; et al.(2014). Dexpramipexole is ineffective in two models of ALS related neurodegeneration. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/8dh6j77j |
| ISSN: | 1932-6203 |
| Popis: | Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy screening in high-copy B6-SJL-SOD1G93A/Gur1 mice, and 2) high-content neuronal survival screening in primary rat cortical neurons transfected with wild-type human TDP43 or mutant human TDP43. In both cases, we exposed the test systems to RPPX levels approximating those achieved in human Phase II clinical investigations. In SOD1G93A mice, no effect was observed on neuromotor disease progression or survival. In primary cortical neurons transfected with either mutant or wild-type human TDP43, a marginally significant improvement in a single indicator of neuronal survival was observed, and only at the 10 µM RPPX treatment. These systems reflect both mutant SOD1- and TDP43-mediated forms of neurodegeneration. The systems also reflect both complex non-cell autonomous and neuronal cell autonomous disease mechanisms. The results of these experiments, taken in context with results produced by other molecules tested in both screening systems, do not argue positively for further study of RPPX in ALS. |
| Databáze: | OpenAIRE |
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