Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model
| Autor: | Nathalie Bernard-Marissal, V. Latyszenok, C. Gouarné, Brigitte Pettmann, Cédric Raoul, T. Arnoux, Claire Sunyach, M. Michaud, Rebecca M. Pruss, J. Aebischer, T. Bordet |
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| Rok vydání: | 2012 |
| Předmět: |
Pathology
medicine.medical_specialty Normal diet Cell Survival Mice Transgenic Gene mutation Biology Neuroprotection Mice 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine medicine Animals Gliosis Amyotrophic lateral sclerosis Cells Cultured Cholestenones 030304 developmental biology Motor Neurons Pharmacology Denervation 0303 health sciences Cell Death Amyotrophic Lateral Sclerosis nutritional and metabolic diseases medicine.disease Muscle Denervation Astrogliosis Mice Inbred C57BL Disease Models Animal chemistry Olesoxime Microglia medicine.symptom Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neuropharmacology Neuropharmacology; Vol 62 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2012.02.013 |
| Popis: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The pathology is mimicked to a striking degree in transgenic mice carrying familial ALS-linked SOD1 gene mutations. Olesoxime (TRO19622), a novel neuroprotective and reparative compound identified in a high-throughput screen based on motoneuron (MN) survival, delays disease onset and improves survival in mutant SOD1(G93A) mice, a model for ALS. The present study further analyses the cellular basis for the protection provided by olesoxime at the neuromuscular junctions (NMJ) and the spinal cord. Studies were carried out at two disease stages, 60 days, presymptomatic and 104 days, symptomatic. Cohorts of wild type and SOD1(G93A) mice were randomized to receive olesoxime-charged food pellets or normal diet from day 21 onward. Analysis showed that olesoxime initially reduced denervation from 60 to 30% compared to SOD1(G93A) mice fed with control food pellets while at the symptomatic stage only a few NMJs were still preserved. Immunostaining of cryostat sections of the lumbar spinal cord with VAChT to visualize MNs, GFAP for astrocytes and Iba1 for microglial cells showed that olesoxime strongly reduced astrogliosis and microglial activation and prevented MN loss. These studies suggest that olesoxime exerts its protective effect on multiple cell types implicated in the disease process in SOD1(G93A) mice, slowing down muscle denervation, astrogliosis, microglial activation and MN death. A Phase 3 clinical study in ALS patients will determine whether olesoxime could be beneficial for the treatment of ALS. |
| Databáze: | OpenAIRE |
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