The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy
| Autor: | Guillem Pina, Stephan Kemp, Anna Vilalta, Marc Cerrada, Isabelle Weinhofer, Sonja Forss-Petter, Marc Martinell, Estefania Traver, Johannes Berger, Uwe Meya, Laura Rodríguez-Pascau, Silvia Pascual, Pilar Pizcueta, Patricia L. Musolino, Jan Bauer |
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| Přispěvatelé: | Laboratory Genetic Metabolic Diseases, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism |
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Central nervous system Inflammation Neuroprotection 03 medical and health sciences Myelin 0302 clinical medicine Internal medicine medicine Humans Remyelination Adrenoleukodystrophy Neuroinflammation 030304 developmental biology 0303 health sciences business.industry Brain Endothelial Cells General Medicine medicine.disease Oligodendrocyte 3. Good health X-ALD neurodegeneration neuroinflammation PPAR gamma agonist cALD rare disease CNS PPAR gamma Oligodendroglia Endocrinology medicine.anatomical_structure medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Science Translational Medicine Science translational medicine, 13(596):eabc0555. American Association for the Advancement of Science |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5'-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid-induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte-derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions. |
| Databáze: | OpenAIRE |
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