神经炎症
再髓鞘化
神经保护
氧化应激
实验性自身免疫性脑脊髓炎
炎症
肾上腺脑白质营养不良
血脑屏障
多发性硬化
中枢神经系统
内分泌学
内科学
医学
过氧化物酶体增殖物激活受体
药理学
兴奋剂
生物
化学
作者
Laura Rodríguez-Pascau,Anna Vilalta,Marc Cerrada,Estefania Traver,Sonja Forss-Petter,Isabelle Weinhofer,Jan Bauer,Stephan Kemp,Guillem Pina,Silvia Pascual,Uwe Meya,Patricia L. Musolino,Johannes Berger,Marc Martinell,Pilar Pizcueta
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-06-02
卷期号:13 (596)
被引量:9
标识
DOI:10.1126/scitranslmed.abc0555
摘要
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.
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