Pharmacologic inhibition of reactive gliosis blocks TNF-α-mediated neuronal apoptosis
| Autor: | Livne-Bar, Izhar, Lam, Susy, Chan, Darren, Guo, Xiaoxin, Askar, Idil, Nahirnyj, Adrian, Flanagan, John G, Sivak, Jeremy M |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Pyridines 1.1 Normal biological development and functioning Oncology and Carcinogenesis Intermediate Filaments Apoptosis Neurodegenerative Inbred C57BL p38 Mitogen-Activated Protein Kinases Polymerization Mice Underpinning research Animals 2.1 Biological and endogenous factors Gliosis Aetiology Withanolides Eye Disease and Disorders of Vision Animal Tumor Necrosis Factor-alpha Imidazoles Neurosciences Astrocytes Disease Models Neurological Biochemistry and Cell Biology Neuroglia Retinal Neurons Corneal Injuries |
| Zdroj: | Cell death & disease, vol 7, iss 9 |
| Popis: | Reactive gliosis is an early pathological feature common to most neurodegenerative diseases, yet its regulation and impact remain poorly understood. Normally astrocytes maintain a critical homeostatic balance. After stress or injury they undergo rapid parainflammatory activation, characterized by hypertrophy, and increased polymerization of type III intermediate filaments (IFs), particularly glial fibrillary acidic protein and vimentin. However, the consequences of IF dynamics in the adult CNS remains unclear, and no pharmacologic tools have been available to target this mechanism in vivo. The mammalian retina is an accessible model to study the regulation of astrocyte stress responses, and their influence on retinal neuronal homeostasis. In particular, our work and others have implicated p38 mitogen-activated protein kinase (MAPK) signaling as a key regulator of glutamate recycling, antioxidant activity and cytokine secretion by astrocytes and related Müller glia, with potent influences on neighboring neurons. Here we report experiments with the small molecule inhibitor, withaferin A (WFA), to specifically block type III IF dynamics in vivo. WFA was administered in a model of metabolic retinal injury induced by kainic acid, and in combination with a recent model of debridement-induced astrocyte reactivity. We show that WFA specifically targets IFs and reduces astrocyte and Müller glial reactivity in vivo. Inhibition of glial IF polymerization blocked p38 MAPK-dependent secretion of TNF-α, resulting in markedly reduced neuronal apoptosis. To our knowledge this is the first study to demonstrate that pharmacologic inhibition of IF dynamics in reactive glia protects neurons in vivo. |
| Databáze: | OpenAIRE |
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