Abstract
Thalidomide was originally used as a sedative and found to be a teratogen, but now thalidomide and its derivatives are widely used to treat haematologic malignancies. Accumulated evidence suggests that thalidomide suppresses nerve cell death in neurologic model mice. However, detailed molecular mechanisms are unknown. Here we examined the molecular mechanism of thalidomide's neuroprotective effects, focusing on its target protein, cereblon (CRBN), and its binding protein, AMP-activated protein kinase (AMPK), which plays an important role in maintaining intracellular energy homeostasis in the brain. We used a cerebral ischemia rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Thalidomide treatment significantly decreased the infarct volume and neurological deficits of MCAO/R rats. AMPK was the key signalling protein in this mechanism. Furthermore, we considered that the AMPK-CRBN interaction was altered when neuroprotective action by thalidomide occurred in cells under ischemic conditions. Binding was strong between AMPK and CRBN in normal SH-SY5Y cells, but was weakened by the addition of H2O2. However, when thalidomide was administered at the same time as H2O2, the binding of AMPK and CRBN was partly restored. These results suggest that thalidomide inhibits the activity of AMPK via CRBN under oxidative stress and suppresses nerve cell death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / genetics*
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AMP-Activated Protein Kinases / metabolism
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ATP-Dependent Proteases / antagonists & inhibitors
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ATP-Dependent Proteases / genetics*
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ATP-Dependent Proteases / metabolism
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Animals
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Brain Ischemia / drug therapy*
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Brain Ischemia / enzymology
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Brain Ischemia / genetics
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Brain Ischemia / pathology
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Cell Death / drug effects
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Cell Line, Tumor
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Disease Models, Animal
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Drug Repositioning
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Gene Expression Regulation
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Humans
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Hydrogen Peroxide / antagonists & inhibitors
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Hydrogen Peroxide / pharmacology
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Immunosuppressive Agents / pharmacology
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Infarction, Middle Cerebral Artery / drug therapy*
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Infarction, Middle Cerebral Artery / enzymology
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Infarction, Middle Cerebral Artery / genetics
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Infarction, Middle Cerebral Artery / pathology
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Male
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Neurons / drug effects
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Neurons / enzymology
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Neurons / pathology
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Neuroprotective Agents / pharmacology*
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Oxidative Stress
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Rats
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Rats, Sprague-Dawley
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Reperfusion Injury / drug therapy*
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Reperfusion Injury / enzymology
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Reperfusion Injury / genetics
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Reperfusion Injury / pathology
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Signal Transduction
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Thalidomide / pharmacology*
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Ubiquitin-Protein Ligase Complexes / antagonists & inhibitors
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Ubiquitin-Protein Ligase Complexes / genetics*
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Ubiquitin-Protein Ligase Complexes / metabolism
Substances
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CRBN protein, rat
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Immunosuppressive Agents
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Neuroprotective Agents
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Thalidomide
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Hydrogen Peroxide
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Ubiquitin-Protein Ligase Complexes
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AMP-Activated Protein Kinases
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ATP-Dependent Proteases