Abstract
Abstract
Background
Celastrol (cel) was one of the earliest isolated and identified chemical constituents of Tripterygium wilfordii Hook. f. Based on a cel probe (cel-p) that maintained the bioactivity of the parent compound, the targets of cel in cerebral ischemia–reperfusion (I/R) injury were comprehensively analyzed by a quantitative chemical proteomics method.
Methods
We constructed an oxygen–glucose deprivation (OGD) model in primary rat cortical neurons and a middle cerebral artery occlusion (MCAO) model in adult rats to detect the direct binding targets of cel in cerebral I/R. By combining various experimental methods, including tandem mass tag (TMT) labeling, mass spectrometry, and cellular thermal shift assay (CETSA), we revealed the targets to which cel directly bound to exert neuroprotective effects.
Results
We found that cel inhibited the proinflammatory activity of high mobility group protein 1 (HMGB1) by directly binding to it and then blocking the binding of HMGB1 to its inflammatory receptors in the microenvironment of ischemia and hypoxia. In addition, cel rescued neurons from OGD injury in vitro and decreased cerebral infarction in vivo by targeting HSP70 and NF-κB p65.
Conclusion
Cel exhibited neuroprotective and anti-inflammatory effects by targeting HSP70 and NF-κB p65 and directly binding to HMGB1 in cerebral I/R injury.
Funder
the fundamental research funds for the central public welfare research institutes
the Major National Science and Technology Program of China for Innovative Drug
the national key research and development program of china
national natural science foundation of china
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience
Cited by
31 articles.
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