Lipidomic Profiling of Ipsilateral Brain and Plasma after Celastrol Post-Treatment in Transient Middle Cerebral Artery Occlusion Mice Model

Abstract

Celastrol, a pentacyclic triterpene isolated from the traditional Chinese medicine Tripterygium wilfordii Hook. F., exhibits effectiveness in protection against multiple central nervous system (CNS) diseases such as cerebral ischemia, but its influence on lipidomics still remains unclear. Therefore, in the present study, the efficacy and potential mechanism of celastrol against cerebral ischemia/reperfusion (I/R) injury were investigated based on lipidomics. Middle cerebral artery occlusion (MCAO) followed by reperfusion was operated in mice to set up a cerebral I/R model. TTC staining and TUNEL staining were used to evaluate the therapeutic effect of celastrol. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) was employed for lipidomics analysis in ipsilateral hemisphere and plasma. Celastrol remarkably reduced cerebral infarct volume and apoptosis positive cells in tMCAO mice. Furthermore, lipidomics analysis showed that 14 common differentially expressed lipids (DELs) were identified in brain and five common DELs were identified in plasma between the Sham, tMCAO and Celastrol-treated tMCAO groups. Through enrichment analysis, sphingolipid metabolism and glycerophospholipid metabolism were demonstrated to be significantly enriched in all the comparison groups. Among the DELs, celastrol could reverse cerebral I/R injury-induced alteration of phosphatidylcholine, phosphatidylethanolamine and sulfatide, which may be responsible for the neuroprotective effect of celastrol. Our findings suggested the neuroprotection of celastrol on cerebral I/R injury may be partially associated with its regulation of lipid metabolism.

The therapeutic potential of triptolide and celastrol in neurological diseases

“…In another study, researchers analyzed the profiles of LncRNAs and mRNAs following celastrol treatment of MCAO by RNA-sequencing and bioinformatic analysis and experimentally verified the significantly different LncRNAs and mRNAs ( Liu J. et al, 2022 ). Liu et al used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) to perform lipidomic analysis after celastrol treatment of MCAO and obtained some differentially expressed components ( Liu M. et al, 2021 ). These studies have provided a theoretical basis for subsequent in-depth investigations.…”

Effect of Celastrol on LncRNAs and mRNAs Profiles of Cerebral Ischemia-Reperfusion Injury in Transient Middle Cerebral Artery Occlusion Mice Model

“…What’s interesting, the KEGG pathway analysis also suggested that lipid metabolism may play a potential role in neuroprotection of celastrol. More recently, a study found lipid metabolism partially regulated the neuroprotection of celastrol on cerebral I/R injury through the lipidomic analysis ( Liu M. et al, 2021 ), but the underlying mechanism need further investigation.…”

“…The brain slices were scanned and the infarct size was analyzed using Image J software (National Institutes of Health, Bethesda, MD, United States) by researchers who were blinded to the study group. In order to exclude the effect of cerebral edema, the following calculation formula was used: (contralateral hemisphere area–ipsilateral non-ischemic hemisphere area)/contralateral hemisphere area × 100% ( Liu M. et al, 2021 ). Five male mice were used in each group.…”

Neuroprotective Effects of Celastrol in Neurodegenerative Diseases-Unscramble Its Major Mechanisms of Action and Targets

“…In our recent study, we presented evidence that celastrol directly bound to HMGB1 to inactivate it, up-regulated HSP70 and down-regulated NF-κB expression to play a neuroprotective effect in cerebral ischemia-reperfusion (I/R) injury in vitro and in vivo [ 27 ]. Lipidomics and enrichment analysis after MCAO model in mice showed that celastrol exhibited neuroprotection and anti-apoptosis effects partially by modulating lipid metabolites in sphingolipid and glycerophospholipid metabolism pathways [ 70 ]. Celastrol significant attenuated I/R-induced hippocampal injury by inhibiting the AK005401/MAP3K12 signaling and activating the PI3K/Akt pathway [ 71 ].…”