Celastrol Protects against Cerebral Ischemia/Reperfusion Injury in Mice by Inhibiting Glycolysis through Targeting HIF-1α/PDK1 Axis

Abstract

Cerebral ischemia/reperfusion (I/R) injury is closely related to dysfunctional glucose metabolism. Celastrol is a bioactive compound that has been found to exhibit neuroprotective effects in cerebral ischemia, while whether it can protect against cerebral I/R injury by regulating glycolysis remains unclear. The goal of this study is to investigate the role of celastrol on cerebral I/R injury and its underlying mechanisms in transient middle cerebral artery occlusion (tMCAO) mice. Methods. To observe the protective effect of celastrol and select its optimal dosage for further study, neurological score, TTC staining, and HE staining were used to evaluate neurological function, cerebral infarct volume, and cortical cell damage, respectively. QRT-PCR and Western blot were used to detect the mRNA and protein expression of hypoxia inducible factor-1α (HIF-1α), pyruvate dehydrogenasekinase1 (PDK1), lactate dehydrogenase A (LDHA), glucose transporter1 (GLUT1), and hexokinase2 (HK2), respectively. The lactate production, ATP level, and glucose content were assessed by assay kits. Results. Our results indicated that celastrol dose-dependently improved neurological function and reduced cerebral infarct volume and cortical cell death of tMCAO mice, and its optimal dosage was 4.5 mg/kg. In addition, celastrol significantly blocked I/R-induced increase of LDHA, GLUT1, HK2, and lactate production as well as decrease of ATP level and glucose content. Moreover, celastrol inhibited the I/R-induced upregulation of HIF-1α and PDK1. Overexpression of HIF-1α by DMOG reversed the protective effect of celastrol on cerebral I/R injury and blocked celastrol-induced suppression of glycolysis. Conclusions. Taken together, these results suggested that celastrol protected against cerebral I/R injury through inhibiting glycolysis via the HIF-1α/PDK1 axis.

The therapeutic potential of triptolide and celastrol in neurological diseases

“…In addition, glycolysis plays a role in the pathogenesis of cerebral ischemia, and some studies have found that inhibition of excessive glycolysis can protect neurons against OGD ( Burmistrova et al, 2019 ; Vojinovic et al, 2020 ). Chen et al reported that celastrol inhibited hypoxia inducible factor-1α (HIF-1α)/pyruvate dehydrogenasekinase1 (PDK1), thus attenuating glycolysis and exerting neuroprotection ( Chen et al, 2022 ). Besides that, studies of long noncoding RNAs (LncRNAs) have received much attention in recent years.…”

“…attenuating glycolysis. Celastrol attenuates glycolysis and exerts neuroprotection by inhibiting HIF-1α/PDK1 pathway ( Chen et al, 2022 ), e). suppressing NOX activation and rapid H 2 O 2 release.…”

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

“…Mice were re-anesthetized and sacrificed 24 h after tMCAO. The concentration of celastrol used in the experiment was based on the concentration reported in previous study ( Chen et al, 2022 ).…”

Circular RNA PUM1 performs as a competing endogenous RNA of microRNA-340-5p to mediate DEAD-box helicase 5 to mitigate cerebral ischemia-reperfusion injury

“…The primer sequences (Sangon Biotech) are clarified in Table 1 . Gene expression was assessed by the 2 −ΔΔCt method [ 30 ].…”