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.
Highlights
Accumulating studies revealed that cerebral I/R injury involves a series of pathological events such as inflammation, oxidative stress, and metabolic dysfunction [6, 7]
The results of triphenyltetrazolium chloride (TTC) staining showed there was no cerebral infarction observed in the sham group, while the cerebral infarct volume was obviously increased in mice subjected to transient middle cerebral artery occlusion (tMCAO)
Induced glycolysis was significantly inhibited by celastrol at 24 h after reperfusion, which was evidenced by lower glucose consumption, less lactate accumulation, more ATP production, and downregulations of glycolysis-related key enzymes including lactate dehydrogenase A (LDHA), HK2, and Glut1. These results revealed that the neuroprotective effect of celastrol on cerebral I/R injury was closely associated with inhibition of glycolysis in the first 24 hours, but the effect of celastrol on glycolysis at different stages of cerebral ischemia and the glycolysisregulating effect to the outcome of I/R injury still need further research to unveil
Summary
Stroke is one of the major causes of disability and death around the world and brings heavy burden to the society [1, 2]. The use of recombinant tissue plasminogen activator (r-tPA) to quickly restore the cerebral blood supply is an effective strategy for relieving ischemic brain injury [4, 5]. Accumulating studies revealed that cerebral I/R injury involves a series of pathological events such as inflammation, oxidative stress, and metabolic dysfunction [6, 7]. Neurons mainly use most of the glucose to produce ATP through the pentose-phosphate pathway (PPP), while the glycolysis state is low [11]. Enhancement of glycolysis can lead to higher glucose consumption, more lactic acid accumulation, and less ATP production, which accelerates neuronal death [13]. It is reported that attenuating hyperglycolysis by inhibition of PFKFB3 activity resulted in the reduction of NADPH oxidation, redox stress, and apoptotic cell death in oxygen and glucose-deprived primary neurons [14]. The inhibition of glycolysis may represent an effective option for the treatment of cerebral I/R injury
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