The Discovery of Novel PGK1 Activators as Apoptotic Inhibiting and Neuroprotective Agents

Abstract

Stroke is the second leading cause of death worldwide and the leading cause of long-term disability that seriously endangers health and quality of human life. Tissue-type fibrinogen activator is currently the only drug approved by FDA for the treatment of ischemic stroke. Neuroprotection is theoretically a common strategy for the treatment of both ischemic and hemorrhagic stroke; therefore, the development of neuroprotective agent has been the focus of research. However, no ideal neuroprotective drug is clinically available. Phosphoglycerate kinase-1 (PGK1) activator has the effect of inhibiting apoptosis and protecting tissue damage, and therefore could be a potential neuroprotective agent. To obtain effective PGK1 activators, we virtually screened a large chemical database and their evaluated the efficacy by the Drosophila oxidative stress model, PGK1 enzymatic activity assay, and oxygen-glucose stripping reperfusion (OGD/R) model. The results showed that compounds 7979989, Z112553128 and AK-693/21087020 are potential PGK1 activators with protective effects against PQ-induced oxidative stress in the Drosophila model and could effectively ameliorate apoptosis induced by OGD/R-induced neuronal cell injury. Additionally, compounds 7979989 and Z112553128 are effective in alleviating LPS-induced cellular inflammation. This study indicated that these compounds are promising lead compounds that provide theoretical and material basis to the neuroprotective drug discovery.

Dysfunction of astrocytic glycophagy exacerbates reperfusion injury in ischemic stroke

“…One study indicated that many glycolytic enzymes are repressed in astrocytes treated with I/R [ 45 ]. Novel drugs aimed at enhancing astrocytic glycolysis appear to be neuroprotective against reperfusion injury after ischemic stroke [ 46 , 47 ]. The development of new approaches to restore glycolytic flux may amplify the neuroprotective effects of glycophagy-liberated glucose on astrocytes by transforming astrocytic glucose metabolism to a more balanced state.…”