Corilagin attenuates high glucose-induced neurotoxicity and mitochondrial dysfunction through restoration of the AMPK-SIRT1-PGC1α-TFAM signalling axis

Mitochondrial dysfunction and oxidative stress represent two interconnected, primary causes for Diabetic Neuropathy (DN); however, the majority of currently available anti-diabetic therapies have focused on glucose control as opposed to neurodegenerative downstream effects. Corilagin, is an ellagitannin having high anti-oxidant properties; however, it has not been evaluated against hyperglycemia induced neuronal injury. The present study demonstrates the ability of Corilagin to protect against mitochondrial dysfunction via models of diabetic nephropathy and cerebral ischemia. High glucose (50 mM, 24 hr) was utilized to induce diabetes like conditions in the SH-SY5Y human neuroblastoma Cell Line. High glucose induced significant decreases in cell viability, increases in intracellular and mitochondrial reactive oxygen species, depletion of reduced glutathione reserves, induces apoptosis, and causes mitochondrial depolarization and fragmentation. Corilagin pre-treatment attenuated each of these high-glucose induced effects by protecting against mitochondrial membrane potential loss and maintaining mitochondrial network morphology while reducing apoptotic cell fraction relative to glucose alone. Additionally, these protective effects were accompanied by restoration of AMPK phosphorylation and up-regulation of SIRT1, PGC1α and TFAM, components that are part of the principal signaling pathway that regulates mitochondrial biogenesis; therefore, therefore, this pathway may contribute mechanistically to the cyto-protective effect of Corilagin. Graphical abstract

Proposed mechanism underlying the neuroprotective effects of Corilagin against high glucose-induced mitochondrial dysfunction.

High glucose suppresses AMPK phosphorylation, leading to downregulation of the SIRT1–PGC-1α–TFAM signaling axis, increased intracellular and mitochondrial reactive oxygen species (ROS), glutathione depletion, apoptosis, mitochondrial depolarization, and mitochondrial fragmentation. Corilagin pretreatment restores AMPK activation and the downstream SIRT1–PGC-1α–TFAM pathway, thereby reducing oxidative stress, preserving intracellular glutathione, preventing apoptosis, maintaining mitochondrial membrane potential, and protecting mitochondrial network integrity.