Figure 6. Proposed mechanism of MB-induced neuronal protection against ischemia and reperfusion injury.

1) Ischemia and/or reperfusion damages cells and tissues by increased ROS and energy depletion which mediated by mitochondrial damage. 2) MB preserves mitochondria function, and increases intracellular O₂ concentration and glucose uptake which culminate in restoration of ATP. 3) Increased energy production increases endogenous pyruvate and other glycolytic metabolites, which stabilize HIF-1α . Additionally, 4) MB enhances nuclear translocation of HIF-1α followed by activation of HIF-1. 5) HIF-1 activation stimulates several protein synthesis, including EPO. Activated EPO in turn activate mTOR signaling pathway. Activated mTOR transcriptionally increases HIF-1α. Therefore, MB could make HIF-1 being involved with protection of HT22 cells against ischemia-reperfusion injury. HIF-1α: Hypoxia inducible factor-1α;EPO: Erythroppietin; mTOR: mammalian target of Raoanycin; ROS: reactive oxygen species; ↓ Positive effect; ↓ Negative effect; * Activation.