Mitochondrial protective effect of Neferine through the modulation of Nrf2 signaling in ischemic stroke

抄録

Background: Ischemic stroke is a leading cause of death and long-term disability. Promising neuroprotective compounds is urgent needed to break the clinical therapeutic limitation. Due to the brain energy particularity requirement, energy microenvironment, centered by mitochondrion is a new research hotspot in the ischemic stroke complex pathology. Neuroprotective agents, which are limited single target agents, and further limited their clinical effectiveness. Here, we studied the effect of Neferine (Nef), a bis-benzylisoquinline alkaloid extracted from the seed embryo of Nelumbo Nucifera Gaertn, on ischemic stroke and its underlying mitochondrial protective mechanism.

Methods: Permanent middle cerebral artery occlusion (pMCAO)-induced focal cerebral ischemia rats and tert-butyl hydroperoxide (t-BHP) injured PC12 cells were used to interpret the neuroprotective effect, especially energy microenvironment regulation by mitochondrion and mechanism of Nef in vivo and in vitro.

Results: Nef protected t-BHP injured PC12 cells in vitro and ameliorated neurological score, infarct volume, regional cerebral blood flow, cerebral microstructure and oxidant related enzymes in pMCAO rat in vivo. It also prevented mitochondrial dysfunction both in vivo and in vitro. The underlying mechanism of mitochondrial protective effect of Nef might be attributed to the increased translocation of Nrf2 to nucleus. Furthermore, the translocation of Nrf2 to nucleus was also decreased by the knocked down of p62.

Conclusions: These data in this study demonstrated that Nef might have therapeutic potential for ischemic stroke and play its protective role through mitochondrial protection. And this protection might be attributed to the modulation of Nrf2 signaling.