Mitochondrial protective effect of neferine through the modulation of Nrf2 signalling in ischemic stroke.

OBJECTIVE

Ischemic stroke is a leading cause of death and long-term disability. Promising neuroprotective compounds are urgently needed to overcome the clinical therapeutic limitations. Neuroprotective agents are limited to single-target agents, which further limited their clinical effectiveness. Due to the brain particular energy requirements, the energy microenvironment, centred in the mitochondria, is a new research hotspot in the complex pathology of ischemic stroke. Here, we studied the effects of neferine (Nef), a bis-benzylisoquinoline alkaloid extracted from the seed embryo of Nelumbo Nucifera Gaertn, on ischemic stroke and its underlying mitochondrial protective mechanisms.

METHODS

Permanent middle cerebral artery occlusion (pMCAO)-induced focal cerebral ischemia rats and tert-butyl hydroperoxide (t-BHP)-injured PC12 cells were used to investigate the neuroprotective effects, particularly regarding energy microenvironment regulation by mitochondria and the 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 enzyme deficits in pMCAO rat in vivo. Nef 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 p62 knockdown.

CONCLUSIONS

The data in this study demonstrated that Nef might have therapeutic potential for ischemic stroke and may exert its protective role through mitochondrial protection. In addition, this protection might be attributed to the modulation of Nrf2 signalling.