BACKGROUND AND PURPOSE

Ischaemic stroke is a leading cause of death and long-term disability. Promising neuroprotective compounds are urgently needed to overcome clinical therapeutic limitations. Neuroprotective agents are limited to single-target agents, which further limit theirclinical effectiveness. Due to the brain’s particular energy requirements, the energy micro-environment, centred in mitochondria,is a new research hotspot in the complex pathology of ischaemic stroke. Here, we studied the effects of neferine (Nef), a bis-benzylisoquinoline alkaloid extracted from the seed embryo of Nelumbo nuciferaGaertn, on ischaemic stroke and its underlyingmitochondrial protective mechanisms.

EXPERIMENTAL APPROACH

Rats with permanent middle cerebral artery occlusion (pMCAO)-induced focal cerebral ischaemia andtert-butyl hydroperoxide(t-BHP)-injured PC12 cells were used to investigate the neuroprotective effects of Nef, particularly with regard to energymicro-environment regulation by mitochondria and its mechanismin vivoandin vitro.

KEY RESULTS

Nef protected t-BHP-injured PC12 cellsin vitro and ameliorated neurological score, infarct volume, regional cerebral blood flow,cerebral microstructure and oxidant-related enzyme deficits in pMCAO rats in vivo. Nef also prevented mitochondrial dysfunction both in vivo and in vitro. The underlying mechanism of the mitochondrial protective effect of Nef might be attributed to theincreased translocation of Nrf2 to the nucleus. Furthermore, the translocation of Nrf2 to nucleus was also decreased bysequestosome 1 (p62) knockdown.

CONCLUSIONS AND IMPLICATIONS

Our results demonstrated that Nef might have therapeutic potential for ischaemic stroke and may exert its protective role throughmitochondrial protection. This protection might be attributed to the modulation of Nrf2 signalling.