Mitochondrial protective effect of neferine through the modulation of nuclear factor erythroid 2‐related factor 2 signalling in ischaemic stroke

Abstract

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 their clinical 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 nucifera Gaertn, on ischaemic stroke and its underlying mitochondrial protective mechanisms. Experimental Approach Rats with permanent middle cerebral artery occlusion (pMCAO)‐induced focal cerebral ischaemia and tert‐butyl hydroperoxide (t‐BHP)‐injured PC12 cells were used to investigate the neuroprotective effects of Nef, particularly with regard to energy micro‐environment regulation by mitochondria and its mechanism in vivo and in vitro. Key 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 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 the increased translocation of Nrf2 to the nucleus. Furthermore, the translocation of Nrf2 to nucleus was also decreased by sequestosome 1 (p62) knockdown. Conclusions and Implications Our results demonstrated that Nef might have therapeutic potential for ischaemic stroke and may exert its protective role through mitochondrial protection. This protection might be attributed to the modulation of Nrf2 signalling.

Luteolin Exerts Neuroprotection via Modulation of the p62/Keap1/Nrf2 Pathway in Intracerebral Hemorrhage

“…In addition, luteolin has been found to enhance autophagy in studies of other diseases (Xu et al, 2014;Hu et al, 2016;Cao et al, 2017). Additionally, the administration of autophagic inhibitors such as CQ, has been shown to be associated with exacerbating disease progression (Yang et al, 2018a;Wu et al, 2019). These findings are consistent with our present results, such that we found that luteolin enhanced autophagy and activated the p62/Keap1/Nrf2 pathway, and this effect was reversed by the autophagic inhibitor, CQ, in our ICH model ( Figure 7).…”

“…The results of related studies have indicated that by physically isolating Keap1 and impairing the ubiquitylation of Nrf2, p62 mediates the activation of Nrf2 and its downstream pathways and plays an important role in antioxidative processes (Jiang et al, 2015). In the process of exploring new drugs, up-regulation of autophagy has been found in numerous disease-model studies (Yang et al, 2018a;Rusmini and Cortese, 2019) and activation of the p62/Keap1/Nrf2 pathway has been shown to play a role in alleviating systemic diseases (Sun et al, 2016;Su et al, 2018) and in ameliorating brain injury, such as ischemic stroke (Wu et al, 2019). Our present findings were similar to those described above.…”

Neferine improves oxidative stress and apoptosis in benign prostate hyperplasia via Nrf2-ARE pathway.

“…Neferine has been reported as antioxidant [ 17 ], anti-tumor [ 18 ], anticancer [ 19 ], antidepressant [ 20 ], autophagy inducer [ 21 ], anti-inflammation [ 22 ] and, anti-diabetic [ 23 ]. The study shows that NF is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2) activator [ 24 ] which can reduce oxidative stress. Sulforaphane, a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is a potent Nrf2 activator and potentially used as anti-cancer therapy [ 25 , 26 ].…”

Activation of Nrf2 by Natural Bioactive Compounds: A Promising Approach for Stroke?

“…Interestingly, Nef induced also autophagy and an association between Nrf2 and autophagy was suggested. In particular, the pathway p62/Keap1/Nrf2 seemed to have a role in Nrf2 activation [ 126 ].…”