Hydroxysafflor Yellow A Alleviates Ischemic Stroke in Rats via HIF-1α, BNIP3, and Notch1-Mediated Inhibition of Autophagy

Abstract

Stroke has become a major cause of death and disability worldwide. The cellular recycling pathway autophagy has been implicated in ischemia-induced neuronal changes, but whether autophagy plays a beneficial or detrimental role is controversial. Hydroxysafflor Yellow A (HSYA), a popular herbal medicine, is an extract of Carthamus tinctorius and is used to treat ischemic stroke (IS) in China. HSYA has been shown to prevent cardiovascular and cerebral ischemia/reperfusion injury in animal models. However, the specific active ingredients and molecular mechanisms of HSYA in IS remain unclear. Here, we investigated the effect of HSYA treatment on autophagy in a rat model of IS. IS was induced in rats by middle cerebral artery occlusion. Rats were treated once daily for 3 days with saline, HYSA, or the neuroprotective agent Edaravone. Neurobehavioral testing was performed on days 1, 2, and 3 post-surgery. Brains were removed on day 3 post-surgery for histological evaluation of infarct area, morphology, and for qRT-PCR and western blot analysis of the expression of the autophagy factor LC3 and the signaling molecules HIF-1[Formula: see text], BNIP3, and Notch1. Molecular docking studies were performed in silico to predict potential interactions between HSYA and LC3, HIF-1[Formula: see text], BNIP3, and Notch1 proteins. The result showed that HSYA treatment markedly alleviated IS-induced neurobehavioral deficits and reduced brain infarct area and tissue damage. HSYA also significantly reduced hippocampal expression levels of LC3, HIF-1[Formula: see text], BNIP3, and Notch1. The beneficial effect of HSYA was generally superior to that of Edaravone. Molecular modeling suggested that HSYA may bind strongly to HIF-1[Formula: see text], BNIP3, and Notch1 but weakly to LC3. In conclusion, HSYA inhibits post-IS autophagy induction in the brain, possibly by suppressing HIF-1[Formula: see text], BNIP3 and Notch1. HSYA may have utility as a post-IS neuroprotective agent.

Network pharmacology and experimental study of phenolic acids in salvia miltiorrhiza bung in preventing ischemic stroke

“…(Pan et al, 2021). The underlying mechanisms of HIF-1 regulated stroke including apoptotic (Cheng et al, 2014), neurogenesis (Wu et al, 2018), BBB integrity (Liu et al, 2021b) inflammation (Pan et al, 2021), autophagy (Xie et al, 2022;Zhang et al, 2022), and oxidative stress (Peng et al, 2020). However, the effect of HIF-1 was doublesided and may be related to the time and degree of ischemia.…”

Protective potential of hydroxysafflor yellow A in cerebral ischemia and reperfusion injury: An overview of evidence from experimental studies

“…In MCAO rats, Qi et al (2014) found that HSYA promoted autophagy in the penumbra through activating AKT-dependent autophagy pathway, which was subsequently verified as a potential mechanism in the HSYA-mediated neuroprotection. In contrast, Yang et al (2018) ; Zhang et al (2022) observed that HSYA inhibited autophagy following ischemia for exerting neuroprotection in OGD/R-insulted BMECs and MCAO rats, which is inconsistent with the observation of Qi et al A body of studies has demonstrated that autophagy increases in cerebral I/R injury, and both harmful and protective potentials of autophagy have been reported ( Wang et al, 2013 ; Luo et al, 2014 ). Yang et al (2018) found that HSYA suppressed excessive autophagy evoked by OGD/R injury in BMECs and such inhibition was partially associated with the activation of Class I PI3K/AKT/mTOR pathway.…”

“… Yang et al (2018) found that HSYA suppressed excessive autophagy evoked by OGD/R injury in BMECs and such inhibition was partially associated with the activation of Class I PI3K/AKT/mTOR pathway. Similarly, Zhang et al (2022) revealed that HSYA suppressed autophagy induced by brain ischemia probably through limiting the expressions of HIF-1, BNIP3 and Notch 1. All together, these results demonstrate that HSYA may regulate autophagy induced by cerebral I/R injury via activating AKT-related pathway and the Class I PI3K/AKT/mTOR pathway, as well as decreasing the expressions of HIF-1, BNIP3 and Notch 1.…”

Neutrophil membrane fusogenic nanoliposomal leonurine for targeted ischemic stroke therapy via remodeling cerebral niche and restoring blood-brain barrier integrity

“…Hypoxia-inducible factor-1 alpha (HIF-1α) is a sensitive regulator of oxygen homeostasis and plays divergent roles in the pathophysiology of IS, which is sophisticatedly regulated by the spatiotemporal expression [ 38 ]. Recent studies showed that elevated HIF-1α level compromised BBB integrity in the acute phase of IS through tight junctions (TJs) alterations in hypoxic conditions [ [39] , [40] , [41] ]. Consistent with previous reports, significantly elevated expression of HIF-1α was observed in tMCAO rats after 72 ​h reperfusion, which was 2-fold that of the sham group ( Fig.…”