Hydroxysafflor yellow A promotes the proliferation and differentiation of endogenous neural stem cells with neural regenerative effects in ischemic stroke

Abstract

Background: Ischemic stroke induced irreversible damage or loss of neurons, severely causing high death rates. Natural medicine has rapidly risen for stroke therapy. Given the activation of neural cells, it is crucial to reveal the neuroregulation and molecular mechanisms of natural medicine for developing effective therapeutical approaches for stroke. Safflower is recommended widely in traditional Chinese medicine for the treatment of ischemic stroke. However, hydroxysafflor yellow A (HSYA) as a bioactive component of safflower underlying its neurogenic effects remains largely unknown.

Purpose: We aimed to study the role and underlying mechanisms of HSYA in regulating neural stem cell (NSC) behaviors and endogenous neural regeneration after stroke.

Methods: CCK-8 assay was performed to detect cell viability. Immunofluorescent staining, RT-qPCR, and western blot were employed to verify the effects of HSYA on cell proliferation and differentiation of NSCs. Finally, the transient middle cerebral artery occlusion-reperfusion (MCAO/R) model, neurofunctional test, laser speckle imaging system, TTC staining, western blot and immunohistochemistry were used to investigate brain injury repair and endogenous neural regeneration in MACO/R rats treated with HSYA.

Results: HSYA could noticeably promote the proliferation and differentiation of NSCs in vitro. Meanwhile, the therapeutic effect of HSYA on MCAO/R rats was evaluated using edaravone as a positive drug. The behavioral functions, infarcted volume, brain water content and apoptosis Nissl bodies of MCAO/R rats were significantly improved after HSYA treatment. Also, HSYA showed neuroprotective, endogenous neural regeneration, blood flow recanalization potential and motor function reconstruction in vivo, as evidenced by enhancement of the neurological function recovery, promotion of endogenous neurogenesis and astrogenesis, and increase of the cerebral blood flow.

Conclusions: HSYA could promote NSC proliferation and neuronal differentiation in vitro, and regulate endogenous neural regeneration post-stroke, providing a novel strategy for investigating the neural effects of natural medicine in stroke therapy. More importantly, the mechanism of HSYA on NSC proliferation and endogenous neurogenesis was revealed in this work.

Keywords: Functional recovery; Hydroxysafflor yellow A; Ischemic stroke; Neural regeneration; Neural stem cells.