Elsevier

Neuroscience

Volume 435, 21 May 2020, Pages 1-9
Neuroscience

Research Article
Musk Ketone Induces Neural Stem Cell Proliferation and Differentiation in Cerebral Ischemia via Activation of the PI3K/Akt Signaling Pathway

https://doi.org/10.1016/j.neuroscience.2020.02.031Get rights and content

Highlights

  • The role of musk ketone in cerebral ischemia is investigated.

  • NSC proliferation and differentiation reduces cerebral ischemic injury.

  • Musk ketone promotes NSC proliferation and differentiation.

  • Musk ketone is neuroprotective in cerebral ischemia injury via PI3K/Akt activation.

  • This study provides a novel therapeutic target for the treatment of cerebral ischemia.

Abstract

Traditional Chinese medicine has been reported to influence the proliferation and differentiation of neural stem cells (NSCs) that may be protective against nervous system diseases. Recent evidence indicates the importance of musk ketone in nerve recovery and preventing secondary damage after cerebral ischemic injury. A middle cerebral artery occlusion (MCAO) rat model was established by a transient filament model, and rats were treated with musk ketone (0.9 or 1.8 μM). Next, an in vitro oxygen-glucose deprivation (OGD) cell model was established to study the effect of musk ketone on the proliferation and differentiation of NSCs. To determine the potential mechanisms of musk ketone involved in activities of NSCs, the effect of musk ketone on the PI3K/Akt signaling pathway activation was assessed. Furthermore, NSCs were treated with musk ketone in the presence of PI3K/Akt inhibitor Akti-1/2 to examine their roles on NSC proliferation and differentiation. Musk ketone reduced cerebral ischemic injury in a dose-dependent manner in rats. In addition, NSCs treated with musk ketone showed enhanced proliferation and differentiation along with increased PI3K/Akt signaling pathway activation. The effects of muck ketone were reversed by Akti-1/2. Altogether, musk ketone promoted NSC proliferation and differentiation and protected against cerebral ischemia by activating the PI3K/Akt signaling pathway, highlighting the potential of musk ketone as a physiologically validated approach for the treatment of cerebral ischemia.

Introduction

Cerebral ischemia remains a formidable challenge in clinical neuroscience (Zhou et al. 2016) and it is a leading cause of death and permanent disability worldwide (Damodaran et al., 2014, Kaviarasi et al., 2019). Multiple risk factors are associated with cerebral ischemia, such as age, sex, hypertension, and diabetes mellitus (Soler and Ruiz 2010). Despite recent advances in the understanding of ischemic injury, current approaches to enhance neurological recovery remain inadequate (Merino et al. 2017). Neural stem cells (NSCs) normally replenish the adult brain with new neurons, and therefore, may present an endogenous repair mechanism after cerebral ischemia (Dong et al. 2012). Importantly, cerebral ischemia has been shown to induce NSC proliferation and differentiation in rodent and human brains (Chen et al. 2010). Therefore, it is crucial to understand the potential mechanisms by which NSCs may be an emerging treatment for cerebral ischemia.

Musk is a commonly used but rare material in traditional Chinese medicine (Ye et al. 2011). Ketone found in musk has been shown to protect cardiac myocytes from ischemia-reperfusion injury (Api et al., 1996, Wu et al., 2011). In the brain, musk ketone is neuroprotective against stroke injury through inhibition of cell apoptosis (Wei et al. 2012). Therefore, the exact mechanism by which musk ketone may be beneficial to neuronal recovery deserves further investigation.

The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, involved in the regulation of cell proliferation and differentiation, has been documented to protect NSCs against oxidative damage (Yu and Cui, 2016, Yan et al., 2017). Activation of the PI3K/Akt signaling pathway has been implicated in neuroprotective effects of various agents against ischemia reperfusion injury (Xu et al., 2008, Lu et al., 2014). In the light of the findings cited above, we hypothesized that the PI3K/Akt signaling pathway is involved in the neuroprotective effects of musk ketone.

Section snippets

Ethics statement

All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (8th Edition, National Research Council, 2011) and approved by the Ethics Committee in Guangxi University of Chinese Medicine.

Experimental animals

Male Sprague Dawley (SD) rats (n = 48, 220–240 g) which were supplied by Animal Centre of Guangxi Medical University, were randomly divided into 4 groups: sham (n = 12), middle cerebral artery occlusion (MCAO, n = 12) only, MCAO + musk ketone (Nanjing Fusu

Musk ketone reduces ischemic brain injury

Neurological deficit score was 0 in the sham group (Fig. 1A), indicating no behavioral impairment. Rats treated with 1.8 μM or 0.9 μM musk ketone had reduced neurological deficit scores when compared with untreated MCAO rat models (p < 0.05). Consistently, no infarcted area was found in sham-operated rats (Fig. 1B, C). Rats treated with 1.8 μM or 0.9 μM musk ketone had significantly lower infarct volume than MCAO rat models (p < 0.05). Moreover, average fluorescence intensity of BrdU was

Discussion

Cerebral ischemia also activates NSCs that may be a protective mechanism; however, the mechanism by which NSCs are activated is not fully determined (Horie et al. 2008). Therefore, obtaining a better understanding of the mechanism NSC activation is critical to improve treatment for cerebral ischemic injury. A number of traditional Chinese medicines or formulas have been reported to be related to the proliferation and differentiation of neural cells (Wang et al., 2007, Tian et al., 2010, Hao et

Conflicts of interest

None.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81760413 and No. 81760902); Research on Key Technologies and Trial Production of New Products in Liuzhou City (No. 2016G020213); Guangxi Natural Science Foundation (No. 2017GXNSFBA198114).

Acknowledgments

We acknowledge and appreciate our colleagues for their valuable efforts and comments on this paper.

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