Research ArticleMusk Ketone Induces Neural Stem Cell Proliferation and Differentiation in Cerebral Ischemia via Activation of the PI3K/Akt Signaling Pathway
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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These authors contributed equally to this work.