Scutellarin may alleviate cognitive deficits in a mouse model of hypoxia by promoting proliferation and neuronal differentiation of neural stem cells

Document Type : Original Article

Authors

1 Department of Cardiology,China

2 Key Laboratory of Stem Cells and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University,PR

3 Department of Anatomy and Development Biology, Monash, Clayton, Australia

4 The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, PR China

5 Mental Health Center of Kunming Medical University, Kunming City, Yunnan Province, PR China

Abstract

Objective(s): Scutellarin, a flavonoid extracted from the medicinal herb Erigeron breviscapus Hand-Mazz, protects neurons from damage and inhibits glial activation. Here we examined whether scutellarin may also protect neurons from hypoxia-induced damage.
Materials and Methods: Mice were exposed to hypoxia for 7 days and then administered scutellarin (50 mg/kg/d) or vehicle for 30 days Cognitive impairment in the two groups was assessed using the Morris water maze test, cell proliferation in the hippocampus was compared using 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry, and hippocampal levels of nestin and neuronal class III β-tubulin (Tuj-1) were measured using Western blotting. These results were validated in vitro by treating cultured neural stem cells (NSCs) with scutellarin (30 μM).
Results: Treating mice with scutellarin shortened escape times and increased the number of platform crossings, it increased the number of BrdU-positive proliferating cells in the hippocampus, and it up-regulated expression of nestin and Tuj-1. Treating NSC cultures with scutellarin increased the number of proliferating cells and the proportion of cells differentiating into neurons instead of astrocytes. The increase in NSC proliferation was associated with phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, while neuronal differentiation was associated with altered expression of differentiation-related genes.
Conclusion: Scutellarin may alleviate cognitive impairment in a mouse model of hypoxia by promo-ting proliferation and neuronal differentiation of NSCs.

Keywords


1. Sola S, Aranha MM, Rodrigues CM. Driving apoptosis-relevant proteins toward neural differentiation. Mol Neurobiol 2012; 46:316-331.
2. Suh H, Deng W, Gage FH. Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 2009; 25:253-275.
3. Acharya MM, Martirosian V, Chmielewski NN, Hanna N, Tran KK, Liao AC, et al. Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction. Cancer Res 2015; 75:676-686.
4. Marei HE, Farag A, Althani A, Afifi N, Abd-Elmaksoud A, Lashen S, et al. Human olfactory bulb neural stem cells expressing hNGF restore cognitive deficit in Alzheimer's disease rat model. J Cell Physiol 2015; 230:116-130.
5. Hassanzadeh K, Nikzaban M, Moloudi MR, Izadpanah E. Effect of selegiline on neural stem cells differentiation: a possible role for neurotrophic factors. Iran J Basic Med Sci 2015; 18:549-554.
6. Yiming L, Wei H, Aihua L, Fandian Z. Neuroprotective effects of breviscapine against apoptosis induced by transient focal cerebral ischaemia in rats. J Pharm Pharmacol 2008; 60:349-355.
7. Wang S, Wang H, Guo H, Kang L, Gao X, Hu L. Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation. Neuroscience 2011; 185:150-160.
8. Guo LL, Guan ZZ, Huang Y, Wang YL, Shi JS. The neurotoxicity of beta-amyloid peptide toward rat brain is associated with enhanced oxidative stress, inflammation and apoptosis, all of which can be attenuated by scutellarin. Exp Toxicol Pathol 2013; 65:579-584.
9. Hong H, Liu GQ. Scutellarin protects PC12 cells from oxidative stress-induced apoptosis. J Asian Nat Prod Res 2007; 9:135-143.
10. Xu W, Zha RP, Wang WY, Wang YP. Effects of scutellarin on PKCgamma in PC12 cell injury induced by oxygen and glucose deprivation. Acta Pharmacol Sin 2007; 28:1573-1579.
11. Guo H, Hu LM, Wang SX, Wang YL, Shi F, Li H, et al. Neuroprotective effects of scutellarin against hypoxic-ischemic-induced cerebral injury via augmentation of antioxidant defense capacity. Chin J Physiol 2011; 54:399-405.
12. Liu M, Li H, Luo G, Liu Q, Wang Y. Pharmacokinetics and biodistribution of surface modification polymeric nanoparticles. Arch Pharm Res 2008; 31:547-554.
13. Wang WW, Lu L, Bao TH, Zhang HM, Yuan J, Miao W, et al. Scutellarin Alleviates Behavioral Deficits in a Mouse Model of Multiple Sclerosis, Possibly Through Protecting Neural Stem Cells. J Mol Neurosci 2016; 58:210-220.
14. Chai L, Guo H, Li H, Wang S, Wang YL, Shi F, et al. Scutellarin and caffeic acid ester fraction, active components of Dengzhanxixin injection, upregulate neurotrophins synthesis and release in hypoxia/-reoxygenation rat astrocytes. JEthnopharmacol 2013; 150:100-107.
15. Liu D, Wang Z, Zhan J, Zhang Q, Wang J, Zhang Q, et al. Hydrogen sulfide promotes proliferation and neuronal differentiation of neural stem cells and protects hypoxia-induced decrease in hippocampal neurogenesis. Pharmacol Biochem Behav 2014; 116:55-63.
16. Lin LL, Liu AJ, Liu JG, Yu XH, Qin LP, Su DF. Protective effects of scutellarin and breviscapine on brain and heart ischemia in rats. J Cardiovasc Pharmacol 2007; 50:327-332.
17. Jin G, Bai D, Yin S, Yang Z, Zou D, Zhang Z, et al. Silibinin rescues learning and memory deficits by attenuating microglia activation and preventing neuroinflammatory reactions in SAMP8 mice. Neurosci Lett 2016; 629:256-261.
18. Zhu YH, Zhang CW, Lu L, Demidov ON, Sun L, Yang L, et al. Wip1 regulates the generation of new neural cells in the adult olfactory bulb through p53-dependent cell cycle control. Stem Cells 2009; 27:1433-1442.
19. Wu XS, Bao TH, Ke Y, Sun DY, Shi ZT, Tang HR,            et al. Hint1 suppresses migration and invasion of hepatocellular carcinoma cells in vitro by modulating girdin activity. Tumour Biol 2016 ; 37:14711-14719.
20. Schwindt TT, Motta FL, Gabriela FB, Cristina GM, Guimaraes AO, Calcagnotto ME, et al. Effects of FGF-2 and EGF removal on the differentiation of mouse neural precursor cells. An Acad Bras Cienc 2009; 81:443-452.
21. Kim YH, Chung JI, Woo HG, Jung YS, Lee SH, Moon CH, et al. Differential regulation of proliferation and differentiation in neural precursor cells by the Jak pathway. Stem Cells 2010; 28:1816-1828.
22. Guo X, Lian R, Guo Y, Liu Q, Ji Q, Chen J. bFGF and Activin A function to promote survival and proliferation of single iPS cells in conditioned half-exchange mTeSR1 medium. Hum Cell 2015; 28:122-132.
23. Rietze RL, Valcanis H, Brooker GF, Thomas T, Voss AK, Bartlett PF. Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 2001; 412:736-739.
24. Wang PS, Wang J, Zheng Y, Pallen CJ. Loss of protein-tyrosine phosphatase alpha (PTPalpha) increases proliferation and delays maturation of oligodendrocyte progenitor cells. J Biol Chem 2012; 287:12529-12540.
25.Veazey KJ, Carnahan MN, Muller D, Miranda RC, Golding MC. Alcohol-induced epigenetic alterations to developmentally crucial genes regulating neural stemness and differentiation. Alcohol Clin Exp Res 2013; 37:1111-1122.
26. Kennea NL, Mehmet H. Neural stem cells. J Pathol 2002; 197:536-550.
27. Piao CS, Li B, Zhang LJ, Zhao LR. Stem cell factor and granulocyte colony-stimulating factor promote neuronal lineage commitment of neural stem cells. Differentiation 2012; 83:17-25.
28. Chu T, Zhou H, Wang T, Lu L, Li F, Liu B, et al. In vitro characteristics of valproic acid and all-trans-retinoic acid and their combined use in promoting neuronal differentiation while suppressing astrocytic differentiation in neural stem cells. Brain Res 2015;1596:31-47.
29. Eendebak RJ, Lucassen PJ, Fitzsimons CP. Nuclear receptors and microRNAs: Who regulates the regulators in neural stem cells. FEBS Lett 2011; 585:717-722.
30. Boissard CG, Lindner MD, Gribkoff VK. Hypoxia produces cell death in the rat hippocampus in the presence of an A1 adenosine receptor antagonist: an anatomical and behavioral study. Neuroscience 1992; 48:807-812.
31. Muthuraju S, Maiti P, Solanki P, Sharma AK, Amitabh, Singh SB, et al. Acetylcholinesterase inhibitors enhance cognitive functions in rats following hypobaric hypoxia. Behav Brain Res 2009; 203:1-14.
32. Chaparro E, Quiroga C, Erasso D, Bosco G, Rubini A, Mangar D, et al. Isoflurane prevents learning deficiencies caused by brief hypoxia and hypotension in adult Sprague Dawley rats. J Enzyme Inhib Med Chem 2014; 29:895-900.
33. Stachowiak EK, Fang X, Myers J, Dunham S, Stachowiak MK. cAMP-induced differentiation of human neuronal progenitor cells is mediated by nuclear fibroblast growth factor receptor-1 (FGFR1). J Neurochem 2003; 84:1296-1312.
34. Fu J, Zhao SD, Liu HJ, Yuan QH, Liu SM, Zhang YM, et al. Melatonin promotes proliferation and differentiation of neural stem cells subjected to hypoxia in vitro. J Pineal Res 2011; 51:104-112.
35. Wang Z, Liu DX, Wang FW, Zhang Q, Du ZX, Zhan JM, et al. L-Cysteine promotes the proliferation and differentiation of neural stem cells via the CBS/H(2)S pathway. Neuroscience 2013; 237:106-117.
36. Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R. Roles of bHLH genes in neural stem cell differentiation. Exp Cell Res 2005; 306:343-348.
37. Kageyama R, Ohtsuka T, Kobayashi T. Roles of Hes genes in neural development. Dev Growth Differ 2008;1:S97-103.
38. Katakura M, Hashimoto M, Shahdat HM, Gamoh S, Okui T, Matsuzaki K, et al. Docosahexaenoic acid promotes neuronal differentiation by regulating basic helix-loop-helix transcription factors and cell cycle in neural stem cells. Neuroscience 2009; 160:651-660.