UM  > 中華醫藥研究院
Substantial protection against MPTP-associated Parkinson's neurotoxicity in vitro and in vivo by anti-cancer agent SU4312 via activation of MEF2D and inhibition of MAO-B
Guo, Baojian1,2; Hu, Shengquan1,2,3; Zheng, Chengyou1,2; Wang, Hongyu1,2; Luo, Fangcheng1,2; Li, Haitao4,5; Cui, Wei6; Yang, Xifei7; Cui, Guozhen8; Mak, Shinghung3; Choi, Tony Chung-Lit3; Ma, Edmond Dik-Lung9; Wang, Yuqiang1,2; Lee, Simon Ming Yuen4,5; Zhang, Zaijun1,2; Han, Yifan3
2017-11
Source PublicationNEUROPHARMACOLOGY
ISSN0028-3908
Volume126Pages:12-24
AbstractWe have previously demonstrated the unexpected neuroprotection of the anti-cancer agent SU4312 in cellular models associated with Parkinson's disease (PD). However, the precise mechanisms underlying its neuroprotection are still unknown, and the effects of SU4312 on rodent models of PD have not been characterized. In the current study, we found that the protection of SU4312 against 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity in PC12 cells was achieved through the activation of transcription factor myocyte enhancer factor 2D (MEF2D), as evidenced by the fact that SU4312 stimulated myocyte enhancer factor 2 (MEF2) transcriptional activity and prevented the inhibition of MEF2D protein expression caused by MPP+, and that short hairpin RNA (ShRNA)-mediated knockdown of MEF2D significantly abolished the neuroprotection of SU4312. Additionally, Western blotting analysis revealed that SU4312 potentiated pro-survival PI3-K/Akt pathway to down-regulate MEF2D inhibitor glycogen synthase kinase-3beta (GSK3 beta). Furthermore, using the in vivo PD model of C57BL/6 mice insulted with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that intragastrical administration of SU4312 (0.2 and 1 mg/kg) greatly ameliorated Parkinsonian motor defects, and restored protein levels of MEF2D, phosphorylated-Ser473-Akt and phosphorylated-Ser9-GSK3 beta. Meanwhile, SU4312 effectively reversed the decrease in protein expression of tyrosine hydroxylase in substantia nigra pars compacta dopaminergic neurons, inhibited oxidative stress, maintained mitochondria biogenesis and partially prevented the depletion of dopamine and its metabolites. Very encouragingly, SU4312 was able to selectively inhibit monoamine oxidase-B (MAO-B) activity both in vitro and in vivo, with an IC50 value of 0.2 mu M. These findings suggest that SU4312 provides therapeutic benefits in cellular and animal models of PD, possibly through multiple mechanisms including enhancement of MEF2D through the activation of PI3-K/Akt pathway, maintenance of mitochondria] biogenesis and inhibition of MAO-B activity. SU4312 thus may be an effective drug candidate for the prevention or even modification of the pathological processes of PD. (C) 2017 Elsevier Ltd. All rights reserved.
KeywordParkinson's disease SU4312 Neuroprotection Myocyte enhancer factor 2D Monoamine oxidase-B
DOI10.1016/j.neuropharm.2017.08.014
URLView the original
Indexed BySCI
Language英语
WOS Research AreaNeurosciences & Neurology ; Pharmacology & Pharmacy
WOS SubjectNeurosciences ; Pharmacology & Pharmacy
WOS IDWOS:000413879900002
PublisherPERGAMON-ELSEVIER SCIENCE LTD
Fulltext Access
Citation statistics
Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.Jinan Univ, Coll Pharm, Inst New Drug Res, Huangpu Rd, Guangzhou, Guangdong, Peoples R China;
2.Jinan Univ, Coll Pharm, Guangzhou Key Lab Innovat Chem Drug Res Cardiocer, Guangzhou, Guangdong, Peoples R China;
3.Hong Kong Polytech Univ, Inst Modern Chinese Med, Dept Appl Biol & Chem Technol, Hong Kong, Hong Kong, Peoples R China;
4.Univ Macau, State Key Lab Qual Res Chinese Med, Taipa, Macao, Peoples R China;
5.Univ Macau, Inst Chinese Med Sci, Taipa, Macao, Peoples R China;
6.Ningbo Univ, Sch Med, Ningbo, Zhejiang, Peoples R China;
7.Ctr Dis Control & Prevent, Key Lab Modern Toxicol Shenzhen, Shenzhen, Peoples R China;
8.Zunyi Med Univ, Dept Bioengn, Zhuhai Campus, Zhuhai, Peoples R China;
9.Hong Kong Baptist Univ, Dept Chem, Hong Kong, Hong Kong, Peoples R China
Recommended Citation
GB/T 7714
Guo, Baojian,Hu, Shengquan,Zheng, Chengyou,et al. Substantial protection against MPTP-associated Parkinson's neurotoxicity in vitro and in vivo by anti-cancer agent SU4312 via activation of MEF2D and inhibition of MAO-B[J]. NEUROPHARMACOLOGY,2017,126:12-24.
APA Guo, Baojian.,Hu, Shengquan.,Zheng, Chengyou.,Wang, Hongyu.,Luo, Fangcheng.,...&Han, Yifan.(2017).Substantial protection against MPTP-associated Parkinson's neurotoxicity in vitro and in vivo by anti-cancer agent SU4312 via activation of MEF2D and inhibition of MAO-B.NEUROPHARMACOLOGY,126,12-24.
MLA Guo, Baojian,et al."Substantial protection against MPTP-associated Parkinson's neurotoxicity in vitro and in vivo by anti-cancer agent SU4312 via activation of MEF2D and inhibition of MAO-B".NEUROPHARMACOLOGY 126(2017):12-24.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Guo, Baojian]'s Articles
[Hu, Shengquan]'s Articles
[Zheng, Chengyou]'s Articles
Baidu academic
Similar articles in Baidu academic
[Guo, Baojian]'s Articles
[Hu, Shengquan]'s Articles
[Zheng, Chengyou]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Guo, Baojian]'s Articles
[Hu, Shengquan]'s Articles
[Zheng, Chengyou]'s Articles
Terms of Use
No data!
Social Bookmark/Share
File name: 10.1016_j.neuropharm.2017.08.014.pdf
Format: Adobe PDF
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.