TY - JOUR
T1 - 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
AU - Guo, Baojian
AU - Hu, Shengquan
AU - Zheng, Chengyou
AU - Wang, Hongyu
AU - Luo, Fangcheng
AU - Li, Haitao
AU - Cui, Wei
AU - Yang, Xifei
AU - Cui, Guozhen
AU - Mak, Shinghung
AU - Choi, Tony Chung Lit
AU - Ma, Edmond Dik Lung
AU - Wang, Yuqiang
AU - Lee, Simon Ming Yuen
AU - Zhang, Zaijun
AU - Han, Yifan
N1 - Funding Information:
This study was supported by grants from by the Natural National Science Foundation of China (NSFC 81303251 ; 81673407 ), the Natural Science Foundation of Guangdong Province ( 2015A030313317 ), the research grants from PolyU ( G-YBGQ , G-YZ95 ), the Research Grants Council of Hong Kong ( 15101014 ), ITSP-Guangdong-Hong Kong Technology Cooperation Funding Scheme ( GHP/012/16GD ), Shenzhen Basic Research Program ( JCYJ20160331141459373 ), China Postdoctoral Science Foundation Grant ( 2015M570753 ), and partially by grants from the Science and Technology Development Fund (FDCT) of Macao SAR (Ref. No. 134/2014/A3 ), Research Committee of University of Macau ( MYRG2016-00129-ICMS-QRCM ), and the Overseas and Hong Kong, Macau Young Scholars Collaborative Research Fund by the Natural National Science Foundation of China ( 81328025 ). We sincerely thank Ms. Josephine Leung for proofreading our manuscript.
PY - 2017/11
Y1 - 2017/11
N2 - We 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 (GSK3β). 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-GSK3β. Meanwhile, SU4312 effectively reversed the decrease in protein expression of tyrosine hydroxylase in substantia nigra pars compacta dopaminergic neurons, inhibited oxidative stress, maintained mitochondrial 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 μM. 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 mitochondrial 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.
AB - We 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 (GSK3β). 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-GSK3β. Meanwhile, SU4312 effectively reversed the decrease in protein expression of tyrosine hydroxylase in substantia nigra pars compacta dopaminergic neurons, inhibited oxidative stress, maintained mitochondrial 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 μM. 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 mitochondrial 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.
KW - Monoamine oxidase-B
KW - Myocyte enhancer factor 2D
KW - Neuroprotection
KW - Parkinson's disease
KW - SU4312
UR - http://www.scopus.com/inward/record.url?scp=85028016768&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2017.08.014
DO - 10.1016/j.neuropharm.2017.08.014
M3 - Journal article
C2 - 28807675
AN - SCOPUS:85028016768
SN - 0028-3908
VL - 126
SP - 12
EP - 24
JO - Neuropharmacology
JF - Neuropharmacology
ER -