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
| Autor: | Tony Chunglit Choi, Yuqiang Wang, Edmond Dik Lung Ma, Baojian Guo, Shinghung Mak, Yifan Han, Fangcheng Luo, Guozhen Cui, Chengyou Zheng, Shengquan Hu, Simon Ming-Yuen Lee, Hongyu Wang, Xifei Yang, Haitao Li, Wei Cui, Zaijun Zhang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Indoles Monoamine Oxidase Inhibitors Substantia nigra Antineoplastic Agents Apoptosis Biology Pharmacology In Vitro Techniques Neuroprotection PC12 Cells Antiparkinson Agents 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine medicine Cortical Bone Animals Monoamine Oxidase PI3K/AKT/mTOR pathway Tyrosine hydroxylase Pars compacta MEF2 Transcription Factors MPTP Dopaminergic Neurons Neurotoxicity MPTP Poisoning medicine.disease Mitochondria Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology chemistry Mitochondrial biogenesis 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Neuropharmacology. 126 |
| ISSN: | 1873-7064 |
| Popis: | 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 IC 50 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. |
| Databáze: | OpenAIRE |
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