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Activation of transcription factor MEF2D by bis(3)-cognitin protects dopaminergic neurons and ameliorates Parkinsonian motor defects.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Oct 05; Vol. 287 (41), pp. 34246-55. Date of Electronic Publication: 2012 Aug 13. - Publication Year :
- 2012
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Abstract
- Parkinson disease (PD) is characterized by the selective demise of dopaminergic (DA) neurons in the substantial nigra pars compacta. Dysregulation of transcriptional factor myocyte enhancer factor 2D (MEF2D) has been implicated in the pathogenic process in in vivo and in vitro models of PD. Here, we identified a small molecule bis(3)-cognitin (B3C) as a potent activator of MEF2D. We showed that B3C attenuated the toxic effects of neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) by activating MEF2D via multiple mechanisms. B3C significantly reduced MPP(+)-induced oxidative stress and potentiated Akt to down-regulate the activity of MEF2 inhibitor glycogen synthase kinase 3β (GSK3β) in a DA neuronal cell line SN4741. Furthermore, B3C effectively rescued MEF2D from MPP(+)-induced decline in both nucleic and mitochondrial compartments. B3C offered SN4741 cells potent protection against MPP(+)-induced apoptosis via MEF2D. Interestingly, B3C also protected SN4741 cells from wild type or mutant A53T α-synuclein-induced cytotoxicity. Using the in vivo PD model of C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), we showed that B3C maintained redox homeostasis, promoted Akt function activity, and restored MEF2D level in midbrain neurons. Moreover, B3C greatly prevented the loss of tyrosine hydroxylase signal in substantial nigra pars compacta DA neurons and ameliorated behavioral impairments in mice treated with MPTP. Collectedly, our studies identified B3C as a potent neuroprotective agent whose effectiveness relies on its ability to effectively up-regulate MEF2D in DA neurons against toxic stress in models of PD in vitro and in vivo.
- Subjects :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
1-Methyl-4-phenylpyridinium adverse effects
1-Methyl-4-phenylpyridinium pharmacology
Animals
Behavior, Animal drug effects
Cell Line
Dopamine Agents adverse effects
Dopamine Agents pharmacology
Dopaminergic Neurons pathology
Herbicides adverse effects
Herbicides pharmacology
MEF2 Transcription Factors
Male
Mice
Parkinsonian Disorders metabolism
Parkinsonian Disorders pathology
Substantia Nigra metabolism
Substantia Nigra pathology
Tacrine pharmacology
Tyrosine 3-Monooxygenase metabolism
Apoptosis drug effects
Dopaminergic Neurons metabolism
Myogenic Regulatory Factors metabolism
Nerve Tissue Proteins metabolism
Neuroprotective Agents pharmacology
Oxidative Stress drug effects
Parkinsonian Disorders drug therapy
Tacrine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 41
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22891246
- Full Text :
- https://doi.org/10.1074/jbc.M112.367540