RRC ID 35751
Author Shin EJ, Nam Y, Lee JW, Nguyen PT, Yoo JE, Tran TV, Jeong JH, Jang CG, Oh YJ, Youdim MBH, Lee PH, Nabeshima T, Kim HC.
Title N-Methyl, N-propynyl-2-phenylethylamine (MPPE), a Selegiline Analog, Attenuates MPTP-induced Dopaminergic Toxicity with Guaranteed Behavioral Safety: Involvement of Inhibitions of Mitochondrial Oxidative Burdens and p53 Gene-elicited Pro-apoptotic Change.
Journal Mol Neurobiol
Abstract Selegiline is a monoamine oxidase-B (MAO-B) inhibitor with anti-Parkinsonian effects, but it is metabolized to amphetamines. Since another MAO-B inhibitor N-Methyl, N-propynyl-2-phenylethylamine (MPPE) is not metabolized to amphetamines, we examined whether MPPE induces behavioral side effects and whether MPPE affects dopaminergic toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Multiple doses of MPPE (2.5 and 5 mg/kg/day) did not show any significant locomotor activity and conditioned place preference, whereas selegiline (2.5 and 5 mg/kg/day) significantly increased these behavioral side effects. Treatment with MPPE resulted in significant attenuations against decreases in mitochondrial complex I activity, mitochondrial Mn-SOD activity, and expression induced by MPTP in the striatum of mice. Consistently, MPPE significantly attenuated MPTP-induced oxidative stress and MPPE-mediated antioxidant activity appeared to be more pronounced in mitochondrial-fraction than in cytosolic-fraction. Because MPTP promoted mitochondrial p53 translocation and p53/Bcl-xL interaction, it was also examined whether mitochondrial p53 inhibitor pifithrin-μ attenuates MPTP neurotoxicity. MPPE, selegiline, or pifithrin-μ significantly attenuated mitochondrial p53/Bcl-xL interaction, impaired mitochondrial transmembrane potential, cytosolic cytochrome c release, and cleaved caspase-3 in wild-type mice. Subsequently, these compounds significantly ameliorated MPTP-induced motor impairments. Neuroprotective effects of MPPE appeared to be more prominent than those of selegiline. MPPE or selegiline did not show any additional protective effects against the attenuation by p53 gene knockout, suggesting that p53 gene is a critical target for these compounds. Our results suggest that MPPE possesses anti-Parkinsonian potentials with guaranteed behavioral safety and that the underlying mechanism of MPPE requires inhibition of mitochondrial oxidative stress, mitochondrial translocation of p53, and pro-apoptotic process.
Volume 53(9)
Pages 6251-6269
Published 2016-11-1
DOI 10.1007/s12035-015-9527-1
PII 10.1007/s12035-015-9527-1
PMID 26563498
MeSH 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Animals Apoptosis / drug effects* Behavior, Animal* Caspase 3 / metabolism Conditioning, Psychological Cytochromes c / metabolism Cytosol / metabolism Dopaminergic Neurons / drug effects Dopaminergic Neurons / metabolism Dopaminergic Neurons / pathology* Electron Transport Complex I Locomotion / drug effects Membrane Potential, Mitochondrial / drug effects Mice, Inbred C57BL Mitochondria / drug effects Mitochondria / metabolism* Monoamine Oxidase / metabolism Neostriatum / drug effects Neostriatum / metabolism Oxidation-Reduction Oxidative Stress / drug effects Phenethylamines / chemistry Phenethylamines / pharmacology* Protein Binding / drug effects Selegiline / analogs & derivatives* Selegiline / chemistry Selegiline / pharmacology Sulfonamides / pharmacology Superoxide Dismutase / metabolism Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism Uncoupling Protein 2 / metabolism bcl-X Protein / metabolism
IF 4.5
Times Cited 16
Mice RBRC01361