Skip to main content
SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Teo KC, Ho SL (2013) Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease. Transl Neurodegener 2(1):19. doi:10.1186/2047-9158-2-19

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ho MC, Cherng CG, Tsai YP, Chiang CY, Chuang JY, Kao SF, Yu L (2009) Chronic treatment with monoamine oxidase-B inhibitors decreases cocaine reward in mice. Psychopharmacology (Berl) 205(1):141–149. doi:10.1007/s00213-009-1524-5

    Article  CAS  Google Scholar 

  3. Bartzokis G, Beckson M, Newton T, Mandelkern M, Mintz J, Foster JA, Ling W, Bridge TP (1999) Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria. Neuropsychopharmacology 20(6):582–590. doi:10.1016/S0893-133X(98)00092-X

    Article  CAS  PubMed  Google Scholar 

  4. Houtsmuller EJ, Notes LD, Newton T, van Sluis N, Chiang N, Elkashef A, Bigelow GE (2004) Transdermal selegiline and intravenous cocaine: safety and interactions. Psychopharmacology (Berl) 172(1):31–40. doi:10.1007/s00213-003-1616-6

    Article  CAS  Google Scholar 

  5. Eisler T, Teravainen H, Nelson R, Krebs H, Weise V, Lake CR, Ebert MH, Whetzel N et al (1981) Deprenyl in Parkinson disease. Neurology 31(1):19–23. doi:10.1212/WNL.31.1.19

    Article  CAS  PubMed  Google Scholar 

  6. Heinonen EH, Myllyla V (1998) Safety of selegiline (deprenyl) in the treatment of Parkinson’s disease. Drug Saf 19(1):11–22. doi:10.2165/00002018-199819010-00002

    Article  CAS  PubMed  Google Scholar 

  7. Lees A (2005) Alternatives to levodopa in the initial treatment of early Parkinson’s disease. Drugs Aging 22(9):731–740. doi:10.2165/00002512-200522090-00002

    Article  CAS  PubMed  Google Scholar 

  8. Engberg G, Elebring T, Nissbrandt H (1991) Deprenyl (selegiline), a selective MAO-B inhibitor with active metabolites; effects on locomotor activity, dopaminergic neurotransmission and firing rate of nigral dopamine neurons. J Pharmacol Exp Ther 259(2):841–847

    CAS  PubMed  Google Scholar 

  9. Kwon YS, Ann HS, Nabeshima T, Shin EJ, Kim WK, Jhoo JH, Jhoo WK, Wie MB et al (2004) Selegiline potentiates the effects of EGb 761 in response to ischemic brain injury. Neurochem Int 45(1):157–170. doi:10.1016/j.neuint.2003.10.005

    Article  CAS  PubMed  Google Scholar 

  10. Okuda C, Segal DS, Kuczenski R (1992) Deprenyl alters behavior and caudate dopamine through an amphetamine-like action. Pharmacol Biochem Behav 43(4):1075–1080. doi:10.1016/0091-3057(92)90484-W

    Article  CAS  PubMed  Google Scholar 

  11. Kwan E, Baker GB, Shuaib A, Ling L, Todd KG (2000) N-methyl, N-propargyl-2-phenylethylamine (MPPE), an analog of deprenyl, increases neuronal cell survival in thiamin deficiency encephalopathy. Drug Development Research 51(4):244–252. doi:10.1002/ddr.5

    Article  CAS  Google Scholar 

  12. Rittenbach K, Sloley BD, Ling L, Coutts RT, Shan J, Baker GB (2005) A rapid, sensitive electron-capture gas chromatographic procedure for analysis of metabolites of N-methyl, N-propargylphenylethylamine, a potential neuroprotective agent. J Pharmacol Toxicol Methods 52(3):373–378. doi:10.1016/j.vascn.2005.07.001

    Article  CAS  PubMed  Google Scholar 

  13. Bar-Am O, Amit T, Weinreb O, Youdim MB, Mandel S (2010) Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein precursor: involvement of MAPK and PKC activation. J Alzheimers Dis 21(2):361–371. doi:10.3233/JAD-2010-100150

    Article  CAS  PubMed  Google Scholar 

  14. Chen JJ, Swope DM (2005) Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease. J Clin Pharmacol 45(8):878–894. doi:10.1177/0091270005277935

    Article  CAS  PubMed  Google Scholar 

  15. Maruyama W, Youdim MB, Naoi M (2001) Antiapoptotic properties of rasagiline, N-propargylamine-1(R)-aminoindan, and its optical (S)-isomer, TV1022. Ann N Y Acad Sci 939:320–329. doi:10.1111/j.1749-6632.2001.tb03641.x

    Article  CAS  PubMed  Google Scholar 

  16. Trudler D, Weinreb O, Mandel SA, Youdim MB, Frenkel D (2014) DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline. J Neurochem 129(3):434–447. doi:10.1111/jnc.12633

    Article  CAS  PubMed  Google Scholar 

  17. Villaran RF, Tomas-Camardiel M, de Pablos RM, Santiago M, Herrera AJ, Navarro A, Machado A, Cano J (2008) Endogenous dopamine enhances the neurotoxicity of 3-nitropropionic acid in the striatum through the increase of mitochondrial respiratory inhibition and free radicals production. Neurotoxicology 29(2):244–258. doi:10.1016/j.neuro.2007.11.001

    CAS  PubMed  Google Scholar 

  18. Weinreb O, Bar-Am O, Amit T, Chillag-Talmor O, Youdim MB (2004) Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. FASEB J 18(12):1471–1473. doi:10.1096/fj.04-1916fje

    CAS  PubMed  Google Scholar 

  19. Camins A, Pallas M, Silvestre JS (2008) Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches. Methods Find Exp Clin Pharmacol 30(1):43–65. doi:10.1358/mf.2008.30.1.1090962

    Article  CAS  PubMed  Google Scholar 

  20. Checler F, Alves da Costa C (2014) p53 in neurodegenerative diseases and brain cancers. Pharmacol Ther 142(1):99–113. doi:10.1016/j.pharmthera.2013.11.009

    Article  CAS  PubMed  Google Scholar 

  21. Sawa A (2001) Mechanisms for neuronal cell death and dysfunction in Huntington’s disease: pathological cross-talk between the nucleus and the mitochondria? J Mol Med (Berl) 79(7):375–381. doi:10.1007/s001090100223

    Article  CAS  Google Scholar 

  22. Sugrue MM, Tatton WG (2001) Mitochondrial membrane potential in aging cells. Biol Signals Recept 10(3–4):176–188. doi:10.1159/000046886

    Article  CAS  PubMed  Google Scholar 

  23. Kang H, Shin JH (2014) Repression of rRNA transcription by PARIS contributes to Parkinson’s disease. Neurobiol Dis 73C:220–228. doi:10.1016/j.nbd.2014.10.003

    Google Scholar 

  24. Mogi M, Kondo T, Mizuno Y, Nagatsu T (2007) p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain. Neurosci Lett 414(1):94–97. doi:10.1016/j.neulet.2006.12.003

    Article  CAS  PubMed  Google Scholar 

  25. Mandir AS, Simbulan-Rosenthal CM, Poitras MF, Lumpkin JR, Dawson VL, Smulson ME, Dawson TM (2002) A novel in vivo post-translational modification of p53 by PARP-1 in MPTP-induced parkinsonism. J Neurochem 83(1):186–192. doi:10.1046/j.1471-4159.2002.01144.x

    Article  CAS  PubMed  Google Scholar 

  26. Endo H, Kamada H, Nito C, Nishi T, Chan PH (2006) Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci 26(30):7974–7983. doi:10.1523/JNEUROSCI.0897-06.2006

    Article  CAS  PubMed  Google Scholar 

  27. Erster S, Mihara M, Kim RH, Petrenko O, Moll UM (2004) In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol Cell Biol 24(15):6728–6741. doi:10.1128/MCB.24.15.6728-6741.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Speidel D (2010) Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol 20(1):14–24. doi:10.1016/j.tcb.2009.10.002

    Article  CAS  PubMed  Google Scholar 

  29. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303(5660):1010–1014. doi:10.1126/science.1092734

    Article  CAS  PubMed  Google Scholar 

  30. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11(3):577–590. doi:10.1016/S1097-2765(03)00050-9

    Article  CAS  PubMed  Google Scholar 

  31. Wolff S, Erster S, Palacios G, Moll UM (2008) p53’s mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity. Cell Res 18(7):733–744. doi:10.1038/cr.2008.62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Trimmer PA, Smith TS, Jung AB, Bennett JP Jr (1996) Dopamine neurons from transgenic mice with a knockout of the p53 gene resist MPTP neurotoxicity. Neurodegeneration 5(3):233–239. doi:10.1006/neur.1996.0031

    Article  CAS  PubMed  Google Scholar 

  33. Duan W, Zhu X, Ladenheim B, Yu QS, Guo Z, Oyler J, Cutler RG, Cadet JL et al (2002) p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Ann Neurol 52(5):597–606. doi:10.1002/ana.10350

    Article  CAS  PubMed  Google Scholar 

  34. Tsukada T, Tomooka Y, Takai S, Ueda Y, Nishikawa S, Yagi T, Tokunaga T, Takeda N et al (1993) Enhanced proliferative potential in culture of cells from p53-deficient mice. Oncogene 8(12):3313–3322

    CAS  PubMed  Google Scholar 

  35. Shin EJ, Nabeshima T, Suh HW, Jhoo WK, Oh KW, Lim YK, Kim DS, Choi KH et al (2005) Ginsenosides attenuate methamphetamine-induced behavioral side effects in mice via activation of adenosine A2A receptors: possible involvements of the striatal reduction in AP-1 DNA binding activity and proenkephalin gene expression. Behav Brain Res 158(1):143–157. doi:10.1016/j.bbr.2004.08.018

    Article  CAS  PubMed  Google Scholar 

  36. Shin EJ, Bing G, Chae JS, Kim TW, Bach JH, Park DH, Yamada K, Nabeshima T et al (2009) Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice. J Neurosci Res 87(16):3679–3686. doi:10.1002/jnr.22166

    Article  CAS  PubMed  Google Scholar 

  37. Shin EJ, Bach JH, Nguyen TT, Jung BD, Oh KW, Kim MJ, Jang CG, Ali SF et al (2011) Gastrodia Elata Bl attenuates cocaine-induced conditioned place preference and convulsion, but not behavioral sensitization in mice: Importance of GABA(A) receptors. Curr Neuropharmacol 9(1):26–29. doi:10.2174/157015911795017326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang W, Shin EJ, Wang T, Lee PH, Pang H, Wie MB, Kim WK, Kim SJ et al (2006) 3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro. FASEB J 20(14):2496–2511. doi:10.1096/fj.06-6006com

    Article  CAS  PubMed  Google Scholar 

  39. Muralikrishnan D, Samantaray S, Mohanakumar KP (2003) D-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Synapse 50(1):7–13. doi:10.1002/syn.10239

    Article  CAS  PubMed  Google Scholar 

  40. Venna VR, Verma R, O’Keefe LM, Xu Y, Crapser J, Friedler B, McCullough LD (2014) Inhibition of mitochondrial p53 abolishes the detrimental effects of social isolation on ischemic brain injury. Stroke 45(10):3101–3104. doi:10.1161/STROKEAHA.114.006553

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shin EJ, Shin SW, Nguyen TT, Park DH, Wie MB, Jang CG, Nah SY, Yang BW et al (2014) Ginsenoside Re rescues methamphetamine-induced oxidative damage, mitochondrial dysfunction, microglial activation, and dopaminergic degeneration by inhibiting the protein kinase Cdelta gene. Mol Neurobiol 49(3):1400–1421. doi:10.1007/s12035-013-8617-1

    Article  CAS  PubMed  Google Scholar 

  42. Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 3rd edn. Academic, San Diego

    Google Scholar 

  43. Borgkvist A, Usiello A, Greengard P, Fisone G (2007) Activation of the cAMP/PKA/DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward. Neuropsychopharmacology 32(9):1995–2003. doi:10.1038/sj.npp.1301321

    Article  CAS  PubMed  Google Scholar 

  44. Mijatovic J, Airavaara M, Planken A, Auvinen P, Raasmaja A, Piepponen TP, Costantini F, Ahtee L et al (2007) Constitutive Ret activity in knock-in multiple endocrine neoplasia type B mice induces profound elevation of brain dopamine concentration via enhanced synthesis and increases the number of TH-positive cells in the substantia nigra. J Neurosci 27(18):4799–4809. doi:10.1523/JNEUROSCI.5647-06.2007

    Article  CAS  PubMed  Google Scholar 

  45. Tran TV, Nam Y, Mai HN, Shin EJ, Kim HC (2014) MPPE, a selegiline analog, attenuates MPTP-induced dopaminergic toxicity with negligible behavioral side effects. Brain Conference 2014 (abstract P-137). Seoul. The Korean Society of Brain and Neural Science, Asian Society for Neuropathology, and the Korean Society for Neurodegenerative Disease. pp. 199

  46. Freed C, Revay R, Vaughan RA, Kriek E, Grant S, Uhl GR, Kuhar MJ (1995) Dopamine transporter immunoreactivity in rat brain. J Comp Neurol 359(2):340–349. doi:10.1002/cne.903590211

    Article  CAS  PubMed  Google Scholar 

  47. Hoffman AF, Lupica CR, Gerhardt GA (1998) Dopamine transporter activity in the substantia nigra and striatum assessed by high-speed chronoamperometric recordings in brain slices. J Pharmacol Exp Ther 287(2):487–496

    CAS  PubMed  Google Scholar 

  48. Sun J, Xu J, Cairns NJ, Perlmutter JS, Mach RH (2012) Dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine transporter (DAT) densities in aged human brain. PLoS One 7(11):e49483. doi:10.1371/journal.pone.0049483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miller GW, Gainetdinov RR, Levey AI, Caron MG (1999) Dopamine transporters and neuronal injury. Trends Pharmacol Sci 20(10):424–429. doi:10.1016/S0165-6147(99)01379-6

    Article  CAS  PubMed  Google Scholar 

  50. Davey GP, Clark JB (1996) Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J Neurochem 66(4):1617–1624. doi:10.1046/j.1471-4159.1996.66041617.x

    Article  CAS  PubMed  Google Scholar 

  51. Davey GP, Peuchen S, Clark JB (1998) Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration. J Biol Chem 273(21):12753–12757. doi:10.1074/jbc.273.21.12753

    Article  CAS  PubMed  Google Scholar 

  52. Perier C, Vila M (2012) Mitochondrial biology and Parkinson’s disease. Cold Spring Harb Perspect Med 2(2):a009332. doi:10.1101/cshperspect.a009332

    Article  PubMed  PubMed Central  Google Scholar 

  53. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909. doi:10.1016/S0896-6273(03)00568-3

    Article  CAS  PubMed  Google Scholar 

  54. Gogvadze V, Orrenius S, Zhivotovsky B (2003) Analysis of mitochondrial dysfunction during cell death. Curr Protoc Cell Biol Chapter 18:Unit 18.5. doi:10.1002/0471143030.cb1805s19

  55. Nam Y, Wie MB, Shin EJ, Nguyen TT, Nah SY, Ko SK, Jeong JH, Jang CG et al (2015) Ginsenoside Re protects methamphetamine-induced mitochondrial burdens and proapoptosis via genetic inhibition of protein kinase C delta in human neuroblastoma dopaminergic SH-SY5Y cell lines. J Appl Toxicol 35(8):927–944. doi:10.1002/jat.3093

    Article  CAS  PubMed  Google Scholar 

  56. Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP (1997) Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14(1):23–34. doi:10.1089/neu.1997.14.23

    Article  CAS  PubMed  Google Scholar 

  57. Nguyen XK, Lee J, Shin EJ, Dang DK, Jeong JH, Nguyen TT, Nam Y, Cho HJ et al (2015) Liposomal melatonin rescues methamphetamine-elicited mitochondrial burdens, pro-apoptosis, and dopaminergic degeneration through the inhibition PKCdelta gene. J Pineal Res 58(1):86–106. doi:10.1111/jpi.12195

    Article  CAS  PubMed  Google Scholar 

  58. Dhingra NK, Raju TR, Meti BL (1997) Selective reduction of monoamine oxidase A and B in the frontal cortex of subordinate rats. Brain Res 758(1–2):237–240. doi:10.1016/S0006-8993(96)01477-1

    Article  CAS  PubMed  Google Scholar 

  59. Janssen AJ, Trijbels FJ, Sengers RC, Smeitink JA, van den Heuvel LP, Wintjes LT, Stoltenborg-Hogenkamp BJ, Rodenburg RJ (2007) Spectrophotometric assay for complex I of the respiratory chain in tissue samples and cultured fibroblasts. Clin Chem 53(4):729–734. doi:10.1373/clinchem.2006.078873

    Article  CAS  PubMed  Google Scholar 

  60. Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, Jeong JH, Bach JH, Park DH et al (2012) Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med 52(7):1159–1174. doi:10.1016/j.freeradbiomed.2011.12.008

    Article  CAS  PubMed  Google Scholar 

  61. Shin EJ, Jeong JH, Bing G, Park ES, Chae JS, Yen TP, Kim WK, Wie MB et al (2008) Kainate-induced mitochondrial oxidative stress contributes to hippocampal degeneration in senescence-accelerated mice. Cell Signal 20(4):645–658. doi:10.1016/j.cellsig.2007.11.014

    Article  CAS  PubMed  Google Scholar 

  62. Kim HC, Jhoo WK, Kim WK, Suh JH, Shin EJ, Kato K, Ho Ko K (2000) An immunocytochemical study of mitochondrial manganese-superoxide dismutase in the rat hippocampus after kainate administration. Neurosci Lett 281(1):65–68. doi:10.1016/S0304-3940(99)00969-6

    Article  CAS  PubMed  Google Scholar 

  63. Kim HC, Yamada K, Nitta A, Olariu A, Tran MH, Mizuno M, Nakajima A, Nagai T et al (2003) Immunocytochemical evidence that amyloid β (1–42) impairs endogenous antioxidant systems in vivo. Neuroscience 119(2):399–419. doi:10.1016/S0306-4522(02)00993-4

    Article  CAS  PubMed  Google Scholar 

  64. Kurobe N, Kato K (1991) Sensitive enzyme immunoassay for rat Mn superoxide dismutase:Tissue distribution and developmental profiles in the rat central nervous tissue, liver, and kidney. Biomed Res 12(2):97–103. doi:10.2220/biomedres.12.97

    Article  CAS  Google Scholar 

  65. Vijitruth R, Liu M, Choi DY, Nguyen XV, Hunter RL, Bing G (2006) Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson’s disease. J Neuroinflammation 3:6. doi:10.1186/1742-2094-3-6

    Article  PubMed  PubMed Central  Google Scholar 

  66. Oliver CN, Ahn BW, Moerman EJ, Goldstein S, Stadtman ER (1987) Age-related changes in oxidized proteins. J Biol Chem 262(12):5488–5491

    CAS  PubMed  Google Scholar 

  67. Shin EJ, Duong CX, Nguyen XK, Li Z, Bing G, Bach JH, Park DH, Nakayama K et al (2012) Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cdelta. Behav Brain Res 232(1):98–113. doi:10.1016/j.bbr.2012.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lebel CP, Bondy SC (1990) Sensitive and rapid quantitation of oxygen reactive species formation in rat synaptosomes. Neurochem Int 17(3):435–440. doi:10.1016/0197-0186(90)90025-O

    Article  CAS  PubMed  Google Scholar 

  69. Wang Q, Shin EJ, Nguyen XK, Li Q, Bach JH, Bing G, Kim WK, Kim HC et al (2012) Endogenous dynorphin protects against neurotoxin-elicited nigrostriatal dopaminergic neuron damage and motor deficits in mice. J Neuroinflammation 9:124. doi:10.1186/1742-2094-9-124

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Jhoo WK, Shin EJ, Lee YH, Cheon MA, Oh KW, Kang SY, Lee C, Yi BC et al (2000) Dual effects of dextromethorphan on cocaine-induced conditioned place preference in mice. Neurosci Lett 288(1):76–80. doi:10.1016/S0304-3940(00)01188-5

    Article  CAS  PubMed  Google Scholar 

  71. He S, Grasing K (2006) L-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats; Insights towards selegiline’s mechanism of action. Pharmacol Biochem Behav 85(4):675–688. doi:10.1016/j.pbb.2006.10.022

    Article  CAS  PubMed  Google Scholar 

  72. Andrews ZB, Horvath B, Barnstable CJ, Elsworth J, Yang L, Beal MF, Roth RH, Matthews RT et al (2005) Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson’s disease. J Neurosci 25(1):184–191. doi:10.1523/JNEUROSCI.4269-04.2005

    Article  CAS  PubMed  Google Scholar 

  73. Lu M, Zhao FF, Tang JJ, Su CJ, Fan Y, Ding JH, Bian JS, Hu G (2012) The neuroprotection of hydrogen sulfide against MPTP-induced dopaminergic neuron degeneration involves uncoupling protein 2 rather than ATP-sensitive potassium channels. Antioxid Redox Signal 17(6):849–859. doi:10.1089/ars.2011.4507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wu WR, Zhu XZ (1999) The amphetamine-like reinforcing effect and mechanism of L-deprenyl on conditioned place preference in mice. Eur J Pharmacol 364(1):1–6. doi:10.1016/S0014-2999(98)00831-0

    Article  CAS  PubMed  Google Scholar 

  75. Yasar S, Schindler CW, Thorndike EB, Szelenyi I, Goldberg SR (1993) Evaluation of the stereoisomers of deprenyl for amphetamine-like discriminative stimulus effects in rats. J Pharmacol Exp Ther 265(1):1–6

    CAS  PubMed  Google Scholar 

  76. Davidson C, Chen Q, Zhang X, Xiong X, Lazarus C, Lee TH, Ellinwood EH (2007) Deprenyl treatment attenuates long-term pre- and post-synaptic changes evoked by chronic methamphetamine. Eur J Pharmacol 573(1–3):100–110. doi:10.1016/j.ejphar.2007.06.046

    Article  CAS  PubMed  Google Scholar 

  77. Krasnova IN, Cadet JL (2009) Methamphetamine toxicity and messengers of death. Brain Res Rev 60(2):379–407. doi:10.1016/j.brainresrev.2009.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ares-Santos S, Granado N, Espadas I, Martinez-Murillo R, Moratalla R (2014) Methamphetamine causes degeneration of dopamine cell bodies and terminals of the nigrostriatal pathway evidenced by silver staining. Neuropsychopharmacology 39(5):1066–1080. doi:10.1038/npp.2013.307

    Article  CAS  PubMed  Google Scholar 

  79. Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217. doi:10.1146/annurev.neuro.22.1.197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kang YK, Oh HS, Cho YH, Kim YJ, Han YG, Nam SH (2010) Effects of a silkworm extract on dopamine and monoamine oxidase-B activity in an MPTP-induced Parkinsons disease model. Laboratory Animal Research 26(3):287–292

    Article  Google Scholar 

  81. Lieu CA, Chinta SJ, Rane A, Andersen JK (2013) Age-related behavioral phenotype of an astrocytic monoamine oxidase-B transgenic mouse model of Parkinson’s disease. PLoS One 8(1):e54200. doi:10.1371/journal.pone.0054200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mallajosyula JK, Kaur D, Chinta SJ, Rajagopalan S, Rane A, Nicholls DG, Di Monte DA, Macarthur H et al (2008) MAO-B elevation in mouse brain astrocytes results in Parkinson’s pathology. PLoS One 3(2):e1616. doi:10.1371/journal.pone.0001616

    Article  PubMed  PubMed Central  Google Scholar 

  83. Siddiqui A, Mallajosyula JK, Rane A, Andersen JK (2010) Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: implications for early intervention on disease progression. Neurobiol Dis 40(2):444–448. doi:10.1016/j.nbd.2010.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, MacGregor R (1997) Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging 18(4):431–435. doi:10.1016/S0197-4580(97)00037-7

    Article  CAS  PubMed  Google Scholar 

  85. Saura J, Andres N, Andrade C, Ojuel J, Eriksson K, Mahy N (1997) Biphasic and region-specific MAO-B response to aging in normal human brain. Neurobiol Aging 18(5):497–507. doi:10.1016/S0197-4580(97)00113-9

    Article  CAS  PubMed  Google Scholar 

  86. Kumar MJ, Andersen JK (2004) Perspectives on MAO-B in aging and neurological disease: where do we go from here? Mol Neurobiol 30(1):77–89. doi:10.1385/MN:30:1:077

    Article  CAS  PubMed  Google Scholar 

  87. Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36(26):2503–2508. doi:10.1016/0024-3205(85)90146-8

    Article  CAS  PubMed  Google Scholar 

  88. Cleeter MW, Cooper JM, Schapira AH (1992) Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement. J Neurochem 58(2):786–789. doi:10.1111/j.1471-4159.1992.tb09789.x

    Article  CAS  PubMed  Google Scholar 

  89. Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS (2014) Mitochondrial oxidative stress in aging and health span. Longev Healthspan 3:6. doi:10.1186/2046-2395-3-6

    Article  PubMed  PubMed Central  Google Scholar 

  90. Zhang Y, Marcillat O, Giulivi C, Ernster L, Davies KJ (1990) The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J Biol Chem 265(27):16330–16336

    CAS  PubMed  Google Scholar 

  91. Diano S, Matthews RT, Patrylo P, Yang L, Beal MF, Barnstable CJ, Horvath TL (2003) Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning. Endocrinology 144(11):5014–5021. doi:10.1210/en.2003-0667

    Article  CAS  PubMed  Google Scholar 

  92. Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF et al (2003) Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 9(8):1062–1068. doi:10.1038/nm903

    Article  CAS  PubMed  Google Scholar 

  93. Sullivan PG, Dubé C, Dorenbos K, Steward O, Baram TZ (2003) Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann Neurol 53(6):711–717. doi:10.1002/ana.10543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Seemann S, Hainaut P (2005) Roles of thioredoxin reductase 1 and APE/Ref-1 in the control of basal p53 stability and activity. Oncogene 24(24):3853–3863. doi:10.1038/sj.onc.1208549

    Article  CAS  PubMed  Google Scholar 

  95. Chi SW (2014) Structural insights into the transcription-independent apoptotic pathway of p53. BMB Rep 47(3):167–172. doi:10.5483/BMBRep.2014.47.3.261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Liu D, Xu Y (2011) p53, oxidative stress, and aging. Antioxid Redox Signal 15(6):1669–1678. doi:10.1089/ars.2010.3644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhao Y, Chaiswing L, Velez JM, Batinic-Haberle I, Colburn NH, Oberley TD, St Clair DK (2005) p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase. Cancer Res 65(9):3745–3750. doi:10.1158/0008-5472.CAN-04-3835

    Article  CAS  PubMed  Google Scholar 

  98. Sagi Y, Mandel S, Amit T, Youdim MB (2007) Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism. Neurobiol Dis 25(1):35–44. doi:10.1016/j.nbd.2006.07.020

    Article  CAS  PubMed  Google Scholar 

  99. Weinreb O, Amit T, Bar-Am O, Youdim MB (2007) Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann N Y Acad Sci 1122:155–168. doi:10.1196/annals.1403.011

    Article  CAS  PubMed  Google Scholar 

  100. Mandel S, Weinreb O, Amit T, Youdim MB (2005) Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. Brain Res Brain Res Rev 48(2):379–387. doi:10.1016/j.brainresrev.2004.12.027

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration and partially by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (no. NRF-2013R1A1A2060894 and no. NRF-2013R1A1A1007378), Republic of Korea, and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2011–0018355). Yunsung Nam and The-Vinh Tran were supported by the BK21 PLUS program, National Research Foundation of Korea, Republic of Korea. Equipment at the Institute of New Drug Development Research (Kangwon National University) was used for this study. The English in this document has been checked by at least two professional editors, both native speakers of English (Beverly Hills English, Los Angeles, CA90024, USA).

Author information

Authors and Affiliations

  1. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea

    Eun-Joo Shin, Yunsung Nam, Ji Won Lee, Phuong-Khue Thi Nguyen, Ji Eun Yoo, The-Vinh Tran & Hyoung-Chun Kim

  2. Hutecs Korea Pharm Co., Ltd., Osan, 18111, Republic of Korea

    Ji Won Lee

  3. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, Republic of Korea

    Ji Hoon Jeong

  4. Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea

    Choon-Gon Jang

  5. Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul, 120-749, Republic of Korea

    Young J. Oh

  6. Eve Topf Centers of Excellence for Neurodegenerative Diseases Research, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel

    Moussa B. H. Youdim

  7. National Creative Research Initiative Center for Catalytic Organic Reactions, Department of Chemistry, Kangwon National University, Chunchon, 200-701, Republic of Korea

    Phil Ho Lee

  8. Department of Regional Pharmaceutical Care and Sciences, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, 468-8503, Japan

    Toshitaka Nabeshima

  9. NPO, Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-8503, Japan

    Toshitaka Nabeshima

Authors
  1. Eun-Joo Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yunsung Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ji Won Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Phuong-Khue Thi Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ji Eun Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. The-Vinh Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ji Hoon Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Choon-Gon Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Young J. Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Moussa B. H. Youdim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Phil Ho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Toshitaka Nabeshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hyoung-Chun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyoung-Chun Kim.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 70 kb)

ESM 2

(PDF 1.94 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, EJ., Nam, Y., Lee, J.W. et al. 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. Mol Neurobiol 53, 6251–6269 (2016). https://doi.org/10.1007/s12035-015-9527-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9527-1

Keywords

Search

Navigation