Antioxidant properties of PF9601N, a novel MAO-B inhibitor: assessment of its ability to interact with reactive nitrogen species
Languages of publication
The novel MAO-B inhibitor PF9601N, its cytochrome P450-dependent metabolite FA72 and l-deprenyl were studied as potential peroxynitrite (ONOO-) scavengers and nitric oxide synthase (NOS) inhibitors. The scavenging activity of these compounds was evaluated by measuring the oxygen consumption through peroxynitrite-mediated oxidation of both linoleic acid and brain homogenate. FA72, PF9601N and l-deprenyl caused a concentration-dependent inhibition of ONOO--induced linoleic acid oxidation with an IC50 value of 60.2 µM, 82.8 µM and 235.8 µM, respectively. FA72 was the most potent also in inhibiting ONOO--induced brain homogenate oxidation with an IC50 value of 99.4 µM, while PF9601N and l-deprenyl resulted weaker inhibitors in the same experimental model, showing an IC50 value of 164.8 and 112.0 µM, respectively. Furthermore, both the novel MAO-B inhibitor as well as its metabolite were able to strongly inhibit rat brain neuronal NOS (IC50 of 183 µM and 192 µM, respectively), while l-deprenyl at the highest concentration used (3 mM), caused only a slight decrease of the enzyme activity. Moreover, inducible NOS was strongly inhibited by FA72 only. All these results suggest that PF9601N could be a promising therapeutic agent in neurodegenerative disorders such as Parkinson's disease.
- Avila M, Balsa MD, Fernandez-Alvarez E, Tipton KF, Unzeta M (1993) The effect of side-chain substitution at positions 2 and 3 of the heterocyclic ring of N-acetylenic analogues of tryptamine as monoamine oxidase inhibitors. Biochem Pharmacol 45: 2231-2237.
- Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87: 1620-1624.
- Beckmann JS, Ye YZ, Anderson PG, Chen J, Accavitti MA, Tarpey MM, White CR (1994) Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol Chem Hoppe Seyler 375: 81-88.
- Bolaños JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB, Heales SJ (1997) Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 68: 2227-2240.
- Byun J, Henderson JP, Mueller DM, Heinecke JW (1999) 8-Nitro-2'-deoxyguanosine, a specific marker of oxidation by reactive nitrogen species, is generated by the myeloperoxidase-hydrogen peroxide-nitrite system of activated human phagocytes. Biochemistry 38: 2590 -2600.
- Chen PF, Tsai AL, BerkaV, Wu KK (1997) Mutation of Glu-361 in human endothelial nitric-oxide synthase selectively abolishes l-arginine binding without perturbing the behaviour of heme and other redox centers. J Biol Chem 272: 6114-6118.
- Chiueh CC, Huang SJ, Murphy DL (1994) Suppression of hydroxyl radical formation by MAO inhibitors: a novel possible neuroprotective mechanism in dopaminergic neurotoxicity. J Neural Transm (Suppl) 41: 189-196.
- Cutillas B, Ambrosio S, Unzeta M (2002) Neuroprotective effect of the monoamine oxidase inhibitor PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] on rat nigral neurons after 6-OH-DA striatal lesion Neuroscience Letters 329: 165-168.
- Dragoni S, Bellik L, Frosini M, Matteucci G, Sgaragli G, Valoti M (2003) Cytochrome P450-dependent metabolism of l-deprenyl in monkey (Cercopithecus aethiops) and C57BL/6 mouse brain microsomal preparations. J Neurochem 86: 1174-1180.
- Dragoni S, Materozzi G, Pessina F, Frosini M, Marco JL, Unzeta M, Sgaragli G, Valoti M (2007) CYP-dependent metabolism of PF9601N, a new monoamine oxidase-B inhibitor, by C57BL/6 mouse and human liver microsomes. J Pharm Pharm Sci 10: 473-485.
- Dragoni S, Porcari V, Travagli M, Castagnolo D, Valoti M (2006) Antioxidant properties of propargylamine derivatives: assessment of their ability to scavenge peroxynitrite. J Pharm Pharmacol 58: 561-565.
- Duda JE, Giasson BI, Chen Q, Gur TL, Hurtig HI, Stern MB, Gollomp SM, Ischiropoulos H, Lee VM, Trojanowski JQ (2000) Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am J Pathol 157: 1439-1445.
- Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews RT, Beal MF (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat Med 2: 1017-1102.
- Hunot S, Boissière F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, Hirsch EC (1996) Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 72: 355-363.
- Inoue S, Kawanishi S (1995) Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett 371: 86-88.
- Knoll J (1986) The pharmacology of (-) deprenyl. J Neural Transm (Suppl) 22: 75-89.
- Knowels GR, Salter M (1998) Measurement of NOS activity by conversion of radiolabeled arginine to citrulline using ion-exchange separation. In Methods in Molecular Biology, vol 100. Nitric oxide protocols. Michael A, eds, pp 75-84. Titheradge, University of Sussex, Brighton.
- Kooy NW, Royall JA, Ischiropoulos H (1997) Oxidation of 2',7'-dichlorofluorescin by peroxynitrite. Free Radic Res 27: 245-254.
- Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5: 1403-1409.
- Lima ES, Di Mascio P, Abdalla DS (2003) Cholesteryl nitrolinoleate, a nitrated lipid present in human blood plasma and lipoproteins. J Lipid Res 44: 1660-1666.
- Marini S, Nannelli A, Sodini D, Dragoni S, Valoti M, Longo V, Gervasi PG (2007) Expression, microsomal and mitochondrial activities of cytochrome P450 enzymes in brain regions from control and phenobarbital-treated rabbits. Life Sci 80: 910-917.
- Obeso JA, Olanow CW (1998) Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. Ann Neurol 44 (Suppl 1): S175-S188.
- O'Donnell VB, Eiserich JP, Chumley PH, Jablonsky MJ, Krishna NR, Kirk M, Barnes S, Darley-Usmar VM, Freeman BA (1999) Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitrous acid, nitrogen dioxide, and nitronium ion. Chem Res Toxicol 12: 83-92.
- Patel RP, Darley-Usmar VM (1996) Using peroxynitrite as oxidant with low-density lipoprotein. Methods Enzymol 269: 3-11.
- Perez V, Marco JL, Fernandez-Alvarez E, Unzeta M (1996) Kinetic studies of N-allenic analogues of tryptamine as monoamine oxidase inhibitors. J Pharm Pharmacol 48: 718-722.
- Perez V, Marco JL, Fernandez-Alvarez E, Unzeta M (1999) Relevance of benzyloxy group in 2-indolyl methylamines in the selective MAO-B inhibition. Br J Pharmacol 127: 869-876.
- Perez V, Unzeta M (2003) PF 9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine], a new MAO-B inhibitor, attenuates MPTP-induced depletion of striatal dopamine levels in C57/BL mice Neurochem Int 42: 221-229.
- Prat G, Pérez V, Rubi A, Casas M, Unzeta M (2000) The novel type-B MAO inhibitor PF9601N enhances the duration of L-DOPA-induced contralateral turning in 6-hydroxydopamine lesioned rats. J Neural Transm 107: 409-417.
- Przedborski S, Jackson-Lewis V, Yokoyama R, Shibata T, Dawson VL, Dawson TM (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci USA 93: 4565-4571.
- Rodriguez MC, Obeso JA, Olanow CW (1998) Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. Ann Neurol 44: S175-S188.
- Sanz E, Quintana A, Battaglia V, Toninello A, Hidalgo J, Ambrosio S, Valoti M, Marco JL, Tipton KF, Unzeta M (2008) Anti-apoptotic effect of Mao-B inhibitor PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] is mediated by p53 pathway inhibition in MPP+-treated SH-SY5Y human dopaminergic cells. J Neurochem 105: 2404-2417.
- Sanz E, Quintana A, Hidalgo J, Marco JL, Unzeta M (2009) PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine], confers MAO-B independent neuroprotection in ER stress-induced cell death. Mol Cell Neurosci 41: 19-31.
- Sanz E, Romera M, Bellik L, Marco JI, Unzeta M (2004) Indolalkylamines derivatives as antioxidant and neuroprotective agents in an experimental model of Parkinson's disease. Med Sci Monit 10: BR477-BR484.
- Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 54: 823-827.
- Schulz JB, Matthews RT, Muqit MM, Browne SE, Beal MF (1995) Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. J Neurochem 64: 936-939.
- Zhou L, Zhu DY (2009) Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications. Nitric Oxide 20: 223-230.
Publication order reference