Monoamine oxidase (MAO) inhibitors were among the first antidepressants to be discovered and introduced into the clinic. Early forms have almost disappeared from use as a consequence of their side effects, which include the 'cheese reaction' — that is, stimulation of cardiovascular sympathetic nervous system activity due to a build-up of dietary amines.
The identification of two forms of MAO, known as MAOA and MAOB, and their respective selective inhibitors has contributed to a better understanding of their physiological roles, regulation of neurotransmitter metabolism and the mechanism of the 'cheese reaction', and has led to the development of selective inhibitors that avoid this side effect.
The two enzymes differ structurally in their substrate–inhibitor recognition sites, but not in their active sites, which contain a covalently bound flavin moiety. Knowledge of the three-dimensional structures of MAOA and MAOB has provided new insights into the way in which MAO interacts with substrates and inhibitors, and has revealed intriguing species differences for MAOA.
The discovery that the synthetic compound MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a substrate of MAOB, which converts this compound to the neurotoxin MPP+ (1-methyl-4-phenylpyridinium), causing a parkinsonism syndrome in some mouse strains and primates including humans, provided a basis for our understanding of the participation of MAO in dopaminergic neurodegeneration, and MAOB inhibitors as neuroprotective drugs with disease-modifying activity.
The propargylamine irreversible MAOB inhibitors, including l-deprenyl (Selegiline) and rasagiline, have shown efficacy in the treatment of Parkinson's disease. These drugs exert a neuroprotective activity not related to MAO inhibition, as shown in cultured neurons and in vivo models of neurodegeneration. The molecular mechanism of this neuroprotective activity involves regulation of B-cell lymphoma/leukaemia 2 (BCL2) family proteins and protein kinase-dependent signalling pathways as well as interactions with glyceraldehyde-3-phosphate dehydrogenase and induction of some antioxidant enzymes.
Although considerable advances have been made in our understanding of the structure of MAO, its neurobiology and the mechanisms of action of its selective inhibitors in neuropsychiatric disorders, much remains to be learnt about MAO and its interactions with both substrates and inhibitors.
Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Youdim, M. B. H., Finberg, J. P. M. & Tipton, K. F. in Catecholamine II. Handbook of Experimental Pharmacology (eds Trendelenburg, U. & Weiner, N.) 127–199 (Springer, Berlin, 1988). A comprehensive review of the biochemistry, physiology and pharmacology of monoamine oxidases up until 1988.
Shih, J. C., Chen, K. & Ridd, M. J. Monoamine oxidase: from genes to behavior. Annu. Rev. Neurosci. 22, 197–217 (1999). A comprehensive review of the cloning of monoamine oxidases, and the physiological and behavioural effects of their knockout.
Tipton, K. F., Boyce, S., O'Sullivan, J., Davey, G. P. & Healy, J. Monoamine oxidases: certainties and uncertainties. Curr. Med. Chem. 11, 1965–1982 (2004). A comprehensive review of established and non-established aspects of MAOs and their inhibitors.
Raddatz, R., Parini, A. & Lanier, S. M. Imidazoline/guanidinium binding domains on monoamine oxidases. Relationship to subtypes of imidazoline-binding proteins and tissue-specific interaction of imidazoline ligands with monoamine oxidase B. J. Biol. Chem. 270, 27961–27968 (1995).
Szutowicz, A., Tomaszewicz, M. & Orsulak, P. J. Modification of substrate-inhibitor affinities of human platelet monoamine oxidase B in vitro. J. Biol. Chem. 264, 17660–17664 (1989).
Nicotra, A., Pierucci, F., Parvez, H. & Senatori, O. Monoamine oxidase expression during development and aging. Neurotoxicology 25, 155–165 (2004).
Tsang, D., Ho, K. P. & Wen, H. L. Ontogenesis of multiple forms of monoamine oxidase in rat brain regions and liver. Dev. Neurosci. 8, 243–250 (1986).
Strolin Benedetti, M., Dostert, P. & Tipton, K. F. Developmental aspects of the monoamine-degrading enzyme monoamine oxidase. Dev. Pharmacol. Ther. 18, 191–200 (1992). Reports that the postnatal development of MAOB in the brain lags behind that of MAOA.
Matsubayashi, K. et al. Localization of monoamine oxidase (MAO) in the rat peripheral nervous system — existence of MAO-containing unmyelinated axons. Brain Res. 368, 30–35 (1986).
Kalaria, R. N. & Harik, S. I. Blood–brain barrier monoamine oxidase: enzyme characterization in cerebral microvessels and other tissues from six mammalian species, including human. J. Neurochem. 49, 856–864 (1987).
O'Carroll, A.-M., Fowler, C. J., Phillips, J. P., Tobbia, I. & Tipton, K. F. The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions. Naunyn Schmiedeberg's Arch. Pharmacol. 322, 198–202 (1983). Shows that dopamine is equally well metabolized by both MAO types in the human brain.
Fowler, J. S. et al. Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 235, 481–485 (1987). PET demonstration of MAOs in the brain.
Westlund, K. N., Denney, R. M., Kochersperger, L. M., Rose, R. M. & Abell. C. W. Distinct monoamine oxidase A and B populations in primate brain. Science 230, 181–183 (1985). Describes the distribution of MAOs in primate brain at regional and cellular levels.
Sivasubramaniam, S. D., Finch, C. C., Rodriguez, M. J., Mahy, N. & Billett, E. E. A comparative study of the expression of monoamine oxidase-A and -B mRNA and protein in non-CNS human tissues. Cell Tissue Res. 313, 291–300 (2003).
O'Carroll, A.-M., Tipton, K. F., Sullivan, J. P., Fowler, C. J. & Ross, S. B. Intra- and extrasynaptosomal deamination of dopamine and noradrenaline by the two forms of human brain monoamine oxidase. Implications for the neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in man. Biogenic Amines 4, 165–178 (1987).
Arai, R. et al. Differential subcellular location of mitochondria in rat serotonergic neurons depends on the presence and the absence of monoamine oxidase type B. Neuroscience 114, 825–835 (2002).
Fornai, F. et al. Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study. J. Neurochem. 73, 2434–2440 (1999).
Liccione, J. & Azzaro, A. J. Different roles for type A and type B monoamine oxidase in regulating synaptic dopamine at D-1 and D-2 receptors associated with adenosine-3',5'-cyclic monophosphate (cyclic AMP) formation. Naunyn Schmiedebergs Arch. Pharmacol. 337, 151–158 (1988).
Klann, E. & Thiels, E. Modulation of protein kinases and protein phosphatases by reactive oxygen species: implications for hippocampal synaptic plasticity. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 359–376 (1999).
Jouvet, M. Biogenic amines and the states of sleep. Science 163, 32–41 (1969).
Yang, L., Omori, K., Suzukawa, J. & Inagaki, C. Calcineurin-mediated BAD Ser155 dephosphorylation in ammonia-induced apoptosis of cultured rat hippocampal neurons. Neurosci. Lett. 357, 73–75 (2004).
Halliwell, B. Reactive oxygen species and the central nervous system. J. Neurochem, 59, 1609–1623 (1992).
Lamensdorf, I. et al. 3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells. Brain Res. 868, 191–201 (2000). Reports that neurotoxic aldehydes, which are normally rapidly metabolized by aldehyde dehydrogenase in the brain, accumulate in parkinsonian substantia nigra because aldehyde dehydrogenase gene expression is significantly reduced.
Galter, D., Buervenich, S., Carmine, A., Anvret, M. & Olson, L. ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia. Neurobiol. Dis. 14, 637–647 (2003).
Shin, M. H., Jang, J. H. & Surh, Y. J. Potential roles of NF-κB and ERK1/2 in cytoprotection against oxidative cell death induced by tetrahydropapaveroline. Free Radic. Biol. Med. 36, 1185–1194 (2004).
Vogel, W. H., Ladman, R. K. & Berrettini, W. H. Further studies on the endogenous inhibitor of monoamine oxidase in schizophrenic plasma. Schizophr. Bull. 6, 232–234 (1980).
Demisch, L., Gebhart, P., Kaczmarczyk, P., von der Muhlen, H. & Bochnik, H. J. Low platelet MAO activity in psychiatric patients and plasma factors: no evidence for inhibitory influences on MAO in the circulating platelet population. Biol. Psychiatry 16, 21–33 (1981).
Orologas, A. G., Buckman, T. D. & Eiduson, S. A comparison of platelet monoamine oxidase activity and phosphatidylserine content between chronic paranoid schizophrenics and normal controls. Neurosci. Lett. 68, 293–298 (1986).
Zhu, Q., Chen, K. & Shih, J. Bidirectional promoter of human monoamine oxidase A (MAO A) controlled by transcription factor Sp1. J. Neurosci. 14, 7393–7403 (1994).
Wong, W. K., Ou, X. M., Chen, K. & Shih, J. C. Activation of human monoamine oxidase B gene expression by a protein kinase C MAPK signal transduction pathway involves c-Jun and Egr-1. J. Biol. Chem. 277, 22222–22230 (2002).
Edelstein, S. B. & Breakefield, X. O. Monoamine oxidases A and B are differentially regulated by glucocorticoids and 'aging' in human skin fibroblasts. Cell. Mol. Neurobiol. 6, 121–150 (1986). Describes the regulation of MAOA activity by steroid hormones.
Youdim, M. B. H., Banerjee, D. K., Kelner, K., Offutt, L. & Pollard, H. B. Steroid regulation of monoamine oxidase activity in the adrenal medulla. FASEB J. 3, 1753–1759 (1989). Shows the upregulation of MAOA by progesterone and its downregulation by oestradiol in endothelial cells; effects not seen for the MAOB found in adrenal gland chromaffin cells.
Lenders, J. W. et al. Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. J. Clin. Invest. 97, 1010–1019 (1996).
Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers, H. H. & van Oost, B. A. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262, 578–580 (1993). Finds that a compulsive-aggressive phenotype results from lack of MAOA expression in humans.
Shih, J. C. Cloning, after cloning, knock-out mice, and physiological functions of MAO A and B. Neurotoxicology 25, 21–30 (2004).
Rebsam, A., Seif, I. & Gaspar, P. Dissociating barrel development and lesion-induced plasticity in the mouse somatosensory cortex. J. Neurosci. 25, 706–710 (2005).
Balciuniene, J., Emilsson, L., Oreland, L., Pettersson, U. & Jazin, E. Investigation of the functional effect of monoamine oxidase polymorphisms in human brain. Hum. Genet. 110, 1–7 (2002).
Tadic, A. et al. Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression. Am. J. Med. Genet. B Neuropsychiatr. Genet. 117, 1–6 (2003).
Vanyukov, M. M. et al. Haplotypes of the monoamine oxidase genes and the risk for substance use disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 125, 120–125 (2004).
Peters, E. J., Slager, S. L., McGrath, P. J., Knowles, J. A. & Hamilton, S. P. Investigation of serotonin-related genes in antidepressant response. Mol. Psychiatry 9, 879–889 (2004).
Fowler, J. S. et al. Low monoamine oxidase B in peripheral organs in smokers. Proc. Natl Acad. Sci. USA 100, 11600–11605 (2003). Shows the possible association of low platelet MAO activity and smoking.
Oreland, L. Platelet monoamine oxidase, personality and alcoholism: the rise, fall and resurrection. Neurotoxicology 25, 79–89 (2004). Shows the possible relevance of lowered MAOB activity in platelets to psychological behaviour.
Scott, W. K. et al. Family-based case-control study of cigarette smoking and Parkinson disease. Neurology 64, 442–447 (2005).
Damberg, M. Transcription factor AP-2 and monoaminergic functions in the central nervous system. J. Neural Transm. 112, 1281–1296 (2005).
Binda, C., Newton-Vinson, P., Hubalek, F., Edmondson, D. E. & Mattevi, A. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nature Struct. Biol. 9, 22–26 (2002). The first to report the crystalline structure of MAOB and its interaction with its inhibitors.
Binda, C. et al. Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class. J. Med. Chem. 47, 1767–1774 (2004).
Hubalek, F. et al. Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues. J. Med. Chem. 47, 1760–1766 (2004).
Ma, J. et al. Structure of rat monoamine oxidase A and its specific recognitions for substrates and inhibitors. J. Mol. Biol. 338, 103–114 (2004). First demonstration of the structure of MAOA.
De Colibus, L. et al. Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B. Proc. Natl Acad. Sci. USA 102, 12684–12689 (2005). Shows important differences between the active sites of rat and human MAOA.
Andrés, A. M. et al. Positive selection in MAOA gene is human exclusive: determination of the putative amino acid change selected in the human lineage. Hum. Genet. 115, 377–386 (2004).
Nandigama, R. K., Miller, J. R. & Edmondson, D. E. Loss of serotonin oxidation as a component of the altered substrate specificity in the Y444F mutant of recombinant human liver MAO A. Biochemistry 40, 14839–14846 (2001).
Li, M. Comparative mechanistic and structural approaches to investigate the membrane-bound enzymes monoamine oxidase A and monoamine oxidase B. Thesis, Emory Univ. (2005).
Edmondson, D. E., Mattevi, A., Binda, C., Li, M. & Hubalek, F. Structure and mechanism of monoamine oxidase. Curr. Med. Chem. 11, 1983–1993 (2004).
Silverman, R. B. Radical ideas about monoamine oxidase. Acc. Chem. Res. 28, 335–342 (1995).
Hubalek, F. et al. Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors. J. Biol. Chem. 280, 15761–15766 (2005).
Garrick, N. A. & Murphy, D. L. Species differences in the deamination of dopamine and other substrates for monoamine oxidase in brain. Psychopharmacology 72, 27–33 (1982).
Garrick, N. A. & Murphy, D. L. Monoamine oxidase type A: differences in selectivity towards l-norepinephrine compared to serotonin. Biochem. Pharmacol. 31, 4061–4066 (1982).
Krueger, M. J., Mazouz, F., Ramsay, R. R., Milcent, R. & Singer, T. P. Dramatic species differences in the susceptibility of monoamine oxidase B to a group of powerful inhibitors. Biochem. Biophys. Res. Commun. 206, 556–562 (1995).
O'Brien, E. M., Dostert, P. & Tipton, K. F. Species differences in the interactions of the anticonvulsant milacemide and some analogues with monoamine oxidase-B. Biochem. Pharmacol. 50, 317–324 (1995).
Reid, A. A., Hill, J. L. & Murphy, D. L. Interactions of tricyclic antidepressant drugs with human and rat monoamine oxidase type B. Naunyn-Schmiedeberg's Arch. Pharmacol. 388, 678–683 (1988).
Inoue, H. et al. Species-dependent differences in monoamine oxidase A and B-catalyzed oxidation of various C4 substituted 1-methyl-4-phenyl-1,2,3,6-tet-rahydropyridinyl derivatives. J. Pharmacol. Exp. Ther. 291, 856–864 (1999).
Pletscher, A. The discovery of antidepressants: a winding path. Experientia 47, 4–8 (1991). A review of the discovery of MAO inhibitors and other antidepressants.
Dostert, P., Strolin Benedetti, M. & Tipton, K. F. Interactions of monoamine oxidase with substrates and inhibitors. Med. Res. Rev. 19, 45–89 (1989). Describes the mechanistic interaction of substrates and inhibitors with MAO.
Da Prada, M., Zürcher, G., Würthrich, I. & Haefely, W. E. On tyramine, food beverages and the reversible MAO inhibitor moclobemide. J. Neural. Transm. 26 (Suppl.), 33–56 (1988). Describes the presence of tyramine in various food items and its possible cardiovascular effects with MAO inhibitors.
Knoll, J. (–)Deprenyl (Selegiline): past, present and future. Neurobiology (Bp.) 8, 179–199 (2000). An authoratative review of the pharmacolgical aspects of l -deprenyl (Selegiline).
Youdim, M. B. H. & Weinstock, M. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology 25, 243–250 (2004).
Hasan, F., McCrodden, J. M., Kennedy, N. P. & Tipton, K. F. The involvement of intestinal monoamine oxidase in the transport and metabolism of tyramine. J. Neural Transm. 26 (Suppl.), 1–9 (1988).
Da Prada, M. et al. From moclobemide to Ro 19-6327 and Ro 41-1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors. J. Neural. Transm. 29 (Suppl.), 279–292 (1990). The rationale and development of reversible MAOA and MAOB inhibitors as antidepressants and anti-parkinsonian drugs.
Anderson, M. C., Hasan, F., McCrodden, J. M. & Tipton, K. F. Monoamine oxidase inhibitors and the cheese effect. Neurochem. Res. 18, 1145–1149 (1993).
Florvall, L., Fagervall, I., Ask, A. L. & Ross, S. B. Selective monoamine oxidase inhibitors. 4.4-Aminophenethylamine derivatives with neuron-selective action. J. Med. Chem. 29, 2250–2256 (1986).
Palfreyman, M. G. et al. Inhibition of monoamine oxidase selectively in brain monoamine nerves using the bioprecursor (E)-β-fluoromethylene-m-tyrosine (MDL 72394), a substrate for aromatic L-amino acid decarboxylase. J. Neurochem. 45, 1850–1860 (1985).
Youdim, M. B. H. & Buccafusco, J. J. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci. 26, 27–35 (2005). Discusses the potential value of developing multifunctional drugs for complex neuropsychiatric disorders, with the drug ladostigil (TV3326) as an example.
Gal, S., Zheng, H., Fridkin, M. & Youdim, M. B. Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J. Neurochem. 95, 79–88 (2005). Reports the potential value of a novel iron chelator and brain-selective irreversible MAOA/B inhibitor for treatment of neurodegenerative diseases.
Zisook, S. E. Clinical overview of monoamine oxidase inhibitors. Psychosomatics 26, 240–251 (1985). A review of MAO inhibitors as antidepressants in the clinic.
Gareri, P., Falconi, U., De Fazio, P. & De Sarro, G. Conventional and new antidepressant drugs in the elderly. Progr. Neurobiol. 61, 353–396 (2000).
Kier, A., Han, J. & Jacobson, L. Chronic treatment with the monoamine oxidase inhibitor phenelzine increases hypothalamic–pituitary–adrenocortical activity in male C57BL/6 mice: relevance to atypical depression. Endocrinology 146, 1338–1347 (2005).
Kasckow, J. W., Baker, D. & Geracioti, T. D. Corticotropin-releasing hormone in depression and post-traumatic stress. Peptides 22, 845–851 (2001).
Houtsmuller, E. J., Thornton, J. A. & Stitzer, M. L. Effects of selegiline (l-deprenyl) during smoking and short-term abstinence. Psychopharmacology (Berl.) 163, 213–220 (2002).
Berlin, I. et al. Lazabemide, a selective, reversible monoamine oxidase B inhibitor, as an aid to smoking cessation. Addiction 97, 1347–1354 (2002).
Berlin, I. et al. A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clin. Pharmacol. Ther. 58, 444–452 (1995). The rationale for the possible use of MAO inhibitors in cessation of smoking, and their mechanisms of action.
Fowler, J. S. et al. Brain monoamine oxidase A inhibition in cigarette smokers. Proc. Natl Acad. Sci. USA 93, 14065–14069 (1996).
Herraiz, T. & Chaparro, C. Human monoamine oxidase is inhibited by tobacco smoke: β-carboline alkaloids act as potent and reversible inhibitors. Biochem. Biophys. Res. Commun. 326, 378–386 (2005).
Birkmayer, W., Riederer, P., Ambrozi, L. & Youdim, M. B. H. Implications of combined treatment with 'Madopar' and l-deprenil in Parkinson's disease. A long-term study. Lancet 309, 439–443 (1977). Describes studies using l -deprenyl (Selegiline) as adjuvant to L -DOPA in Parkinson's disease.
Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. New Engl. J. Med. 328, 176–183 (1993).
Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP subjects not requiring levodopa. Ann. Neurol. 39, 29–36 (1996). Results of long-term studies showing l -deprenyl to be of short-term benefit during the early stages of Parkinson's disease.
Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch. Neurol. 62, 241–248 (2005). Reports on a clinical trial indicating that rasagiline is of value in the therapy of Parkinson's disease.
Tetrud, J. W. & Koller, W. C. A novel formulation of selegiline for the treatment of Parkinson's disease. Neurology 63 (Suppl. 2), S2–S6 (2004).
Rascol, O. et al. LARGO study group. Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 365, 947–954 (2005). Reports on a clinical study of rasagiline and a comparison with the catecol- O -methytransferase inhibitor, entacapone, in the treatment of Parkinson's disease.
Parkinson Study Group. Effect of lazabemide on the progression of disability in early Parkinson's disease. Ann. Neurol. 40, 99–107 (1996). The first successful clinical trial of the reversible MAOB inhibitor lazabemide in Parkinson's disease.
Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch. Neurol. 61, 561–566 (2004).
Macleod, A. D., Counsell, C. E., Ives, N. & Stowe, R. Monoamine oxidase B inhibitors for early Parkinson's disease. [online], Cochrane Database Syst. Rev. CD004898 (2005). A comprehensive analysis that suggests that the value of MAOB inhibitors has not yet been convincingly established.
Clarke, C. E. A 'Cure' for Parkinson's disease: can neuroprotection be proven with current trial designs? Mov. Disord. 19, 491–498 (2004).
Green, A. R., Mitchell, B. D., Tordoff, A. F. & Youdim M. B. H. Evidence for dopamine deamination by both type A and type B monoamine oxidase in rat brain in vivo and for the degree of inhibition of enzyme necessary for increased functional activity of dopamine and 5-hydroxytryptamine. Br. J. Pharmacol. 60, 343–349 (1977). In vivo demonstration that dopamine is equally well metabolized by brain MAOA and MAOB in the rat.
Janssen, P. A., Leysen, J. E., Megens, A. A. & Awouters, F. H. Does phenylethylamine act as an endogenous amphetamine in some patients? Int. J. Neuropsychopharmcol. 2, 229–240 (1999). Discusses the importance of phenylethylamine in relation to dopaminergic activity in the CNS.
Li, X. M., Juorio, A. V., Qi, J. & Boulton, A. A. L-deprenyl induces aromatic L-amino acid decarboxylase (AADC) mRNA in the rat substantia nigra and ventral tegmentum. An in situ hybridization study. Mol. Chem. Neuropathol. 35, 149–155 (1998).
Boulton, A. A. Phenylethylaminergic modulation of catecholaminergic neurotransmission. Prog. Neuropsychopharmacol. Biol. Psychiatry 15, 139–156 (1991). Describes the importance of phenylethylamine function in relation to dopaminergic activity in the CNS.
Sieradzan, K. et al. The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in Parkinson's disease. J. Clin. Psychopharmacol. 15 (Suppl. 2), S1–S59 (1995). Controlled study reporting the effectiveness of the reversible MAOA inhibitor moclobemide in Parkinson's disease.
Yasar, S., Goldberg, J. P. & Goldberg, S. R. Are metabolites of l-deprenyl (selegiline) useful or harmful? Indications from preclinical research. J. Neural Transm. 48 (Suppl.), 61–73 (1996).
Sziraki, I. et al. Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2'-methyl-MPTP. J. Neural Transm. 41 (Suppl.), 207–219 (1994).
Tipton, K. F. What is it that l-deprenyl (selegiline) might do? Clin. Pharmacol. Ther. 56, 781–796 (1994).
Le, W., Jankovic, J., Xie, W., Kong, R. & Appel S. H. (–)-Deprenyl protection of 1-methyl-4 phenylpyridium ion (MPP+)-induced apoptosis independent of MAO-B inhibition. Neurosci. Lett. 224, 197–200 (1997).
Magyar, K. & Szende, B. (–)-Deprenyl, a selective MAO-B inhibitor, with apoptotic and anti-apoptotic properties. Neurotoxicology 25, 233–242 (2004).
Seymour, C. B., Mothersill, C., Mooney, R., Moriarty, M. & Tipton, K. F. Monoamine oxidase inhibitors l-deprenyl and clorgyline protect nonmalignant human cells from ionising radiation and chemotherapy toxicity. Br. J. Cancer 89, 1979–1986 (2003). Demonstration that the cytoprotective effects of propargylamines are not restricted to neuronal cells.
Birks, J. & Flicker, L. Selegiline for Alzheimer's disease. [online], Cochrane Database Syst. Rev. CD000442 (2003).
Kennedy, B. P. et al. Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer's disease. J. Neural Transm. 110, 789–801 (2003).
Marin, D. B. et al. L-deprenyl and physostigmine for the treatment of Alzheimer's disease. Psychiatry Res. 58, 181–189 (1995).
Youdim, M. B. H. & Weinstock, M. Molecular basis of neuroprotective activities of rasagiline and the anti- Alzheimer drug, TV3326, [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell. Mol. Neurobiol. 21, 555–573 (2002).
Weinstock, M. et al. A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 555–561 (2003). Description of the pharmacological activity of the multifunctional neuroprotective cholinesterase and brain-selective MAOA/B inhibitor ladostigil (TV3326).
Buccafusco, J. J., Terry, A. V., Goren, T. & Blaugrun, E. Potential cognitive actions of (n-propargly-(3r)-aminoindan-5-yl)-ethyl, methyl carbamate (tv3326), a novel neuroprotective agent, as assessed in old rhesus monkeys in their performance of versions of a delayed matching task. Neuroscience 119, 669–678 (2003).
Poltyrev, T., Gorodetsky, E., Bejar, C., Schorer-Apelbaum, D. & Weinstock, M. Effect of chronic treatment with ladostigil (TV-3326) on anxiogenic and depressive-like behaviour and on activity of the hypothalamic–pituitary–adrenal axis in male and female prenatally stressed rats. Psychopharmacology (Berl.) 181, 118–125 (2005).
Lange, D. J. et al. Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis. Arch. Neurol. 55, 93–96 (1998).
Waibel, S., Reuter, A., Malessa, S., Blaugrund, E. & Ludolph, A. C. Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J. Neurol. 251, 1080–1084 (2004).
Sagot, Y. et al. An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease. Br. J. Pharmacol. 131, 721–728 (2000).
Patel, S. V., Tariot, P. N. & Asnis, J. L-Deprenyl augmentation of fluoxetine in a patient with Huntington's disease. Ann. Clin. Psychiatry 8, 23–26 (1966).
Qin, F., Shite, J., Mao, W. & Liang, C. S. Selegiline attenuates cardiac oxidative stress and apoptosis in heart failure: association with improvement of cardiac function. Eur. J. Pharmacol. 461, 149–158 (2003).
Kunduzova, O. R. et al. Regulation of JNK/ERK activation, cell apoptosis, and tissue regeneration by monoamine oxidases after renal ischemia-reperfusion. FASEB J. 16, 1129–1131 (2002).
Simon, L., Szilagyi, G., Bori, Z., Orbay, P. & Nagy, Z. (–)-D-Deprenyl attenuates apoptosis in experimental brain ischaemia. Eur. J. Pharmacol. 430, 235–241 (2001).
Kunduzova, O. R., Bianchi, P., Parini, A. & Cambon, C. Hydrogen peroxide production by monoamine oxidase during ischemia/reperfusion. Eur. J. Pharmacol. 448, 225–230 (2002).
Vondriska, T. M., Klein, J. B. & Ping, P. Use of functional proteomics to investigate PKCε-mediated cardioprotection: the signaling module hypothesis. Am. J. Physiol. Heart Circ. Physiol. 280, H1434–H1441 (2001).
Weinreb, O., Bar-Am, O., Amit, T., Chillag-Talmor, O. & Youdim, M. B. H. Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. FASEB J. 18, 1471–1473 (2004). Demonstrates that the molecular mechanism of neuroprotective activity of propargylamines involves activation of PKC.
Sivenius, J. et al. Selegiline treatment facilitates recovery after stroke. Neurorehabil. Neural Repair 15, 183–190 (2001).
Oreland, L. & Gottfries, C. G. Brain and brain monoamine oxidase in aging and in dementia of Alzheimer's type. Prog. Neuropsychopharmacol. Biol. Psychiatry 10, 533–540 (1986).
Kitani, K. et al. Why (–)deprenyl prolongs survivals of experimental animals: increase of anti-oxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic anti-aging effects. Mech. Ageing Dev. 123, 1087–1100 (2002). Review on the ability of propargylamine MAO inhibitors to increase anti-oxidant enzyme activities.
Carageorgiou, H., Zarros, A. & Tsakiris, S. Selegiline long-term effects on brain acetylcholinesterase, (Na+, K+)-ATPase activities, antioxidant status and learning performance of aged rats. Pharmacol. Res. 48, 245–251 (2003).
Birkmayer, W. et al. Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a longterm study. J. Neural Transm. 64, 113–127 (1985). Study suggesting that l -deprenyl can increase life expectancy in patients with Parkinson's disease.
Grimsby, J. et al. Increased stress response and β-phenylethylamine in MAO B-deficient mice. Nature Genet. 17, 206–210 (1997).
Magyar, K. Behaviour of (–)-deprenyl and its analogues. J. Neural Transm. 41 (Suppl.), 167–175 (1994).
Cutillas, B., Ambrosio, S. & Unzeta, M. Neuroprotective effect of the monoamine oxidase inhibitor PF 9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl)methylamine] on rat nigral neurons after 6-hydroxydopamine-striatal lesion. Neurosci. Lett. 329, 165–168 (2002).
Boulton, A. A., Yu, P. H., Davis, B. A. & Boulton, A. A. Aliphatic propargylamines, a new series of potent selective, irreversible non-amphetamine-like MAO-B inhibitors. Their structures, function and pharmacological implications. Adv. Exp. Med. Biol. 363, 17–23 (1995). Demonstration that aliphatic propargylamines act as MAO inhibitors, and their possible anti-parkinson activity.
Berry, M. D. & Boulton, A. A. Aliphatic propargylamines as symptomatic and neuroprotective treatments for neurodegenerative diseases. Neurotoxicol. Teratol. 24, 667–673 (2002).
Maruyama, W., Boulton, A. A., Davis, B. A., Dostert, P. & Naoi, M. Enantio-specific induction of apoptosis by an endogenous neurotoxin N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells: suppression of apoptosis by N-(2-heptyl)-N-methylpropargylamine. J. Neural Transm. 108, 11–24 (2001). Anti-apoptotic actions of an aliphatic propargylamine.
Uversky, V. N. Neurotoxicant-induced animal models of Parkinson's disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration. Cell Tissue Res. 318, 225–241 (2004).
Burke, W. J. et al. Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. Neurotoxicology 25, 101–115 (2004).
Burke, W. J. 3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease. Curr. Drug Targets CNS Neurol. Disord. 2, 143–148 (2003). Suggests that prevention of dopamine-derived aldehyde formation by MAO inhibitors might contribute to their possible neuroprotective actions.
Ansari, K. S., Yu, P. H., Kruck, T. P. & Tatton, W. G. Rescue of axotomized immature rat facial motoneurons by R(–)-deprenyl: stereospecificity and independence from monoamine oxidase inhibition. J. Neurosci. 13, 4042–4053 (1993). Reports the ability of l -deprenyl to rescue nerves from the consequences of physical damage, and the ineffectiveness of d -deprenyl.
Mytilineou, C. et al. Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion. J. Pharmacol. Exp. Ther. 284, 700–706 (1998).
Kragten, E. et al. Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(–)-deprenyl. J. Biol. Chem. 273, 5821–5828 (1998). Reports that glyceraldehyde-3-phosphate dehydrogenase is a target for the anti-apoptotic propargylamines.
Waldmeier, P. C., Boulton, A. A., Cools, A. R., Kato, A. C. & Tatton, W. G. Neurorescuing effects of the GAPDH ligand CGP 3466B. J. Neural Transm. 60 (Suppl.), 197–214 (2000). Describes a neuroprotective propargylamine dervative that does not inhibit MAO.
Huang, W., Chen, Y., Shohami, E. & Weinstock, M. Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. Eur. J. Pharmacol. 366, 127–135 (1999).
Sharma, S. K., Carlson, E. C. & Ebadi, M. Neuroprotective actions of Selegiline in inhibiting 1-methyl,4-phenyl,pyridinium ion (MPP+)-induced apoptosis in SK-N-SH neurons. J. Neurocytol. 32, 329–343 (2003).
Tatton, W. G. et al. Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells. J. Pharmacol. Exp. Ther. 301, 753–764 (2002).
Tipton, K. F. & Singer, T. P. Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J. Neurochem. 61, 1191–1206 (1993). Review on the mechansism of MPTP neurotoxicity in relation to its inhibition of mitochondrial complex I.
Kruman, I. I. & Mattson, M. P. Pivotal role of mitochondrial calcium uptake in neural cell apoptosis and necrosis. J. Neurochem. 72, 529–540 (1999).
Mattson, M. P. & Kroemer, G. Mitochondria in cell death: novel targets for neuroprotection and cardioprotection. Trends Mol. Med. 9, 196–205 (2003).
Cleeter, M. W., Cooper, J. M. & Schapira, A. H. Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement. J. Neurochem. 58, 786–789 (1992).
Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889–909 (2003).
Emerit, J., Edeas, M. & Bricaire, F. Neurodegenerative diseases and oxidative stress. Biomed. Pharmacother. 58, 39–46 (2004).
Barnham, K. J., Masters, C. L. & Bush, A. I. Neurodegenerative diseases and oxidative stress. Nature Rev. Drug Discov. 3, 205–214 (2004).
Andersen, J. K. Oxidative stress in neurodegeneration: cause or consequence? Nature Med. 10 (Suppl.), S18–S25 (2004).
Mizuta, I. et al. Selegiline and desmethylselegiline stimulate NGF, BDNF, and GDNF synthesis in cultured mouse astrocytes. Biophys. Res. Commun. 279, 751–755 (2000).
Li, X. M., Qi, J., Juorio, A. V. & Boulton, A. A. Reduction in glial fibrillary acidic protein mRNA abundance induced by (–)-deprenyl and other monoamine oxidase B inhibitors in C6 glioma cells. J. Neurochem. 61, 1573–1576 (1993).
Munirathinam, S., Lakshmana, M. K. & Raju, T. R. (–) Deprenyl attenuates aluminium induced neurotoxicity in primary cortical cultures. Neurodegeneration 5, 161–167 (1996).
Finnegan, K. T., Skratt, J. J., Irwin, I., DeLanney, L. E. & Langston, J. W. Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B. Eur. J. Pharmacol. 184, 119–126 (1990).
Salonen, T., Haapalinna, A., Heinonen, E., Suhonen, J. & Hervonen, A. Monoamine oxidase B inhibitor selegiline protects young and aged rat peripheral sympathetic neurons against 6-hydroxydopamine-induced neurotoxicity. Acta Neuropathol. (Berl.) 91, 466–474 (1996).
Mytilineou, C., Radcliffe, P., Leonardi, E. K., Werner, P. & Olanow, C. W. L-deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro. J. Neurochem. 68, 33–39 (1997).
Naoi, M., Maruyama, W., Takahashi, T., Akao, Y. & Nakagawa, Y. Involvement of endogenous N-methyl(R)salsolinol in Parkinson's disease: induction of apoptosis and protection by (–)deprenyl. J. Neural Transm. 58 (Suppl.), 111–121 (2000). Describes the possible importance of dopamine-derived isoquinolines in Parkinson's disease.
Maruyama, W., Takahashi, T. & Naoi, M. (–)-Deprenyl protects human dopaminergic neuroblastoma SH-SY5Y cells from apoptosis induced by peroxynitrite and nitric oxide. J. Neurochem. 70, 2510–2515 (1998).
de la Cruz, C. P. et al. Protection of the aged substantia nigra of the rat against oxidative damage by (–)-deprenyl. Br. J. Pharmacol. 117, 1756–1760 (1996).
Knollema, S., Aukemam, W., Hom, H., Korf, J. & ter Horst, G. J. L-deprenyl reduces brain damage in rats exposed to transient hypoxia-ischemia. Stroke 26, 1883–1887 (1995).
Buys, Y. M., Trope, G. E. & Tatton, W. G. (–)-Deprenyl increases the survival of rat retinal ganglion cells after optic nerve crush. Curr. Eye Res. 14, 119–126 (1995).
Tatton, W. G. & Greenwood, C. E. Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J. Neurosci. Res. 30, 666–672 (1991). Demonstration that l -deprenyl has 'neurorescue' activity when administered after neurons have been induced to degenerate.
Bar-Am, O., Weinreb, O., Amit, T. & Youdim, M. B. Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J. 19, 1899–1901 (2005). The neuroprotective/neurorescue activites of propargylamines, including propargylamine itself, also involve alterations in APP processing.
De Girolamo, L. A., Hargreaves, A. J. & Billett, E. E. Protection from MPTP-induced neurotoxicity in differentiating mouse N2a neuroblastoma cells. J. Neurochem. 76, 650–660 (2001).
LeWitt, P. A. Clinical trials of neuroprotection for Parkinson's disease. Neurology 63, S23–S31 (2004). Review of clinical studies on neuroprotective drugs; their limitations and failures, and what to do next.
Lee, C. S., Han, E. S. & Lee, W. B. Antioxidant effect of phenelzine on MPP-induced cell viability loss in differentiated PC12 cells. Neurochem. Res. 28, 1833–1841 (2003).
Bonnet, U., Leniger, T. & Wiemann, M. Moclobemide reduces intracellular pH and neuronal activity of CA3 neurones in guinea-pig hippocampal slices — implication for its neuroprotective properties. Neuropharmacology 39, 2067–2074 (2000).
Marzo, A. et al. Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol. Res. 50, 77–85 (2004).
Stocchi, F. et al. Improvement of motor function in early Parkinson disease by safinamide. Neurology 63, 746–748 (2004). Reports the effectiveness of safinamide — a reversible MAOB inhibitor that is not a propargylamine derivative — in the treatment of Parkinson's disease.
Maj, R. et al. PNU-151774E protects against kainate-induced status epilepticus and hippocampal lesions in the rat. Eur. J. Pharmacol. 359, 27–32 (1998).
Ashe, P. C. & Berry, M. D. Apoptotic signaling cascades. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 199–214 (2003).
Blum, D. et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease. Prog. Neurobiol. 65, 135–172 (2001).
Waldmeier, P. C. & Tatton, W. G. Interrupting apoptosis in neurodegenerative disease: potential for effective therapy? Drug Disc. Today 9, 210–218 (2004).
Stocchi, F. & Olanow, C. W. Neuroprotection in Parkinson's disease: clinical trials. Ann. Neurol. 53 (Suppl. 3), S87–S99 (2003).
Wadia, J. S. et al. Mitochondrial membrane potential and nuclear changes in apoptosis caused by serum and nerve growth factor withdrawal: time course and modification by (–)-deprenyl. J. Neurosci. 18, 932–947 (1998). Shows that l -deprenyl protects against alterations in mitochondrial function, which can result in apoptosis.
Akao, Y. et al. Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and Rasagiline, N-Propargyl-1(R)-aminoindan. J. Neurochem. 82, 913–923 (2002).
Keller, J. N., Huang, F. F., Dimayuga, E. R. & Maragos, W. F. Dopamine induces proteasome inhibition in neural PC12 cell line. Free Radic. Biol. Med. 29, 1037–1042 (2000).
Kitazawa, M., Wagner, J. R., Kirby, M. L., Anantharam, V. & Kanthasamy, A. G. Oxidative stress and mitochondrial-mediated apoptosis in dopaminergic cells exposed to methylcyclopentadienyl manganese tricarbonyl. J. Pharmacol. Exp. Ther. 302, 26–35 (2002).
Tatton, W. G., Wadia, J. S., Ju, W. Y., Chalmers-Redman, R. M. & Tatton, N. A. (–)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. J. Neural Transm. 48 (Suppl.), 45–59 (1996). l -Deprenyl alters the synthesis of several proteins, including increased expression of Bcl-2, and protein-synthesis inhibitors prevent its protective actions.
Ekblom, J. et al. mRNA expression of neurotrophins and members of the trk family in the rat brain after treatment with L-deprenyl. Acta Neurol. Scand. 89, 147–148 (1994). Shows that l -deprenyl causes increased expression of mRNA for neurotrophins.
Andoh, T., Chock, P. B., Murphy, D. L. & Chiueh, C. C. Role of the redox protein thioredoxin in cytoprotective mechanism evoked by (–)-deprenyl. Mol. Pharmacol. 68, 1408–1414 (2005).
Thiffault, C., Aumont, N., Quirion, R. & Poirier, J. Effect of MPTP and L-deprenyl on antioxidant enzymes and lipid peroxidation levels in mouse brain. J. Neurochem. 65, 2725–2733 (1995).
Kitani, K. et al. Common properties for propargylamines of enhancing superoxide dismutase and catalase activities in the dopaminergic system in the rat: implications for the life prolonging effect of (–) deprenyl. J. Neural Transm. 60 (Suppl.), 139–156 (2000). Shows that propargylamines increase the levels of the antioxidant enzymes superoxide dismutase and catalase in the rat.
Kim, S. G., Lee, C. H. & Park, J. W. Deprenyl, a therapeutic agent for Parkinson's disease, inhibits arsenic toxicity potentiated by GSH depletion via inhibition of JNK activation. J. Toxicol. Environ. Health A67, 2013–2024 (2004).
Saporito, M. S., Thomas, B. A. & Scott, R. W. MPTP activates c-Jun NH2-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J. Neurochem. 75, 1200–1208 (2000).
Bar-Am, O., Yogev-Falach, M., Amit, T., Sagi, I. & Youdim, M. B. H. Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo. J. Neurochem. 89, 1119–1125 (2004).
Xu, L., Ma, J., Seigel, G. M. & Ma, J. X. l-Deprenyl, blocking apoptosis and regulating gene expression in cultured retinal neurons. Biochem. Pharmacol. 58, 1183–1190 (1999).
Youdim, M. B. H., Maruyama, W. & Naoi, M. Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. Drugs Today (Barc.) 41, 369–391 (2005). A recent review on the pharmacological activity of rasagiline and the molecular mechanism of its neuroprotective and neurorescue activities.
Muller, T., Kuhn, W., Kruger, R. & Przuntek, H. Selegiline as immunostimulant — a novel mechanism of action? J. Neural Transm. 52 (Suppl.), 321–328 (1998).
Holt, A., Berry, M. D. & Boulton, A. A. On the binding of monoamine oxidase inhibitors to some sites distinct from the MAO active site, and effects thereby elicited. Neurotoxicology 25, 251–266 (2004).
Ekblom, J., Oreland, L., Chen, K. & Shih, J. C. Is there a 'non-MAO' macromolecular target for L-deprenyl?: studies on MAOB mutant mice. Life Sci. 63, PL181–PL186 (1998).
Maruyama, W., Akao, Y., Youdim, M. B., Davis, B. A. & Naoi, M. Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J. Neurochem. 78, 727–735 (2001).
Tatton, W., Chalmers-Redman, R. & Tatton, N. Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B. J. Neural Transm. 110, 509–515 (2003). The neuroprotective ability of propargylamines results from their binding to GAPDH, which, in turn, mediates decreases in the expression of pro-apoptotic proteins and increases the synthesis of anti-apoptotic proteins.
Marras, C. et al. Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. Neurology 64, 87–93 (2005). Reports that l -deprenyl is safe for long-term administration to humans.
Youdim, M. B. & Bakhle, Y. S. Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness. Br. J. Pharmacol. 47 (Suppl. 1), S287–S296 (2006). A recent review on the neuropharmacology of MAO inhibitors.
M.B.H.Y. would like to thank the National Parkinson Foundation, Miami, USA, the Michael J. Fox Foundation, New York, USA, and Technion Research and Development and Teva Pharmaceutical Co., Netanya, Israel, for their support. K.F.T. is grateful to the Health Research Board and Science Foundation of Ireland for support.
M.B.H.Y. has received research support and will profit from the sale of rasagiline and ladostigil, which are being developed by Teva Pharamaceutical Co., Israel, and M30, which is being developed by Varinel Inc., USA.
- Microsomal fraction
An artefactual particulate fraction, obtained as a result of cell disruption and high-speed centrifugation, comprising fragments of the endoplasmic reticulum with which ribosomes and monooxygenase enzymes are associated.
- Endoneurial vessels
The capillaries that normally constitute a blood–nerve barrier in peripheral nerves, and help to optimize the endoneurial environment.
A preparation of the presynaptic terminal, often containing a portion of the target cell — sometimes amounting to a complete dendritic spine — adhering to their external surface. This structure retains the anatomical integrity of the terminal and can take up, store and release neurotransmitters.
- K m
(The Michaelis–Menten constant). A kinetic parameter corresponding to the substrate concentration that gives half-maximum velocity enzyme-catalysed reaction. Under certain conditions the Km for a substrate may equate to the dissociation constant of the enzyme–substrate complex, and the lower the value of Km, the tighter the substrate binds.
- Norrie disease
A rare genetic disorder characterized by bilateral congenital blindness due to a maldeveloped retina. The Norrie disease gene and MAO genes are tandemly arranged on the human X chromosome, and syndromes resulting from chromosomal deletions in two or three of these genes have been identified.
- Flavin moiety
A tricyclic heteronuclear organic ring, derived from riboflavin, that is capable of undergoing reduction-oxidation reactions. This structure is normally attached to an ADP to form the enzyme co-factor FAD.
- Re face
A stereoheterotropic face of a trigonal atom is designated Re if the ligands of the trigonal atom appear in a clockwise sense in order of priority when viewed from that side of the face.
- R and S isomers
The R/S system identifies optical isomers based on the configuration of ligands that have been assigned a priority. When the centre of a molecule is orientated so that the lowest priority of four ligands is pointed away from the viewer, the centre is labelled R if ligands of decreasing priority are arranged in a clockwise orientation, or S if this arrangement is anticlockwise.
The use of a single drug or other therapy to treat a condition.
About this article
Cite this article
Youdim, M., Edmondson, D. & Tipton, K. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7, 295–309 (2006). https://doi.org/10.1038/nrn1883
Comment on: “Monoamine Oxidase Inhibitors (MAOIs) in Psychiatric Practice: How to Use them Safely and Effectively”
CNS Drugs (2022)
Site-activated multi target iron chelators with acetylcholinesterase (AChE) and monoamine oxidase (MAO) inhibitory activities for Alzheimer’s disease therapy
Journal of Neural Transmission (2022)
Molecular Brain (2021)
Screening natural product extracts for potential enzyme inhibitors: protocols, and the standardisation of the usage of blanks in α-amylase, α-glucosidase and lipase assays
Plant Methods (2021)
Molecular Psychiatry (2021)