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An update on amine oxidase inhibitors: multifaceted drugs

Contents lists available at Progress in Neuro-Psychopharmacology & Biological An update on amine oxidase inhibitors: Multifaceted drugs Mee-Sook Song Dmitriy Matveychuk , Erin M. MacKenzie , Maryana Duchcherer Darrell D. Mousseau Glen B. Baker a Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canadab Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Although not used as extensively as other antidepressants for the treatment of depression, the monoamine Received 8 September 2012 oxidase (MAO) inhibitors continue to hold a niche in psychiatry and to have a relatively broad spectrum Received in revised form 31 January 2013 with regard to treatment of psychiatric and neurological disorders. Experimental and clinical research on Accepted 3 February 2013 MAO inhibitors has been expanding in the past few years, primarily because of exciting findings indicating Available online 11 February 2013 that these drugs have neuroprotective properties (often independently of their ability to inhibit MAO). Thenon-selective and irreversible MAO inhibitors tranylcypromine (TCP) and phenelzine (PLZ) have demonstrated neuroprotective properties in numerous studies targeting elements of apoptotic cascades and neurogenesis.
Monoamine oxidase l-Deprenyl and rasagiline, both selective MAO-B inhibitors, are used in the management of Parkinson's disease, but these drugs may be useful in the treatment of other neurodegenerative disorders given that they demon- Primary amine oxidase strate neuroprotective/neurorescue properties in a wide variety of models in vitro and in vivo. Although the focus of studies on the involvement of MAO inhibitors in neuroprotection has been on MAO-B inhibitors, there is a growing body of evidence demonstrating that MAO-A inhibitors may also have neuroprotective properties.
In addition to MAO inhibition, PLZ also inhibits primary amine oxidase (PrAO), an enzyme implicated in theetiology of Alzheimer's disease, diabetes and cardiovascular disease. These multifaceted aspects of amine oxidaseinhibitors and some of their metabolites are reviewed herein.
2013 Elsevier Inc. All rights reserved.
Non-selective inhibitors of MAO: phenelzine and tranylcypromine MAO-B inhibitors: l-deprenyl and rasagiline . . . . . . . . . . . . . . . . . . . . . . . .
Primary amine oxidase and its inhibition Metabolism of amine oxidase inhibitors and its relevance Future applications and drug development Abbreviations: MAO, monoamine oxidase; PrAO, primary amine oxidase; SSAO, semicarbazide-sensitive amine oxidase; TCP, tranylcypromine; PLZ, phenelzine; PEH, Monoamine oxidase (MAO) inhibitors are not prescribed as widely β-phenylethylidenehydrazine; BDNF, brain-derived neurotrophic factor; EAE, experi-mental autoimmune encephalomyelitis; GABA, γ-aminobutyric acid; GABA-T, GABA as other antidepressants ), but they continue to transaminase; AD, Alzheimer's disease.
hold an important niche in the treatment of psychiatric and neurolog- ⁎ Corresponding author at: Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, AB, Canada T6G 2R7. Tel.: +1 780 492 5994; fax: +1 780 492 6841.
E-mail address: (G.B. Baker).
in these drugs has increased significantly in recent years following 0278-5846/$ – see front matter 2013 Elsevier Inc. All rights reserved.

M.-S. Song et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 118–124 numerous reports of their neuroprotective/neurorescue properties are formed from amines, from lipid peroxidation, in glycolytic path- ways and through the metabolism of some amino acids. Such aldehydes, which include 3-aminopropanal, acrolein, 4-hydroxy-2-nonenal, form- exciting findings with primary amine oxidase [PrAO, previously called aldehyde and aldehyde metabolites of catecholamines, are very reactive semicarbazide-sensitive amine oxidase (SSAO)] and its inhibitors have and can covalently modify proteins, nucleic acids, lipids and carbohy- stimulated research on amine oxidase inhibitors and increased our drates and activate apoptotic pathways knowledge of the etiology of several neuropsychiatric disorders and associated diabetes and cardiovascular disease ( ). Because of its In this review, we will provide an update on neuroprotection hydrazine structure, PLZ is very effective at sequestering aldehydes by amine oxidase inhibitors, on the importance of metabolism of these through a direct chemical reaction ( drugs and on possible future drug applications in this area.
resulting in the formation of an inert hydrazone molecule andreduced concentrations of toxic aldehydes. Reactive aldehydes have 2. Non-selective inhibitors of MAO: phenelzine been implicated in the pathophysiology of a number of conditions in- and tranylcypromine cluding Alzheimer's disease (AD) and various cardiovascular diseases Phenelzine (2-phenylethylhydrazine, PLZ) ) is an irreversible, Interestingly, the reactive aldehyde non-selective MAO inhibitor (i.e. inhibits both MAO-A and MAO-B) that acrolein has recently been suggested to be a potential factor in oxida- has been used for many years as an antidepressant drug and is also tive stress and myelin loss in multiple sclerosis (), effective in treating panic disorder, social anxiety disorder, and post- and was shown to induce marked myelin damage to isolated spinal traumatic stress disorder (PTSD) cords in vitro () and to be involved in spinal cord injury . Although it is an MAO inhibitor, it also pro- in vivo Furthermore, acrolein-protein adduct duces marked increases in brain levels of γ-aminobutyric acid (GABA) levels were significantly increased in experimental autoimmune en- by inhibiting GABA transaminase (GABA-T) ( cephalomyelitis (EAE), an animal model of multiple sclerosis, and se- ). PLZ has been reported to be neuroprotective in questration of acrolein with hydralazine improved behavioral outcomes a transient cerebral ischemia model in gerbils ) and and reduced demyelination in the spinal cord in that model in the N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP)-4-induced ). PLZ has also been shown to improve behavioral outcomes in noradrenaline depletion rodent model ). Several other EAE mice ), possibly due to its multiple actions, GABAergic agents have been reported to be neuroprotective in animal including its ability to increase levels of serotonin, noradrenaline and models of ischemia (presumably due at GABA in the ventral horn of the spinal cord and some brain regions of least in part to their ability to counteract the excitotoxic effects of in- EAE mice ) and its ability to sequester acrolein creased extracellular glutamate in such models ().
). In addition, acetaldehyde, produced from the me- PLZ has also been reported to decrease K+-induced glutamate overflow tabolism of ethanol, is thought to play an important role in the develop- in the prefrontal cortex in rats (to alter glu- ment of alcoholic liver disease (and alcohol-related tamate–glutamine cycling flux between neurons and glia ( cancers ); thus, sequestra- to affect the GLUT-1 glutamate transporter in astrocytes tion of acetaldehyde may be beneficial in protecting chronic alcoholics and neurons, and to reverse the decreased astrocytic glutamate uptake from development or exacerbation of these alcohol-related diseases.
and the alteration of the signaling kinases AKT and p38 induced by Despite its vast therapeutic potential, PLZ, like other hydrazine- formaldehyde Chronic (21 day) treatment of rats containing drugs, is not without adverse effects; PLZ may produce with PLZ has been reported to increase brain-derived neurotrophic pyridoxal phosphate depletion [though not factor (BDNF) protein expression in the frontal cortex ) all studies have supported this idea (in which and in the whole brain ().
case ongoing vitamin supplementation could be warranted ( In addition to these pharmacological effects, the potent ability of Furthermore, overdoses of PLZ could potentially induce hepa- PLZ, a hydrazine, to sequester reactive aldehydes may contribute to totoxic and neurotoxic effects, including seizures in isolated cases its neuroprotective actions ). Reactive aldehydes However, this drug hasbeen available commercially for over fifty years and continues to beused clinically.
Tranylcypromine (TCP) (an irreversible, non-selective MAO inhibitor, has not been investigated as extensively as some of the otherMAO inhibitors with regard to neuroprotection. Yet several reports linkTCP treatment with an increase in the expression of messenger ribo-nucleic acid (mRNA) for BDNF ( and cyclic adenosine monophosphate (cAMP) re-sponse element binding protein (CREB) ) in the rat brain hippocampus—effects that could lead toneurogenesis (It has also been reported thatTCP increases expression of the antiapoptotic factors B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell lymphoma extra large (Bcl-XL) in sev-eral brain areas ).
3. MAO-B inhibitors: l-deprenyl and rasagiline ), a selective irreversible MAO-B inhibitor, was originally devel-oped in the hope that it would be an effective antidepressant withoutthe pressor effect ( Fig. 1. Structures of the non-selective, irreversible MAO inhibitors phenelzine (PLZ) "cheese effect") which can occur in patients that and tranylcypromine (TCP).
ingest tyramine-rich foods while taking irreversible MAO-A inhibitors.

M.-S. Song et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 118–124 The mechanisms of neuroprotective action of these N-propargyl drugs appear to be complex (). Recent evidence demonstrates that l-deprenyl,rasagiline and R-(−)-aminoindan exert concentration-dependentneuroprotective effects in vitro by modulating glutamatergic receptoractivity in the rat hippocampus ().
indicated that l-deprenyl and rasagiline interactwith the outer mitochondrial membrane, preventing neurotoxin-induced collapse of mitochondrial membrane potential and permeabil-ity transition, and the opening of the voltage-dependent anion channel;these effects are thought to reflect the upregulation of antiapoptoticBcl-2 protein and the downregulation of proapoptotic proteins suchas Bcl-associated death promoter (BAD) and Bcl-associated protein X(BAX), as well as via a mechanism dependent on the inactivation andnuclear localization of glyceraldehyde-3-phosphate dehydrogenase(GAPDH), an initiator of apoptotic cascades ().
Interestingly, a recent report suggests that the increase in Bcl-2 mRNAin vitro induced by rasagiline is mediated by MAO-A, whereas theupregulation of Bcl-2 mRNA by l-deprenyl is not ). l-Deprenyl has also been reported to increase levels ofBDNF protein in some brain areas ), and to haveanti-amyloidogenic activity in vitro ). Furthermore,l-deprenyl was shown to reverse both scopolamine-induced decreasesin antioxidants and increases in malondialdehyde (an important bio-logical marker for in vivo lipid peroxidation) in a mouse model of AD,providing additional support for the possible utility of this drug in AD(Indeed, increased MAO activity and expres-sion of MAO mRNA have been reported in AD ),suggesting that MAO inhibitors should be investigated more exten-sively as possible adjunctive drugs in this disorder. Ladostigil ( Fig. 2. Structures of the MAO-B inhibitors l-deprenyl, rasagiline and ladostigil.
combines the activities described above for rasagiline with an addi-tional anticholinesterase component and is a promising drug for AD( It turned out to be a poor antidepressant drug, except at higher doses when its selectivity was lost and it also inhibited MAO-A [althoughrecent reports indicate that transdermal administration allows doses 4. MAO-A and its inhibitors of l-deprenyl to be used that are sufficient to inhibit brain MAO-Aand produce an antidepressant effect without substantially inhibiting Much of the work on neuroprotection provided by MAO inhibitors MAO-A in the gut )]. l-Deprenyl is used has focused on selective MAO-B inhibitors such as L-deprenyl and in Parkinson's disease (and rasagiline, but selective MAO-A inhibitors may also exert protective has more recently been reported to be of some use in global ischemia, effects (Moclobemide (), a reversible MAO-A Gilles de la Tourette syndrome, narcolepsy and AD inhibitor, has been reported to have anti-Parkinson activity and neuro- although clinically meaningful benefit in AD continues to be a matter protective effects in a model of cerebral ischemia, but these effects ap- of debate ). l-Deprenyl is remarkable in that pear to be independent of MAO-A inhibition ).
it has been demonstrated to have neuroprotective or neurorescueproperties in a wide variety of neurotoxicity tests in vivo and in vitro(It has also been suggested that l-deprenyl has the potentialto be utilized as a radiolabeled biomarker for the early detection ofAD and other degenerative diseases that exhibit increased MAO-B ex-pression A result of research on l-deprenyl has been the development of rasagiline (), a structurally related drug (also containing anN-propargyl group), which has now been approved for use in Parkinson'sdisease in several countries ). Rasagiline has an advantage over l-deprenylin that it is not metabolized to the potentially neurotoxic productsl-amphetamine and l-methamphetamine; in fact, its active metabo-lite, R-(−)-aminoindan, shows neuroprotective properties that areindependent of MAO-B inhibition ).
The neuroprotective effects of l-deprenyl are apparently lost athigh concentrations ), pos- sibly due to the formation of high levels of l-amphetamine andl-methamphetamine.
Fig. 3. Structures of the MAO-A inhibitors moclobemide and clorgyline.

M.-S. Song et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 118–124 It has also been suggested that moclobemide may facilitate selecteddifferentiation of stem cells into functional neurons ).
reported that moclobemide reduced anoxia- andglutamate-induced neuronal damage in neuronal–astroglial culturesfrom rat cerebral cortex via a mechanism independent of its interaction with glutamate receptor subtypes. The irreversible MAO-A inhibitorclorgyline has been reported to be neuroprotective in vitro Fig. 4. Structures of ß-phenylethylidenehydrazine (PEH).
(protective against apoptosis induced by serum starvation) and in vivo (protective against damage caused by the mitochon- 7. Other effects of MAO inhibitors drial toxin malonate) As with l-deprenyl andrasagiline, clorgyline contains an N-propargyl group. Recent research As discussed herein, MAO inhibitors may be useful in treating psy- has also suggested that MAO-A may have a role in the induction and chiatric and neurologic disorders other than depression, including regulation of apoptosis panic disorder, social anxiety disorder, PTSD, Parkinson's disease, Gille de la Tourette's syndrome, and possibly AD ( and that MAO-A activity and function could rely on its physical interac- ). MAO inhibitors tion with certain AD-related presenilin-1 variants ( have also been reported to be useful in treating bulimia nervosa andvarious pain disorders ). Pharmacologically, bothPLZ and TCP can affect the uptake and release of neurotransmitter 5. Primary amine oxidase and its inhibition amines as well as alter the metabolism of a number of drugs throughinhibition of cytochrome P450 (CYP) enzymes (for PrAO, an enzyme containing copper and quinine as cofactors and located on the outer membrane of vascular smooth muscles and en- Both of these MAO inhibitors can also alter the activity of a dothelial cells, catalyzes the oxidation of several primary amines to number of other enzymes ). TCP produce the corresponding aldehyde as well as hydrogen peroxide has been reported to alter levels of endogenous ligands of the and ammonia. Methylamine and aminoacetone are examples of PrAO endocannabinoid system and to increase CB substrates, and their metabolism results in the production of the reac- 1 receptor binding in var- ious rat brain regions (There is a close association be- tive aldehydes formaldehyde and methylglyoxal, respectively. Both tween imidazoline binding sites and MAO binding sites (although the aldehydes have been shown to facilitate the conversion of β-amyloid nature of this association is still a matter of debate), and some amine to the hydrophobic β-sheet conformation and subsequent fibrillogenesis oxidase inhibitors also appear to interact with sigma receptors in vitro ), suggesting an involvement ). It is well known that MAO inhibitors can with the etiology of AD. In addition, increased serum PrAO activity, rela- cause a marked increase in brain levels of the so-called "trace amines" tive to control subjects, has been reported in various vascular disorders, β-phenylethylamine, tyramine, octopamine, and tryptamine ( including complications of diabetes and in congestive heart failure, all of which can alter uptake atherosclerosis, multiple cerebral infarctions and AD ( and release and receptor sensitivity of the classical biogenic amine ). reported a strong expression of PrAO neurotransmitters. Interest in the trace amines has increased marked- co-localized with β-amyloid deposits on blood vessels of postmortem ly in the last few years with the discovery of a family of G-protein brain samples from patients with AD. Interestingly, PLZ, in addition to coupled receptors, some of which appear to be selectively activated its ability to inhibit MAO and GABA-T and to sequester reactive aldehydes, by trace amines ( is a relatively potent inhibitor of PrAO ); these receptors have since been termed which could certainly contribute to its neuroprotective "trace amine-associated receptors". It has been proposed that the am- effects. Several specific PrAO inhibitors have been developed and it will be phetamines exert their effects, at least in part, through these receptors interesting to determine their efficacy in the clinical setting in the future ), and given the structural similarities between the amphetamines and TCP, PLZ and l-deprenyl, it is conceivable that theseMAO inhibitors may also act on these receptors directly in addition to 6. Metabolism of amine oxidase inhibitors and its relevance indirect effects caused by their ability to dramatically elevate brainlevels of the trace amines.
The possible importance of metabolites of N-propargyl drugs should be taken into consideration with regard to contributions to 8. Future applications and drug development neuroprotective properties and adverse effects. Two metabolites ofl-deprenyl (l-amphetamine and l-methamphetamine) are potentially Several MAO inhibitors and structurally similar drugs are "in the neurotoxic, whereas another metabolite, N-propargylamphetamine, pipeline" and are undergoing preclinical or clinical testing (see may have neuroprotective properties, although the latter conclusion for review). Some of these remains contentious ). l-Amphetamine has are propargylamines, and they may also prove to be useful for treatment been reported to interfere with the neuroprotective action of l-deprenyl, of several neurodegenerative disorders. For example, rasagiline and whereas aminoindan and hydroxyaminoindan, major metabolites of CGP 3466 (a propargylamine which does not inhibit MAO) have been rasagiline and ladostigil, are neuroprotective themselves reported to be beneficial in an animal model of amyotrophic lateral MAO inhibitors such as aliphatic propargylamines sclerosis (). A series of aliphatic propargylamines were synthesized because they are not metabolized to amphetamines have also been reported to be excellent neuroprotective agents in sev- PLZ is metabolized to β-phenylethylidenehydrazine eral toxicity models in vivo and in vitro The (PEH) ) and this me- aldehyde-sequestering actions of PLZ suggest that various analogs of tabolite appears to contribute significantly to the neurochemical and this drug should be investigated as possible neuroprotective agents.
pharmacological effects of the parent drug, including elevation of brain By changing the length of the alkyl chain, the GABA-T-inhibiting activ- ity and/or the MAO-inhibiting activity of PLZ can be altered ), sequestration of reactive aldehydes ), inhibition ) while still retaining aldehyde-sequestering properties.
of PrAO and conferring neuroprotection in a model of Studies addressing the structure–activity relationships could then be transient cerebral ischemia conducted in vivo to determine the relative importance of sequestering M.-S. Song et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 118–124 aldehydes on neuroprotection in models such as the transient cerebral Bar-Am O, Weinreb O, Amit T, Youdim MB. The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline.
ischemia model. The utility of MAO inhibitors in drug withdrawal has J Neurochem 2010;112:1131–7.
been considered; recent work has suggested that MAO-A inhibitors Berry MD. The potential of trace amines and their receptors for treating neurological may be useful in the early stages of withdrawal from heavy cigarette and psychiatric diseases. Rev Recent Clin Trials 2007;2:3-19.
Berry MD, Boulton AA. Aliphatic propargylamines as symptomatic and neuroprotective smoking ). In addition, found treatments for neurodegenerative diseases. Neurotoxicol Teratol 2002;24:667–73.
that several MAO inhibitors modulated the discriminative stimulus ef- Birks J, Flicker L. Selegiline for Alzheimer's disease. Cochrane Database Syst Rev 2003: fects of cocaine and suggested that they may be useful for the treatment of cocaine abuse. GABAergic drugs have also been suggested as poten- Blanco C, Heimberg RG, Schneier FR, Fresco DM, Chen H, Turk CL, et al. A placebo- controlled trial of phenelzine, cognitive behavioral group therapy, and their com- tially useful drugs in management of cocaine and methamphetamine bination for social anxiety disorder. Arch Gen Psychiatry 2010;67:286–95.
Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. Trace ), and PLZ and PEH should be tested in this regard. PEH has been amines: identification of a family of mammalian G protein-coupled receptors.
Proc Natl Acad Sci U S A 2001;98:8966–71.
reported to reduce epileptiform activity in rat hippocampal slices Bortolato M, Chen K, Shih JC. Monoamine oxidase inactivation: from pathophysiology (and studies on its potential as an anticonvulsant to therapeutics. Adv Drug Deliv Rev 2008;60:1527–33.
are warranted. have suggested that hydrazines, Boulton AA, Baker GB, Dewhurst WG, Sandler M. Neurobiology of the trace amines: an- alytical, physiological, pharmacological, behavioral, and clinical aspects. Clifton, including PLZ, could be useful therapeutic agents for atherosclerosis N.J.: Humana Press; 1984 and its cardiovascular complications because of their ability to neutralize Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al.
reactive carbonyl components like reactive aldehydes.
Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide,and metabolites of the catecholamine neurotransmitters are agonists of a rat traceamine receptor. Mol Pharmacol 2001;60:1181–8.
Burke WJ, Li SW, Chung HD, Ruggiero DA, Kristal BS, Johnson EM, et al. Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerativediseases. Neurotoxicology 2004;25:101–15.
The amine oxidase inhibitors continue to be of considerable inter- Carlile GW, Chalmers-Redman RM, Tatton NA, Pong A, Borden KE, Tatton WG. Reduced est and the subject of extensive research. Some of them may prove apoptosis after nerve growth factor and serum withdrawal: conversion of tetramericglyceraldehyde-3-phosphate dehydrogenase to a dimer. Mol Pharmacol 2000;57: useful for treating specific neurodegenerative disorders, stroke and drug abuse, either alone or in combination with other drugs. In fact, Chen K, Maley J, Yu PH. Potential implications of endogenous aldehydes in beta-amyloid their multifaceted nature may be an advantage, making them suitable misfolding, oligomerization and fibrillogenesis. J Neurochem 2006;99:1413–24.
for treating several disorders. Investigations to date have demonstrat- Chiou SH, Ku HH, Tsai TH, Lin HL, Chen LH, Chien CS, et al. Moclobemide upregulated Bcl-2 expression and induced neural stem cell differentiation into serotoninergic ed that the neuroprotective actions of such drugs are complex and, neuron via extracellular-regulated kinase pathway. Br J Pharmacol 2006;148:587–98.
in many, but not all, cases are independent of MAO inhibition. They Davidson JR. Pharmacotherapy of social anxiety disorder: what does the evidence tell continue to be valuable pharmacological tools that have done much us? J Clin Psychiatry 2006;67(Suppl. 12):20–6.
DeMarco A, Dalal RM, Pai J, Aquilina SD, Mullapudi U, Hammel C, et al. Racemic gamma to increase our knowledge of mechanisms involved in neuroprotection vinyl-GABA (R, S-GVG) blocks methamphetamine-triggered reinstatement of con- and have provided important clues for future development of neuro- ditioned place preference. Synapse 2009;63:87–94.
protective drugs.
Dimpfel W, Hoffmann JA. Effects of rasagiline, its metabolite aminoindan and selegiline on glutamate receptor mediated signalling in the rat hippocampus slice in vitro.
BMC Pharmacol 2011;11:2.
Druesne-Pecollo N, Tehard B, Mallet Y, Gerber M, Norat T, Hercberg S, et al. Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol 2009;10:173–80.
Funds were provided by: the Canadian Institutes of Health Re- Duffy S, Nguyen PV, Baker GB. Phenylethylidenehydrazine, a novel GABA-transaminase search (CIHR), the Canada Research Chairs Program, the University inhibitor, reduces epileptiform activity in rat hippocampal slices. Neuroscience2004;126:423–32.
of Alberta Distinguished Professor Program (GBB), Alberta Health Dwivedi Y, Rizavi HS, Pandey GN. Antidepressants reverse corticosterone-mediated Services (fellowship funding for EMM), the Alzheimer Society of decrease in brain-derived neurotrophic factor expression: differential regulation of spe- Saskatchewan and the Saskatchewan Health Research Foundation cific exons by antidepressants and corticosterone. Neuroscience 2006;139:1017–29.
Ebadi M, Brown-Borg H, Ren J, Sharma S, Shavali S, El ReFaey H, et al. Therapeutic efficacy (DDM), a QEII studentship (DM), the Abraham and Freda Berger of selegiline in neurodegenerative disorders and neurological diseases. Curr Drug Fund and a donation from Donald R. and Nancy Romanow Cranston.
Egan CG. Differentiation of hippocampal stem cells into functional neurons: evolving our understanding of monoamine oxidase-A inhibition. Br J Pharmacol 2006;148: Eliash S, Dror V, Cohen S, Rehavi M. Neuroprotection by rasagiline in thiamine deficient Akao Y, Maruyama W, Yi H, Shamoto-Nagai M, Youdim MB, Naoi M. An anti-Parkinson's rats. Brain Res 2009;1256:138–48.
disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of Elovaara H, Kidron H, Parkash V, Nymalm Y, Bligt E, Ollikka P, et al. Identification of two anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells. Neurosci Lett 2002;326: imidazole binding sites and key residues for substrate specificity in human primary amine oxidase AOC3. Biochemistry 2011;50:5507–20.
Bacher I, Houle S, Xu X, Zawertailo L, Soliman A, Wilson AA, et al. Monoamine oxidase A Emilsson L, Saetre P, Balciuniene J, Castensson A, Cairns N, Jazin EE. Increased mono- binding in the prefrontal and anterior cingulate cortices during acute withdrawal amine oxidase messenger RNA expression levels in frontal cortex of Alzheimer's from heavy cigarette smoking. Arch Gen Psychiatry 2011;68:817–26.
disease patients. Neurosci Lett 2002;326:56–60.
Baker GB, Coutts RT, Greenshaw AJ. Neurochemical and metabolic aspects of antide- Frampton JE, Plosker GL. Selegiline transdermal system in major depressive disorder: pressants: an overview. J Psychiatry Neurosci 2000;25:481–96.
profile report. CNS Drugs 2007;21:521–4.
Baker GB, Sowa B, Todd KG. Amine oxidases and their inhibitors: what can they tell us Galvani S, Coatrieux C, Elbaz M, Grazide MH, Thiers JC, Parini A, et al. Carbonyl scavenger about neuroprotection and the development of drugs for neuropsychiatric disorders? and antiatherogenic effects of hydrazine derivatives. Free Radic Biol Med 2008;45: J Psychiatry Neurosci 2007;32:313–5.
Baker GB, Wong JT, Yeung JM, Coutts RT. Effects of the antidepressant phenelzine on Gatch MB, Taylor CM, Flores E, Selvig M, Forster MJ. Effects of monoamine oxidase brain levels of gamma-aminobutyric acid (GABA). J Affect Disord 1991;21:207–11.
inhibitors on cocaine discrimination in rats. Behav Pharmacol 2006;17:151–9.
Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I. Differential Gerlach M, Youdim MB, Riederer P. Pharmacology of selegiline. Neurology 1996;47: regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 2008;1211:37–43.
Gillman PK. Advances pertaining to the pharmacology and interactions of irreversible Bar-Am O, Amit T, Youdim MB. Contrasting neuroprotective and neurotoxic actions of nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol 2011;31:66–74.
respective metabolites of anti-Parkinson drugs rasagiline and selegiline. Neurosci Gomez-Gil E, Salmeron JM, Mas A. Phenelzine-induced fulminant hepatic failure. Ann Intern Med 1996;124:692–3.
Bar-Am O, Amit T, Youdim MB. Aminoindan and hydroxyaminoindan, metabolites Goverdhan P, Sravanthi A, Mamatha T. Neuroprotective effects of meloxicam and of rasagiline and ladostigil, respectively, exert neuroprotective properties in vitro.
selegiline in scopolamine-induced cognitive impairment and oxidative stress. Int J Neurochem 2007;103:500–8.
J Alzheimers Dis 2012;2012:974013.
Bar-Am O, Weinreb O, Amit T, Youdim MB. The novel cholinesterase-monoamine oxidase Green AR, Hainsworth AH, Jackson DM. GABA potentiation: a logical pharmacological inhibitor and antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells approach for the treatment of acute ischaemic stroke. Neuropharmacology 2000;39: and aged rats. J Mol Neurosci 2009;37:135–45.
M.-S. Song et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 118–124 Gulyas B, Pavlova E, Kasa P, Gulya K, Bakota L, Varszegi S, et al. Activated MAO-B in the Muller JE, Koen L, Seedat S, Stein DJ. Social anxiety disorder: current treatment recom- brain of Alzheimer patients, demonstrated by [11C]-l-deprenyl using whole hemi- mendations. CNS Drugs 2005;19:377–91.
sphere autoradiography. Neurochem Int 2011;58:60–8.
Musgrave T, Benson C, Wong G, Browne I, Tenorio G, Rauw G, et al. The MAO inhibitor Gyarfas T, Knuuttila J, Lindholm P, Rantamaki T, Castren E. Regulation of brain-derived phenelzine improves functional outcomes in mice with experimental autoimmune neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) by encephalomyelitis (EAE). Brain Behav Immun 2011a;25:1677–88.
anti-parkinsonian drug therapy in vivo. Cell Mol Neurobiol 2010;30:361–8.
Musgrave T, Tenorio G, Rauw G, Baker GB, Kerr BJ. Tissue concentration changes of Hamann K, Shi R. Acrolein scavenging: a potential novel mechanism of attenuating amino acids and biogenic amines in the central nervous system of mice with experi- oxidative stress following spinal cord injury. J Neurochem 2009;111:1348–56.
mental autoimmune encephalomyelitis (EAE). Neurochem Int 2011b;59:28–38.
Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, et al. Neuroprotection by Naoi M, Maruyama W, Akao Y, Yi H, Yamaoka Y. Involvement of type A monoamine ox- pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci U S A idase in neurodegeneration: regulation of mitochondrial signaling leading to cell death or neuroprotection. J Neural Transm Suppl 2006:67–77.
Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ. Long-term out- Naoi M, Maruyama W, Inaba-Hasegawa K, Akao Y. Type A monoamine oxidase regu- come of early versus delayed rasagiline treatment in early Parkinson's disease. Mov lates life and death of neurons in neurodegeneration and neuroprotection. Int Rev Neurobiol 2011;100:85-106.
Hill MN, Ho WS, Hillard CJ, Gorzalka BB. Differential effects of the antidepressants Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by tranylcypromine and fluoxetine on limbic cannabinoid receptor binding and chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci endocannabinoid contents. J Neural Transm 2008;115:1673–9.
Holt A. Imidazoline binding sites on receptors and enzymes: emerging targets for novel Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the antidepressant drugs? J Psychiatry Neurosci 2003;28:409–14.
expression of cAMP response element binding protein (CREB) in rat hippocampus.
Holt A, Berry MD, Boulton AA. On the binding of monoamine oxidase inhibitors to some J Neurosci 1996;16:2365–72.
sites distinct from the MAO active site, and effects thereby elicited. Neurotoxicology Ono K, Hasegawa K, Naiki H, Yamada M. Anti-Parkinsonian agents have anti-amyloidogenic activity for Alzheimer's beta-amyloid fibrils in vitro. Neurochem Int 2006;48:275–85.
Inaba-Hasegawa K, Akao Y, Maruyama W, Naoi M. Type A monoamine oxidase is asso- Ou XM, Chen K, Shih JC. Monoamine oxidase A and repressor R1 are involved in apo- ciated with induction of neuroprotective Bcl-2 by rasagiline, an inhibitor of type B ptotic signaling pathway. Proc Natl Acad Sci U S A 2006;103:10923–8.
monoamine oxidase. J Neural Transm 2012;119:405–14.
Parent MB, Master S, Kashlub S, Baker GB. Effects of the antidepressant/antipanic drug Ivanova S, Botchkina GI, Al-Abed Y, Meistrell III M, Batliwalla F, Dubinsky JM, et al.
phenelzine and its putative metabolite phenylethylidenehydrazine on extracellular Cerebral ischemia enhances polyamine oxidation: identification of enzymatically gamma-aminobutyric acid levels in the striatum. Biochem Pharmacol 2002;63:57–64.
formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell Paslawski T, Knaus E, Iqbal N, Baker GB. 2-Phenylethylidenehydrazine, a novel inhibitor death. J Exp Med 1998;188:327–40.
of GABA transaminase. Drug Dev Res 2001;54:35–9.
Jiang ZJ, Richardson JS, Yu PH. The contribution of cerebral vascular semicarbazide- Peng XQ, Li X, Gilbert JG, Pak AC, Ashby Jr CR, Brodie JD, et al. Gamma-vinyl GABA sensitive amine oxidase to cerebral amyloid angiopathy in Alzheimer's disease.
inhibits cocaine-triggered reinstatement of drug-seeking behavior in rats by a Neuropathol Appl Neurobiol 2008;34:194–204.
non-dopaminergic mechanism. Drug Alcohol Depend 2008;97:216–25.
Karila L, Gorelick D, Weinstein A, Noble F, Benyamina A, Coscas S, et al. New treatments Popov N, Matthies H. Some effects of monoamine oxidase inhibitors on the metabolism for cocaine dependence: a focused review. Int J Neuropsychopharmacol 2008;11: of gamma-aminobutyric acid in rat brain. J Neurochem 1969;16:899–907.
Rascol O, Lozano A, Stern M, Poewe W. Milestones in Parkinson's disease therapeutics.
Kennedy SH, Holt A, Baker GB. Monoamine oxidase inhibitors. In: Sadock BJ, Sadock VA, Mov Disord 2011;26:1072–82.
Ruiz P, editors. Kaplan and Sadock's comprehensive textbook of psychiatry. 9th ed.
Riederer P, Lachenmayer L, Laux G. Clinical applications of MAO-inhibitors. Curr Med Philadelphia: Lippincott Williams & Wilkins; 2009. p. 3154–63.
Khundakar AA, Zetterstrom TS. Biphasic change in BDNF gene expression following Rubinstein S, Malone MA, Roberts W, Logan WJ. Placebo-controlled study examining antidepressant drug treatment explained by differential transcript regulation. Brain effects of selegiline in children with attention-deficit/hyperactivity disorder.
J Child Adolesc Psychopharmacol 2006;16:404–15.
Kosten TA, Galloway MP, Duman RS, Russell DS, D'Sa C. Repeated unpredictable stress and Sabelli HC, Mosnaim AD. Phenylethylamine hypothesis of affective behavior. Am J Psychiatry antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures. Neuropsychopharmacology Salaspuro M. Acetaldehyde: a cumulative carcinogen in humans. Addiction 2009;104: Leung G, Sun W, Zheng L, Brookes S, Tully M, Shi R. Anti-acrolein treatment improves Salsali M, Holt A, Baker GB. Inhibitory effects of the monoamine oxidase inhibitor behavioral outcome and alleviates myelin damage in experimental autoimmune tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6.
encephalomyelitis mouse. Neuroscience 2011;173:150–5.
Cell Mol Neurobiol 2004;24:63–76.
Lindemann L, Hoener MC. A renaissance in trace amines inspired by a novel GPCR Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of family. Trends Pharmacol Sci 2005;26:274–81.
hippocampal neurogenesis for the behavioral effects of antidepressants. Science Ling L, Urichuk LJ, Sloley BD, Coutts RT, Baker GB, Shan JJ, et al. Synthesis of N-propargylphenelzine and analogues as neuroprotective agents. Bioorg Med Chem Seiler N. Oxidation of polyamines and brain injury. Neurochem Res 2000;25:471–90.
Setshedi M, Wands JR, Monte SM. Acetaldehyde adducts in alcoholic liver disease. Oxid London DR, Milne MD. Dangers of monoamine oxidase inhibitors. Br Med J 1962;2:1752.
Med Cell Longev 2010;3:178–85.
LoPachin RM, Gavin T, Barber DS. Type-2 alkenes mediate synaptotoxicity in neurode- Shi Y, Sun W, McBride JJ, Cheng JX, Shi R. Acrolein induces myelin damage in mammalian generative diseases. Neurotoxicology 2008;29:871–82.
spinal cord. J Neurochem 2011;117:554–64.
Lovell MA, Xie C, Markesbery WR. Acrolein is increased in Alzheimer's disease brain Shuaib A, Kanthan R. Amplification of inhibitory mechanisms in cerebral ischemia: an and is toxic to primary hippocampal cultures. Neurobiol Aging 2001;22:187–94.
alternative approach to neuronal protection. Histol Histopathol 1997;12:185–94.
Lydiard RB, Laraia MT, Howell EF, Fossey MD, Reynolds RD, Ballenger JC. Phenelzine Shulman KI, Fischer HD, Herrmann N, Huo CY, Anderson GM, Rochon PA. Current pre- treatment of panic disorder: lack of effect on pyridoxal phosphate levels. J Clin scription patterns and safety profile of irreversible monoamine oxidase inhibitors: a population-based cohort study of older adults. J Clin Psychiatry 2009;70:1681–6.
MacKenzie, E.M., 2009. Neurochemistry of novel neuroprotective hydrazines (PhD Singh M, Dang TN, Arseneault M, Ramassamy C. Role of by-products of lipid oxidation Thesis). University of Alberta.
in Alzheimer's disease brain: a focus on acrolein. J Alzheimers Dis 2010;21:741–56.
MacKenzie EM, Song MS, Dursun SM, Baker GB. Phenelzine: an old drug that may hold Smith SE, Lambourn J, Tyrer PJ. Antipyrine elimination by patients under treatment clues to the development of new neuroprotective agents. Bull Clin Psychopharmacol with monoamine oxidase inhibitors. Br J Clin Pharmacol 1980;9:21–5.
Song MS, Baker GB, Dursun SM, Todd KG. The antidepressant phenelzine protects neurons Magyar K, Szende B. (−)-Deprenyl, a selective MAO-B inhibitor, with apoptotic and and astrocytes against formaldehyde-induced toxicity. J Neurochem 2010;114: anti-apoptotic properties. Neurotoxicology 2004;25:233–42.
Malcolm DE, Yu PH, Bowen RC, O'Donovan C, Hawkes J, Hussein M. Phenelzine reduces Sowa B, Todd KG, Tanay VA, Holt A, Baker GB. Amine oxidase inhibitors and develop- plasma vitamin B6. J Psychiatry Neurosci 1994;19:332–4.
ment of neuroprotective drugs. Curr Neuropharmacol 2004;2:153–68.
Malorni W, Giammarioli AM, Matarrese P, Pietrangeli P, Agostinelli E, Ciaccio A, et al.
Springer JE, Azbill RD, Mark RJ, Begley JG, Waeg G, Mattson MP. 4-Hydroxynonenal, Protection against apoptosis by monoamine oxidase A inhibitors. FEBS Lett 1998;426: a lipid peroxidation product, rapidly accumulates following traumatic spinal cord injury and inhibits glutamate uptake. J Neurochem 1997;68:2469–76.
Maragos WF, Young KL, Altman CS, Pocernich CB, Drake J, Butterfield DA, et al. Striatal Stewart JW. Treating depression with atypical features. J Clin Psychiatry 2007;68(Suppl. 3): damage and oxidative stress induced by the mitochondrial toxin malonate are reduced in clorgyline-treated rats and MAO-A deficient mice. Neurochem Res 2004;29:741–6.
Tafazoli S, Mashregi M, O'Brien PJ. Role of hydrazine in isoniazid-induced hepatotoxicity in Marchitti SA, Deitrich RA, Vasiliou V. Neurotoxicity and metabolism of the catecholamine- a hepatocyte inflammation model. Toxicol Appl Pharmacol 2008;229:94-101.
Tanay VA, Todd KG, Baker GB. Phenylethylidenehydrazine, a novel GABA-T inhibitor, the role of aldehyde dehydrogenase. Pharmacol Rev 2007;59:125–50.
rescues neurons from cerebral ischemia. Proceedings of the 23rd Congress of the Matveychuk D, Dursun SM, Wood PL, Baker GB. Reactive aldehydes and neurodegener- Collegium Internationale Neuropsychopharmacologicum. Montreal, Canada; 2002.
ative disorders. Bull Clin Psychopharmacol 2011;21:277–88.
Tatton W, Chalmers-Redman R, Tatton N. Neuroprotection by deprenyl and other McKernan DP, Dinan TG, Cryan JF. "Killing the Blues": a role for cellular suicide (apoptosis) propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than mono- in depression and the antidepressant response? Prog Neurobiol 2009;88:246–63.
amine oxidase B. J Neural Transm 2003;110:509–15.
Michael-Titus AT, Bains S, Jeetle J, Whelpton R. Imipramine and phenelzine decrease Tazik S, Johnson S, Lu D, Johnson C, Youdim MB, Stockmeier CA, et al. Comparative glutamate overflow in the prefrontal cortex—a possible mechanism of neuroprotection neuroprotective effects of rasagiline and aminoindan with selegiline on in major depression? Neuroscience 2000;100:681–4.
dexamethasone-induced brain cell apoptosis. Neurotox Res 2009;15:284–90.
M.-S. Song et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 118–124 Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S, et al. cAMP response Xiao H, Lv F, Xu W, Zhang L, Jing P, Cao X. Deprenyl prevents MPP(+)-induced oxida- element-mediated gene transcription is upregulated by chronic antidepressant tive damage in PC12 cells by the upregulation of Nrf2-mediated NQO1 expression treatment. J Neurosci 2000;20:4030–6.
through the activation of PI3K/Akt and Erk. Toxicology 2011;290:286–94.
Todd KG, Banigesh AI, Baker GB, Coutts RT, Shuaib A. Phenylethylidenehydrazine, a Yang J, Shen J. In vivo evidence for reduced cortical glutamate–glutamine cycling in rats novel GABA-T inhibitor, has neuroprotective actions in transient global ischemia.
treated with the antidepressant/antipanic drug phenelzine. Neuroscience 2005;135: J Neurochem 1999;73(Suppl):S202B.
Verleye M, Steinschneider R, Bernard FX, Gillardin JM. Moclobemide attenuates anoxia Yogev-Falach M, Bar-Am O, Amit T, Weinreb O, Youdim MB. A multifunctional, and glutamate-induced neuronal damage in vitro independently of interaction neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and pro- with glutamate receptor subtypes. Brain Res 2007;1138:30–8.
cessing. FASEB J 2006;20:2177–9.
Volkel W, Sicilia T, Pahler A, Gsell W, Tatschner T, Jellinger K, et al. Increased brain Youdim MB, Amit T, Bar-Am O, Weinreb O, Yogev-Falach M. Implications of co-morbidity levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer's disease.
for etiology and treatment of neurodegenerative diseases with multifunctional Neurochem Int 2006;48:679–86.
neuroprotective–neurorescue drugs; ladostigil. Neurotox Res 2006a;10:181–92.
Wang EY, Gao H, Salter-Cid L, Zhang J, Huang L, Podar EM, et al. Design, synthesis, and Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase biological evaluation of semicarbazide-sensitive amine oxidase (SSAO) inhibitors inhibitors. Nat Rev Neurosci 2006b;7:295–309.
with anti-inflammatory activity. J Med Chem 2006;49:2166–73.
Yu PH, Davis BA, Boulton AA. Aliphatic propargylamines: potent, selective, irreversible Wei Z, Gabriel GG, Rui L, Cao X, Pennington PR, Chlan-Fourney J, et al. Monoamine monoamine oxidase B inhibitors. J Med Chem 1992;35:3705–13.
oxidase—A physically interacts with presenilin-1(M146V) in the mouse cortex.
Yu PH, Wright S, Fan EH, Lun ZR, Gubisne-Harberle D. Physiological and pathological J Alzheimers Dis 2012;28:403–22.
implications of semicarbazide-sensitive amine oxidase. Biochim Biophys Acta Weinreb O, Amit T, Bar-Am O, Youdim MB. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol Zhang W, Davidson JR. Post-traumatic stress disorder: an evaluation of existing pharmacotherapies and new strategies. Expert Opin Pharmacother 2007;8: Weinstock M, Luques L, Bejar C, Shoham S. Ladostigil, a novel multifunctional drug for the treatment of dementia co-morbid with depression. J Neural Transm Suppl Zhu W, Xie W, Pan T, Jankovic J, Li J, Youdim MB, et al. Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin-induced Wood P. Neurodegeneration and aldehyde load: from concept to therapeutics. Rev nigrostriatal dopaminergic degeneration. J Neurochem 2008;105:1970–8.
Psychiatry Neurosci 2006;31:296–7.
Wood PL, Khan MA, Moskal JR, Todd KG, Tanay VA, Baker G. Aldehyde load in ischemia– reperfusion brain injury: neuroprotection by neutralization of reactive aldehydeswith phenelzine. Brain Res 2006;1122:184–90.


Microsoft word - final jssuni syllabus 28072012.docx

REGULATIONS AND SYLLABUS BACHELOR OF PHARMACY (B.PHARM) COURSE JSS UNIVERSITY SRI SHIVARATHREESHWARA NAGAR MYSORE – 570 015 JSS University Sri Shivarathreeshwara Nagar Mysore – 570 015 Bachelor of Pharmacy (B.Pharm) course REGULATIONS These regulations shall be called as "The Regulations for the B. Pharmacy Degree course of the J.S.S. University, Mysore". They shall come into force from the Academic Year 2012 - 2013. The regulations framed are subject to modifications from time to time by the authorities of the university Minimum qualification for admission to the course

Drinks: Good Hosts The very name sends pleasurable sensations down one's throat! These drinks are everywhere, in myriad avatars - sending celebrities into swoons or into undertaking death defying feats!Sparkling and twinkling, creating a fizzy haze, making consumers down vast quantities of junk food, helped by the pleasurable gulps. We tested 16 brands - a merry mix of colas and orange drinks, the sparkling variety and