propargylamine and Parkinson-Disease

Topics: Amphetamines; Animals; Antiparkinson Agents; Apoptosis; Clinical Trials as Topic; Drug Evaluation, Preclinical; Haplorhini; Humans; Inactivation, Metabolic; Indans; Mice; Mice, Transgenic; Models, Neurological; Monoamine Oxidase Inhibitors; Neurons; Neuroprotective Agents; Oxepins; Oxidative Stress; Pargyline; Parkinson Disease; Propylamines; Selegiline

Deprenyl and other propargylamines are clinically beneficial in Parkinson's disease (PD). The benefits were thought to depend on monoamine oxidase B (MAO-B) inhibition. A large body of research has now shown that the propargylamines increase neuronal survival independently of MAO-B inhibition by interfering with apoptosis signaling pathways. The propargylamines bind to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GAPDH binding is associated with decreased synthesis of pro-apoptotic proteins like BAX, c-JUN and GAPDH but increased synthesis of anti-apoptotic proteins like BCL-2, Cu-Zn superoxide dismutase and heat shock protein 70. Anti-apoptotic propargylamines that do not inhibit MAO-B are now in PD clinical trial.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cell Survival; Glyceraldehyde-3-Phosphate Dehydrogenases; HSP70 Heat-Shock Proteins; Humans; Monoamine Oxidase; Neurons; Neuroprotective Agents; Pargyline; Parkinson Disease; Propylamines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Selegiline; Superoxide Dismutase

The etiology of idiopathic Parkinson's disease remains as an enigma. N-Methyl (R)salsolinol [NM (R) Sal] is a candidate of dopaminergic neurotoxins, and is synthesized from dopamine by 2 enzymes: (R) Salsolinol synthase and a neutral (R) Salsolinol N-methyltransferase (nNMT). NM (R) Sal injection in the rat striatum caused selective depletion of dopamine neurons in the substantia nigra without tissue reaction, suggesting NM (R) Sal induced apoptosis in dopamine neurons. NM (R) Sal level was found to increase significantly in the cerebrospinal fluid of parkinsonian patients, and NM (R) Sal accumulated in the nigrostriatum. By the analysis of the human brain, it was suggested nNMT is the rate-limiting step to synthesize dopamine-derived neurotoxins. The activity of nNMT was found to increase in the lymphocytes from parkinsonian patients. The mechanism of toxicity by NM (R) Sal was studied in vitro using human dopaminergic neuroblastoma SH-SY5Y cells. NM (R) Sal induced apoptosis stereo-specifically, suggesting that a molecule in mitochondria can distinguish the stereo-chemical structure of NM (R) Sal and activate intracellular signal of apoptosis. Recently, we found that propargylamines, inhibitors of type B monoamine oxidase, can prevent the apoptosis induced by NM (R) Sal. Further study on the mechanism underlying increase in nNMT activity in parkinsonian patients will clarify the involvement of genetic and environmental factors in the pathogenesis of Parkinson's disease.

Topics: Aging; Animals; Apoptosis; Dopamine; Humans; Methyltransferases; Mitochondria; Neurotoxins; Pargyline; Parkinson Disease; Propylamines; Salsoline Alkaloids; Tetrahydroisoquinolines

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC

Topics: Humans; Indans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Parkinson Disease; Propylamines; Selegiline; Tetrahydronaphthalenes; Tyramine

Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress.. The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons.. Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease.

Topics: Animals; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Male; Oxidative Stress; Pargyline; Parkinson Disease; Propylamines; Rats, Wistar; Substantia Nigra

To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively. It was observed that some of the compounds tested yielded a marked increase in survival in PC-12 cells treated with the neurotoxins. This indicates that these propargylamines are able to confer protection against the effects of the toxins and may also be considered as novel disease-modifying anti-Parkinsonian agents, which are much needed for the therapy of Parkinson's disease.

Topics: Animals; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Mice; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Pargyline; Parkinson Disease; PC12 Cells; Propylamines; Rats; Structure-Activity Relationship

Neuroprotective therapy has been proposed for age-related neurodegenerative disorders, including Parkinson's disease. Inhibitors of type B monoamine oxidase (MAOB-Is), rasagiline and (-)deprenyl, are the most promising candidate neuroprotective drugs. Clinical trials of rasagiline in patients with Parkinson's disease suggest that rasagiline may have some disease-modifying effects. Results using animal and cellular models have proved that the MAOB-Is protect neurons by the intervention of 'intrinsic' mitochondrial apoptotic cascade and the induction of prosurvival antiapoptotic Bcl-2 and neurotrophic factors. Rasagiline-related MAOB-Is prevent mitochondrial permeability transition induced by various insults and activation of subsequent apoptotic cascades: cytochrome c release, casapase activation, and condensation and fragmentation of nuclear DNA. MAOB-Is increase transcription of prosurvival genes through activating the nuclear transcription factor-(NF) system. Rasagiline increases the protein and mRNA levels of GDNF in dopaminergic SH-SY5Y cells, whereas (-)deprenyl increases those of BDNF. Systemic administration of (-)deprenyl and rasagiline increases these neurotrophic factors in the cerebrospinal fluid from patients with Parkinson's disease and nonhuman primates. This review presents recent advances in our understanding of the neuroprotection offered by MAOB-Is and possible evaluation of neuroprotective efficacy in clinical samples is discussed.

Topics: Apoptosis; Clinical Trials as Topic; Dopamine; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; NF-kappa B; Pargyline; Parkinson Disease; Propylamines; Signal Transduction

In Parkinson's and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (-)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-kappaB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.

Topics: Alkynes; Cell Death; Cell Line, Tumor; Energy Metabolism; Genetic Markers; Glial Cell Line-Derived Neurotrophic Factor; Humans; Indans; Membrane Potentials; Mitochondria; Neuroblastoma; Neuroprotective Agents; NF-kappa B; Oligonucleotide Array Sequence Analysis; Pargyline; Parkinson Disease; Propylamines; Proto-Oncogene Proteins c-bcl-2; Selegiline

A neuroprotective therapy that slows or stops disease progression is the major unmet medical need in Parkinson's disease (PD). Current evidence indicates that cell death in PD occurs, at least in part, by way of a signal-mediated apoptotic process. This raises the possibility that anti-apoptotic agents might be neuroprotective in PD. Propargylamines have been demonstrated to be potent anti-apoptotic agents in both in vitro and in vivo studies, presumably by maintaining glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a dimer and thereby preventing its nuclear translocation where it blocks upregulation of anti-apoptotic proteins. Selegiline is a monamine oxidase type B (MAO-B) inhibitor that incorporates a propargyl ring within its molecular structure. It was shown to delay the need for symptomatic therapy in untreated PD patients in the DATATOP study, but interpretation is confounded by its symptomatic effects. Rasagiline is another MAO-B inhibitor that contains a propargyl ring and has protective effects in laboratory models. A clinical trial utilizing a delayed start design demonstrated that patients initiated on rasagiline at baseline are improved at one year in comparison to patients initiated on placebo and switched to rasagiline at 6 months even though both groups were on the same treatment for the last 6 months of the study. These results argue against the benefit being due to a symptomatic effect and are consistent with rasagiline having a protective effect.

Topics: Clinical Trials as Topic; Evidence-Based Medicine; Humans; Indans; Neuroprotective Agents; Pargyline; Parkinson Disease; Practice Guidelines as Topic; Practice Patterns, Physicians'; Propylamines; Selegiline; Treatment Outcome

Parkinsonism (PD) is a neurodegenerative disorder of the brain resulting in dopamine deficiency caused by the progressive death of dopaminergic neurons. PD is characterized by a combination of rigidity, poverty of movement, tremor and postural instability. Selegiline is a selective and irreversible propargylamine type B monoamine oxidase (MAO-B) inhibitor. This drug, which inhibits dopamine metabolism, has been effectively used in the treatment of PD. However, its therapeutic effects are compromised by its many neurotoxic metabolites. To circumvent this obstacle, a novel MAO-B inhibitor, rasagiline, was developed. Paradoxically, the neuroprotective mechanism of propargylamines in different neuronal models appears to be independent of MAO-B inhibition. Recent investigations into the neuroprotective mechanism of propargylamines indicate that glyceraldehyde-3-phosphate dehydrogenase (GAPDH), MAO-B and/or other unknown proteins may represent pivotal proteins in the survival of the injured neurons. Delineation of the mechanism(s) involved in the neuroprotective effects exerted by MAO-B inhibitors may provide the key to preventive novel therapeutic modalities.

Topics: Animals; Apoptosis; Enzyme Inhibitors; Humans; Indans; Models, Chemical; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurons; Neurotoxins; Pargyline; Parkinson Disease; Propylamines; Time Factors

Iron has been shown to accumulates at site where neurons degenerate in neurodegenerative diseases of Parkinson's disease, Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis and Friedreich ataxia. Iron is thought to participate or initiate oxidative stress via generation of reactive oxygen species (ROS), such as hydroxyl radical. Iron chelators are neuroprotective and prevent 6-hydroxydoapmine and MPTP dopaminergic neurotoxicity in rats and mice. However, their action on monoamine oxidase (MAO) A and B have not been determined previously since MAO-B inhibitors have been shown to be neuroprotective in cellular and animal models of Parkinson's disease. The chelators 8-hydroxyquinoline, O-phenanthroline, 2,2'-dipyridyl, U74500A and U74600F showed a preference for inhibition of rat brain mitochondrial MAO-A over MAO-B. Their IC(50) ranged from 10(-3) M to 10(-6) M, with 21-amino steroids (U74500A and U74006F) showing a greater selectivity and potency for MAO-A. Desferrioxamine (desferal), a prototype potent iron chelator, exhibited relatively poor MAO inhibitory. The inhibitions of MAO-A and B by 21-amino steroids (Lazaroids) were time dependent and irreversible. Those initiated by 8-hydroxyquinoline, 2,2'-dipyridyl and O-phenanthroline were fully reversible by enzyme dilution experiments. Both Fe(2+) and Fe(3+) reverse the MAO-A and B inhibition induced by the latter chelators, but not those initiated by 21-amino steroids. The data infer that either the inhibition of MAO by 21-amino steroids is either the resultant of their conversion to an irreversible covalently bound ligand or that the iron chelation moiety and MAO inhibitory activity in these compounds are not mutually shared. The results suggest that bifunctional brain penetrable drugs with iron chelating property and MAO inhibitory activity in could be the most feasible approach for neuroprotection in neurodegenerative diseases. Such drug would prevent participation of elevated iron in oxidative stress and formation of reactive hydroxyl radical, via its interaction with H(2)O2 (Fenton chemistry), generated as a consequence MAO and other oxidative enzyme reactions to generative cytotoxic reactive hydroxyl radical. We have now developed several of these compounds with neuroprotective, MAO inhibitory and iron chelating properties from our prototype iron chelators, VK-28 possessing propargylamine moiety of our anti-parkinson drug, rasagiline.

Topics: Animals; Brain; Drug Delivery Systems; In Vitro Techniques; Indans; Iron Chelating Agents; Male; Mitochondria; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroprotective Agents; Pargyline; Parkinson Disease; Piperazines; Propylamines; Quinolines; Rats; Rats, Sprague-Dawley