Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both deprenyl and rasagiline (R(+)-N-propargyl-1-aminoindane mesylate), at a concentration of 1-10 microM, increased survival in vitro of rat E14 mesencephalic dopaminergic neurons that had been primed with 10% serum for 12 h (p < 0.05). Rasagiline, but not deprenyl, also increased total neuronal (MAP2-positive) survival (p < 0.05) Under serum-free conditions, rasagiline, but not deprenyl, retained its neuroprotective action on dopaminergic neurones. GABAergic neurons were not affected by either deprenyl or rasagiline. Clorgyline, an MAO-A inhibitor, did not exert any of these effects. The protective action of rasagiline on dopaminergic neurons, even under stringent serum-free conditions, is striking, and warrants further investigation for a role in the treatment of Parkinson's disease.
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PMID:Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. 955 42

The stereospecific form of the known acetylenic mechanism-based MAO-inhibitor AGN1135 (Rasagiline, TVP-1012) is devoid of sympathomimetic amphetamine-like properties. To evaluate the efficiency and selectivity of subcutaneous injections of TVP-1012 (dose range from 0.01 up to 10 mg/kg for 7 days) the activities of monoamine oxidases A and B (MAO-A,-B) were determined in different brain regions of the common marmoset. At a dose of 0.1 mg/kg TVP-1012, almost 80% of MAO-B activity is inhibited in all brain regions investigated (prefrontal and occipital cortex, cerebellum, caudate nucleus, putamen, nucleus accumbens). In contrast, MAO-A is not inhibited in putamen and nucleus accumbens. However, by increasing the TVP-1012 dose to 0.5 mg/kg, MAO-A is inhibited to a significant extent as well, concomitant to total inhibition of MAO-B. The results obtained indicate that TVP-1012 irreversibly inhibits both types of MAO in the common marmoset with selectivity for MAO-B at doses less than 0.5 mg/kg. TVP-1012 could be useful in studies requiring selective MAO-B inhibition without concomitant sympathomimetic amphetamine-like effects and could thus be of therapeutic interest for Parkinson's disease and retarded depression.
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PMID:Chronic TVP-1012 (rasagiline) dose--activity response of monoamine oxidases A and B in the brain of the common marmoset. 956 27

(+)-N-Propargyl-1-aminoindan (rasagiline) and a series of derivatives have been synthesized and screened for monoamine oxidase inhibitory activity. Rasagiline and several analogues were found be highly selective and potent inhibitors of the B form of the enzyme in contrast to the levorotatory enantiomer which was not active. The results indicate that rasagiline has potential for the treatment of Parkinson's Disease. This compound is currently under development for that indication.
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PMID:(R)(+)-N-propargyl-1-aminoindan (rasagiline) and derivatives: highly selective and potent inhibitors of monoamine oxidase B. 956 30

A potent inhibitor of type B monoamine oxidase, (-)deprenyl, is known to protect or rescue dying neurons, independent of inhibition of the enzyme activity. After long term administration to rodents, a propargylamine structurally related to (-)deprenyl, (R)(+)-N-propargyl-1-aminoindan (rasagiline) increased the activities of anti-oxidative enzymes, superoxide dismutase and catalase. Rasagiline protected in vitro dopamine cells from apoptosis induced by oxidative stress or neurotoxins. The mechanism of the anti-apoptotic effect was studied by in vitro experiments using human dopaminergic neuroblastoma, SH-SY5Y cells. Peroxynitrite-generating N-morpholino sydonimine (SIN-1) induced apoptosis in SH-SY5Y cells via disruption of mitochondrial membrane potential (DeltaPsim), followed by caspase 3 activation. Rasagiline prevented the loss of DeltaPsim, the initial step to apoptosis, and also following caspase 3-activation and DNA fragmentation. The results suggest that rasagiline may interact with the specific molecule in the mitochondria and suppress the death signal transduction. By the anti-apoptotic function, rasagiline may rescue or protect declining neurons in aging and neurodegenerative disorders, such as Parkinson's disease.
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PMID:Mechanism underlying anti-apoptotic activity of a (-)deprenyl-related propargylamine, rasagiline. 1099 18

1. Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(-) enantiomer is relatively inactive in the tissues examined. 3. The in vitro IC(50) values for inhibition of rat brain MAO activity by rasagiline are 4.43+/-0.92 nM (type B), and 412+/-123 nM (type A). The ED(50) values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1+/-0.01, 0.042+/-0.0045 mg kg(-1) respectively for MAO-B, and 6.48+/-0.81, 2.38+/-0.35 mg kg(-1) respectively for MAO-A. 4. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED(50) values of 0.014+/-0.002 and 0.013+/-0.001 mg kg(-1) respectively. 5. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.
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PMID:Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. 1115

In Parkinson's disease, apoptosis was proposed to cause cell death in nigral dopamine neurons. An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, stereo-selectively induced apoptosis in human neuroblastoma SH-SY5Y cells. In this paper the intracellular mechanism of apoptosis was studied using N-methyl(R)salsolinol, 6-hydroxydopamine and peroxynitrite as inducers of apoptosis. Apoptotic cascade was initiated by opening of mitochondrial permeability transition pore, as shown by collapse of mitochondrial membrane potential, deltapsim. Apoptosis was executed by caspase 3 activation, followed by DNA fragmentation, which was antagonized by overexpressed Bcl-2. Propargylamines were found to protect the cells from apoptosis, and rasagiline, a selective irreversible inhibitor of type B monoamine oxidase was the most potent to prevent the cell death. Rasagiline preserved deltapsim, which was proved also in isolated mitochondria, and rasagiline completely suppressed the activation of caspases and DNA fragmentation. These results suggest that mitochondria regulate apoptotic process, which may be a target of neuroprotection by rasagiline.
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PMID:Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-1(R)- and (S)-aminoindan, rasagiline and TV1022. 1120 38

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors.
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PMID:Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline. 1171 51

Clinical trials for treatment of Parkinson's disease suggest that (-)deprenyl (selegiline), an inhibitor of type B monoamine oxidase, may slow the disease progression. However, the mechanism underlying protection of nigral dopamine neurons by selegiline remains an enigma. Recently, rasagiline, (R)(+)-N-propargyl-1-aminoindan, was reported to be neuroprotective by in vivo and in vitro experiments, which is another selective irreversible inhibitor of type B monoamine oxidase and not metabolized into amphetamine-like derivatives as in the case of selegiline. In this paper, the mechanism of the neuroprotection was examined using human dopaminergic neuroblastoma SH-SY5Y cells against apoptosis induced by peroxynitrite generated from SIN-1. After treatment with SIN-1, the apoptotic DNA damage in the cells was quantified by a single cell gel electrophoresis (comet) assay and by staining with Hoechst 33342. Change in mitochondrial membrane potential, Deltapsim, was measured by use of a fluorescent indicator, JC-1. Rasagiline reduced apoptosis with much more potency than selegiline, and the protection required 20 min pre-incubation before SIN-1 treatment. The protection by rasagiline was proved to be due to stabilization of mitochondrial membrane potential against the collapse induced by SIN-1, whereas rasagiline did not scavenge peroxynitrite directly. The studies on structure-activity relationship showed that a propargylamine group and a hydrophobic group with an adequate intermediate space were required for the protection. These results suggest that rasagiline may protect declining neurons through its anti-apoptotic activity in neurodegenerative diseases.
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PMID:The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. 1195 66

N-Propargyl-1(R)-aminoindan (rasagiline) is now under phase III clinical trials for Parkinson's disease (PD), and it rescues dopamine neurons from cell death in animal and cellular models of PD. Recently, we proved that rasagiline protected dopaminergic SH-SY5Y cells against apoptosis induced by a dopaminergic neurotoxin, N-methyl(R)salsolinol, and the mechanism was clarified to be due to suppression of death signal transduction in mitochondria. In this paper, the effects of rasagiline on the levels of anti-apoptotic bcl-2 gene family were studied. Rasagiline increased the levels of bcl-2 and bcl-x(l) mRNA at 100-10 nM and 100-10 pM, but not the level of pro-apoptotic bax mRNA. Enhanced expression of bcl-2 family indicates the ability of rasagiline to adjust the apoptotic threshold and protect degenerating neurons in PD.
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PMID:An anti-Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells. 1205 39

Rasagiline is a selective and potent irreversible MAO(B) inhibitor which is under development by Teva for the treatment of neurological diseases. Rasagiline is in phase III trials in the US, Canada and Europe for Parkinson's disease (PD) and has completed phase II trials in Israel and Hungary. Teva planned to submit a filing in 2002 and expected to launch rasagiline in 2003. Lundbeck acquired European development and commercialization rights to rasagiline in November 1999 and, in September 2001, the company reported that it planned to file an NDA in 2003. In March 2002, analysts at Morgan Stanley Dean Witter predicted that H Lundbeck would make sales of rasagiline of DKr 100 million in 2003, rising to DKr 300 million in 2008. In the same month, launch was predicted in 2004/2005 for the PD indication, and 2005/2006 for the AD indication, by analysts at Deutsche Banc Alex Brown.
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PMID:Rasagiline. Teva Pharmaceutical. 1209 May 55


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