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

  title={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},
  author={Yukihiro Akao and Wakako Maruyama and Hong Yi and Masayo Shamoto-Nagai and Moussa B. H. Youdim and Makoto Naoi},
  journal={Neuroscience Letters},
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… 
N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-κB transcription factor
N-Propargyl-l(R)-aminoindan, rasagiline, an anti-Parkinson drug, was found to increase the protein and mRNA levels of glial cell line-derived neurotrophic factor (GDNF) in human neuroblastoma SH-SY5Y
N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2
The neuroprotective activity of free N-propargylamine was studied using SH-SY5Y cells expressing only type A monoamine oxidase (MAO) against apoptosis induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, indicating that MAO inhibition is not prerequisite for the protective function of N-PropargYlamine.
Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives
Structural activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax.
Neuroprotection by propargylamines in Parkinson's disease: intracellular mechanism underlying the anti-apoptotic function and search for clinical markers.
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.
Rasagiline: A novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity
It is demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasgiline.
Rasagiline: an anti-Parkinson drug with neuroprotective activity
  • M. Youdim
  • Chemistry, Medicine
    Expert review of neurotherapeutics
  • 2003
Rasagiline is a novel neuroprotective–antiapoptotic second-generation potent irreversible selective inhibitor of monoamine oxidase B that prevents the neurotoxin-initiated demise of mitochondria via modulation of cell survival/death Bcl-2 family proteins at the mitochondria permeability transition pore.
Rasagiline in treatment of Parkinson’s disease
Analysis of delayed-start clinical trial suggests the potential for disease modification, and further trials are examining this effect of rasagiline as an adjunct to levodopa.
Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson’s disease
Recent advances in understanding of the neuroprotection offered by MAOB-Is are presented and possible evaluation of neuroprotective efficacy in clinical samples is discussed.
The importance of propargylamine moiety in the anti‐ Parkinson drug rasagiline and its derivatives for MAPK‐ dependent amyloid precursor protein processing
It is demonstrated that MAO‐B inhibition is not a prerequisite for either sAPPα‐induced release or ERK phosphorylation, and structure‐activity relationship among rasagiline‐related compounds suggests the crucial role of the propargyl moiety in these molecules.
Rationale for considering that propargylamines might be neuroprotective in Parkinson’s disease
Results argue against the benefit being due to a symptomatic effect and are consistent with rasagiline having a protective effect.


Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-1(R)- and (S)-aminoindan, rasagiline and TV1022.
It is suggested that mitochondria regulate apoptotic process, which may be a target of neuroprotection by rasagiline, a selective irreversible inhibitor of type B monoamine oxidase to prevent the cell death.
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
The results suggest that mitochondria play a key role in the induction of apoptosis by the neurotoxin and the prevention by aliphatic propargylamines.
Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, is mediated by activation of caspase 3
It is demonstrated that caspase 3 mediates apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, which may cause apoptotic cell death of dopamine neurons in Parkinson's disease.
Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor
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.
Future of neuroprotection in Parkinson's disease.
The mechanism underlying neuroprotection by selegiline and related propargylamines was studied against apoptosis induced by an endogenous toxin, N-methyl(R)salsolinol, synthetic 6-hydroxydopamine and peroxynitrite in dopaminergic SH-SY5Y cells and results suggest that propargYlamines may rescue or protect dopamine neurons in Parkinson's disease.
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
The results suggest that GAPDH may accumulate in nuclei as a consequence of signal transduction, which is antagonized by anti‐apoptotic Bcl‐2 protein family and rasagiline.
Neuroprotective Action of Cycloheximide Involves Induction of Bcl-2 and Antioxidant Pathways
Evidence is provided that in embryonic rat hippocampal cell cultures, CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including the antiapoptotic gene bcl-2 and antioxidant enzymes.
Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse.
Early administration of rasagiline or TVP1022 can reduce the immediate sequelae of brain injury and the mechanism of action does not appear to involve monoamine oxidase-B inhibition but could be mediated by the maintenance of cholinergic transmission in brain neurons.
Tumor Necrosis Factor Induces Bcl-2 and Bcl-x Expression through NFκB Activation in Primary Hippocampal Neurons*
Findings indicate that induction of Bcl-2 and B cl-x expression through NFκB activation is involved in the neuroprotective action of TNF against hypoxia- or nitric oxide-induced injury.
Increased Caspase 3 and Bax Immunoreactivity Accompany Nuclear GAPDH Translocation and Neuronal Apoptosis in Parkinson's Disease
  • N. Tatton
  • Medicine, Biology
    Experimental Neurology
  • 2000
Interestingly, both Lewy bodies and the intranuclear Marinesco's bodies were GAPDH immunoreactive in the PD brain, suggesting apoptotic rather than necrotic cell death.