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

Akao, Yukihiro; Maruyama, Wakako; Yi, Hong; Shamoto-Nagai, Masayo; Youdim, Moussa B. H.; Naoi, Makoto

doi:10.1016/s0304-3940(02)00332-4

Cited by 123 publications

(87 citation statements)

References 12 publications

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“…Both TIQ and MPP + are reported to cause apoptosis in PC12 cells (7,8) and dopaminergic neurons (2,6,8,27). However, several investigators suggest that MPP + elicits nonapoptotic cell death in PC12 cells (11,28).…”

Section: Discussionmentioning

confidence: 99%

Possible Role of Interleukin-6 in PC12 Cell Death Induced by MPP+ and Tetrahydroisoquinoline

et al. 2003

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Abstract. Interleukin (IL)-6 has been shown to protect neuronal cells from cell death induced by various stimulants. Although neuronal cells including PC12 cells were shown to produce IL-6, little is known about the effects of dopaminergic neurotoxins, 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-4-phenylpyridinium ion (MPP + ), on IL-6 expression in PC12 cells. In the present study, we investigated the role of IL-6 in the TIQ-and MPP + -induced cell death in PC12 cells. Treatment with 3.2 mM TIQ for 24 h caused a delayed cell death (lactate dehydrogenase (LDH) leakage and nuclear DNA fragmentation) markedly 72 h after the addition. Addition of 0.4 mM MPP + caused LDH leakage and nuclear DNA fragmentation 24 h after the addition. The cell death induced by MPP + was inhibited by an inhibitor of caspases, z-Val-Ala-Asp(OMe)-fluoromethylketone. The cell death induced by TIQ or MPP + was inhibited by nerve growth factor and 10% serum and significantly enhanced by the treatment with anti-IL-6 antibody. Both neurotoxins decreased the IL-6 mRNA level in PC12 cells without changing the other tested mRNA levels (IL-1a , b-actin, etc.). These findings suggest that dopaminergic neurotoxins cause cell death in PC12 cells at least partially by changing IL-6 expression.

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Section: Discussionmentioning

confidence: 99%

Possible Role of Interleukin-6 in PC12 Cell Death Induced by MPP+ and Tetrahydroisoquinoline

et al. 2003

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“…Rasagiline prevents apoptosis via multiple intracellular processes including the induction of survival genes and the suppression of proapoptotic genes (483,825,869). In addition, rasagiline can mediate direct PTP inhibition, as demonstrated in cellula and in isolated mitochondria (8). Whether this effect is truly responsible for the neuroprotective effect of rasagiline, however, remains to be proven.…”

Section: Inhibitors Of the Permeability Transition Porementioning

confidence: 99%

Mitochondrial Membrane Permeabilization in Cell Death

Kroemer¹,

Galluzzi²,

Brenner³

2007

Physiological Reviews

3,103

2,693

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Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

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“…Also, pre-administration of the drug was shown to protect against MPTP- [125] and 6-OHDA-induced [126] opening of the mPTP, rupture of the mitochondrial outer membrane and a decline in mitochondrial membrane potential. In this regard, rasagiline was seen to bind directly to the mPTP, thereby stabilizing mitochondrial membrane potential [129].…”

Section: Reviewmentioning

confidence: 96%

“…The observation that the neuroprotective benefits of rasagiline are only observed at concentrations below the MAO inhibition threshold in preclinical animal models, while the same was reported in cellular systems not containing MAO-B [128,129], suggests that the neuroprotection provided by the drug is not entirely attributable to MAO-B inhibition and that multiple mechanisms, in particular mitochondria-based, may be involved. This includes rasagiline-induced increased expression of the anti-apoptotic proteins Bcl-2 and BclxL and downregulating the expression of Bax and Bad, the gateway proteins to the mitochondrial pathway of apoptosis [130,131].…”

Section: Reviewmentioning

confidence: 99%

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

Pienaar¹,

Dexter²,

Burkhard³

2010

Expert Review of Proteomics

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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

Cited by 123 publications

References 12 publications

Possible Role of Interleukin-6 in PC12 Cell Death Induced by MPP+ and Tetrahydroisoquinoline

Possible Role of Interleukin-6 in PC12 Cell Death Induced by MPP+ and Tetrahydroisoquinoline

Mitochondrial Membrane Permeabilization in Cell Death

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

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