Chapter 12 Neurochemical, neuroprotective and neurorescue effects of aliphatic N-methylpropargylamines; new MAO-B inhibitors without amphetamine-like properties

Yu, Peter H.; Davis, Bruce A.; Zhang, X.; Zuo, Dongmei; Fang, Jim; Lai, Chien‐Tsai; Li, X.M.; Paterson, I.A.; Boulton, Alan A.

doi:10.1016/s0079-6123(08)61208-x

Cited by 21 publications

(10 citation statements)

References 40 publications

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“…(–)Deprenyl (selegiline), a propargylamine inhibitor of type B monoamine oxidase [monoamine: oxygen oxidoreductase (deaminating), EC 1.4.3.4; MAO‐B], is now used as a monotherapy or an adjunct of l ‐DOPA therapy in Parkinson's disease. A series of (–)deprenyl and structurally related propargylamines were found to protect neuronal cells, as confirmed by in vivo and in vitro experiments (Yu et al . 1995; Maruyama et al .…”

mentioning

confidence: 70%

“…(-)Deprenyl (selegiline), a propargylamine inhibitor of type B monoamine oxidase [monoamine: oxygen oxidoreductase (deaminating), EC 1.4.3.4; MAO-B], is now used as a monotherapy or an adjunct of L-DOPA therapy in Parkinson's disease. A series of (-)deprenyl and structurally related propargylamines were found to protect neuronal cells, as confirmed by in vivo and in vitro experiments (Yu et al 1995;Maruyama et al 1998;Youdim et al 2001). We previously showed that the rasagiline [N-propargyl-1(R)aminoindan; Maruyama et al 2000Maruyama et al , 2001a and R-(2heptyl)-N-methyl-propargylamine (Maruyama et al 2001b) protected SH-SY5Y cells from apoptosis induced by NM(R)Sal.…”

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confidence: 77%

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Mitochondrial permeability transition mediates apoptosis induced by N‐methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl‐2 and rasagiline, N‐propargyl‐1(R)‐aminoindan

Akao

Maruyama

Shimizu

et al. 2002

Journal of Neurochemistry

166

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The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, DYm, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of DYm. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis. In mitochondria isolated from rat liver, NM(R)Sal induced swelling and reduced DYm, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that NM(R)Sal induced the PT by direct action on the mitochondria. Rasagiline, N-propargyl-1(R)-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the DYm reduction, release of cytochrome c, and apoptosis induced by NM(R)Sal in SH-SY5Y cells. Rasagiline also inhibited the NM(R)Salinduced loss of DYm and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline.

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confidence: 70%

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confidence: 77%

Mitochondrial permeability transition mediates apoptosis induced by N‐methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl‐2 and rasagiline, N‐propargyl‐1(R)‐aminoindan

Akao

Maruyama

Shimizu

et al. 2002

Journal of Neurochemistry

166

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“…The aliphatic N-methyl propargylamines and their desmethyl metabolites, the aliphatic propargylamines (usually the heptyl analogue), have been assessed in several of the experimental rescue paradigms listed in Table 2; the results are shown in Table 4. From this it is clear that the aliphatic N-methyl propargylamines and the aliphatic propargylamines are effective rescue agents [Li et al, 1995a;Yu et al, 1995Yu et al, , 1998Boulton and Eisenhofer, 1998]. Furthermore, as opposed to the situation for MAO inhibition, rescue requires absolute stereochemical specificity, so that only the R enantiomers are effective [Durden et al, 1997;Paterson and Tatton, 1998;].…”

Section: Aliphatic Propargylamines As Rescue Agentsmentioning

confidence: 99%

Aliphatic propargylamines: New antiapoptotic drugs

et al. 1997

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Two series of drugs, the aliphatic‐N‐methyl propargylamines and the aliphatic propargylamines, have been synthesised and shown to be specific, irreversible, and potent monoamine oxidase B inhibitors and neural rescue agents. In the latter case, an absolute stereochemical requirement for the R isomer exists. Both series of compounds have been shown, in numerous in vitro and in vivo experimental paradigms, to be effective neuronal rescue agents. Candidates from both series exhibit excellent bioavailability and pharmacokinetics and offer opportunities for treating neurodegenerative disorders and stroke and cognitive decline in companion animals. Drug Dev. Res. 42:150–156, 1997. © 1997 Wiley‐Liss, Inc.

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“…R-2HMP in addition to being a potent, irreversible MAO-B inhibitor (Yu et al, 1992a(Yu et al, ,b, 1993 is also a neural rescue agent, which appears to inhibit some forms of apoptosis (Boulton et al, 1997Berry, 1999a). Whereas both the R and the S isomers of 2HMP are effective MAO-B inhibitors (Yu et al, 1992a(Yu et al, ,b, 1993, there is enantiomeric specificity for the antiapoptotic effects (Ansari et al, 1993;Yu et al, 1995;Zhang et al, 1996;Paterson et al, 1997aPaterson et al, ,b, 1998Berry, 1999a). In fact, recent evidence suggests that the S-isomer is antagonistic of R-2HMP's neural rescue properties Berry 1999c).…”

Section: Introductionmentioning

confidence: 99%

Loss of mitochondrial membrane potential is dependent on the apoptotic program activated: Prevention by R-2HMP

et al. 1999

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Recent evidence suggests that the mitochondrial membrane potential begins to decrease well before the cells commit to apoptotic death. By using cultured cerebellar granule cells, two types of apoptosis can be induced, one by adding cytosine arabinoside (Ara-c; p53-dependent apoptosis) and one by lowering the K(+) concentrations of the medium (p53-independent apoptosis). Cultures show clear signs of increased apoptosis (chromatin condensation as visualized with bis-benzamide) after 12 hr which increases with time up to 24 hr. A fluorescent probe, chloromethyl-tetramethylrhodamine methyl ester (CMTMR), a lipophilic, potentiometric dye, which when introduced into the media accumulates within mitochondria in proportion to the mitochondrial membrane potential, was added at various time points after the induction of apoptosis. In Ara-c-induced apoptosis, there was a shift in the distribution of cell populations towards low-intensity CMTMR fluorescence, whereas in control and low-K(+) cultures, there was no such shift. This effect was observed as early as 6 hr after adding Ara-c. The antiapoptotic drug R-N-2-heptyl-N-methylpropargylamine hydrochloride (R-2HMP) reversed this loss of mitochondrial membrane potential in Ara-c-induced apoptosis; the effect was antagonized by the S-2HMP.

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Chapter 12 Neurochemical, neuroprotective and neurorescue effects of aliphatic N-methylpropargylamines; new MAO-B inhibitors without amphetamine-like properties

Cited by 21 publications

References 40 publications

Mitochondrial permeability transition mediates apoptosis induced by N‐methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl‐2 and rasagiline, N‐propargyl‐1(R)‐aminoindan

Mitochondrial permeability transition mediates apoptosis induced by N‐methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl‐2 and rasagiline, N‐propargyl‐1(R)‐aminoindan

Aliphatic propargylamines: New antiapoptotic drugs

Loss of mitochondrial membrane potential is dependent on the apoptotic program activated: Prevention by R-2HMP

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