Reserpine as an uncoupler of oxidative phosphorylation and the relevance to its psychoactive properties

Weinbach, Eugene C.; Costa, Jonathan L.; Claggett, C.Elwood; Fay, Denise D.; Hundal, Torill

doi:10.1016/0006-2952(83)90449-5

Cited by 17 publications

(4 citation statements)

References 19 publications

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“…The toxicity of dopamine may result from oxidation of itself. Reserpine is also known to be an uncoupler of the mitochondrial respiration chain (Mania, 1974;Weinbach et al, 1983), and the uncoupler does not generate ROS (Watabe and Nakaki, 2007). Therefore, we examined whether ROS were produced by rote- jpet.aspetjournals.org none under our experimental conditions.…”

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confidence: 99%

“…Oxidation of dopamine itself in the cytosol is a key event in dopamine toxicity. Reserpine is also known to be an uncoupler of the mitochondrial respiration chain (Mania, 1974;Weinbach et al, 1983), and the uncoupler does not generate ROS (Watabe and Nakaki, 2007). Therefore, in rotenoneinduced apoptosis, it is significant that dopamine redistribution to the cytosol is caused by rotenone when ROS levels are Fig.…”

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confidence: 99%

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Mitochondrial Complex I Inhibitor Rotenone-Elicited Dopamine Redistribution from Vesicles to Cytosol in Human Dopaminergic SH-SY5Y Cells

Watabe¹,

Nakaki²

2007

J Pharmacol Exp Ther

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Parkinson's disease is a chronic neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Rotenone, a pesticide, produces selective degeneration of dopaminergic neurons and motor dysfunction in rats. To determine the mechanisms underlying rotenoneinduced neuronal death, we investigated whether intracellular dopamine plays a role in rotenone (0.1-0.4 M)-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. The 40% decrease of dopamine content by inhibition of dopamine synthesis suppressed rotenoneinduced apoptosis. On the other hand, the 30% increase of dopamine content by inhibition of dopamine metabolism enhanced rotenone-induced apoptosis. Depletion of intracellular dopamine using reserpine (0.1-10 M) also prevented rotenone-induced apoptosis, and this effect was counteracted by dopamine (10 -100 M) replenishment. Inhibition of dopamine reverse transport increased cytosolic dopamine and enhanced rotenone-induced apoptosis. We examined the intracellular localization of dopamine in rotenone-treated cells immunocytochemically and quantitatively. Rotenone induced dopamine redistribution from vesicles to the cytosol. In this process, rotenone stimulated reactive oxygen species and protein carbonylation and decreased an antioxidant, glutathione. Addition of an antioxidant, N-acetylcysteine (3 mM), prevented dopamine being expelled from vesicles and inhibited rotenone-induced apoptosis. Our findings demonstrate that rotenone-generated reactive oxygen species are involved in dopamine redistribution to the cytosol, which in turn may play a role in rotenone-induced apoptosis of dopaminergic cells.Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of dopamine neurons in the substantia nigra, decreased striatal dopamine level, and consequent motor dysfunction (Dawson and Dawson, 2003). The etiology of the nigral dopamine neuronal degeneration is unknown, although both genetic mutations and environmental factors have been identified as contributing to certain forms of this disorder (Shastry, 2001). An established hallmark of PD is a reduction in the activity of brain mitochondrial enzyme complex I (Schapira et al., 1990). Complex I inhibitors, such as 1-methyl-4-phenylpyridinium ion (MPP ϩ ) and rotenone, have been shown to cause apoptosis of nigral dopaminergic neurons and parkinsonian dysfunction (Heikkila et al., 1985;Forno et al., 1993;Greenamyre et al., 2001;Ayala et al., 2007). Poly-(ADP-ribose) polymerase-1 (PARP-1) is involved in MPP ϩ -induced apoptosis and efficacious effects of PARP-1 inhibitors have been demonstrated in a PD model using MPP ϩ , although the role of PARP-1 in the pathogenesis of PD is unclear (Outeiro et al., 2007). These observations suggest that a defect in mitochondrial complex I activity may contribute to the neurodegenerative process in PD. These dopaminergic neurotoxins enhance production of reactive oxygen species (ROS) in mitochondria, but much less is known about ho...

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confidence: 99%

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Mitochondrial Complex I Inhibitor Rotenone-Elicited Dopamine Redistribution from Vesicles to Cytosol in Human Dopaminergic SH-SY5Y Cells

Watabe¹,

Nakaki²

2007

J Pharmacol Exp Ther

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“…The findings here help to further elucidate the intracellular functions of CADs and in particular of antidepressants. Such knowledge is essential since other mechanisms of action than enhancement of monoaminergic neurotransmission may play an important role in conveying beneficial clinical effects4748495051525354.…”

Section: Discussionmentioning

confidence: 99%

New insights into the intracellular distribution pattern of cationic amphiphilic drugs

Vater

Möckl

Gormanns

et al. 2017

Sci Rep

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Cationic amphiphilic drugs (CADs) comprise a wide variety of different substance classes such as antidepressants, antipsychotics, and antiarrhythmics. It is well recognized that CADs accumulate in certain intracellular compartments leading to specific morphological changes of cells. So far, no adequate technique exists allowing for ultrastructural analysis of CAD in intact cells. Azidobupramine, a recently described multifunctional antidepressant analogue, allows for the first time to perform high-resolution studies of CADs on distribution pattern and morphological changes in intact cells. We showed here that the intracellular distribution pattern of azidobupramine strongly depends on drug concentration and exposure time. The mitochondrial compartment (mDsRed) and the late endo-lysosomal compartment (CD63-GFP) were the preferred localization sites at low to intermediate concentrations (i.e. 1 μM, 5 μM). In contrast, the autophagosomal compartment (LC3-GFP) can only be reached at high concentrations (10 μM) and long exposure times (72 hrs). At the morphological level, LC3-clustering became only prominent at high concentrations (10 μM), while changes in CD63 pattern already occurred at intermediate concentrations (5 μM). To our knowledge, this is the first study that establishes a link between intracellular CAD distribution pattern and morphological changes. Therewith, our results allow for gaining deeper understanding of intracellular effects of CADs.

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“…To our knowledge, the possibility of reserpine acting as an uncoupling agent has only been investigated in mammalian mitochondria (Maina 1974 ; Weinbach et al . 1983 ).…”

Section: Cccpmentioning

confidence: 99%

Critical discussion on drug efflux in Mycobacterium tuberculosis

Remm

Earp

Dick

et al. 2021

FEMS Microbiology Reviews

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Mycobacterium tuberculosis (Mtb) can withstand months of antibiotic treatment. An important goal of tuberculosis research is shortening the treatment to reduce the burden on patients, increase adherence to the drug regimen and thereby slow the spread of drug resistance. Inhibition of drug efflux pumps by small molecules has been advocated as a promising strategy to attack persistent Mtb and shorten therapy. Although mycobacterial drug efflux pumps have been broadly investigated, mechanistic studies are scarce. In this critical review, we shed light on drug efflux in its larger mechanistic context by considering the intricate interplay between membrane transporters annotated as drug efflux pumps, membrane energetics, efflux inhibitors and cell wall biosynthesis processes. We conclude that a great wealth of data on mycobacterial transporters is insufficient to distinguish by what mechanism they contribute to drug resistance. Recent studies suggest that some drug efflux pumps transport structural lipids of the mycobacterial cell wall and that the action of certain drug efflux inhibitors involves dissipation of the proton-motive force, thereby draining the energy source of all active membrane transporters. We propose recommendations on the generation and interpretation of drug efflux data to reduce ambiguities and promote assigning novel roles to mycobacterial membrane transporters.

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Reserpine as an uncoupler of oxidative phosphorylation and the relevance to its psychoactive properties

Cited by 17 publications

References 19 publications

Mitochondrial Complex I Inhibitor Rotenone-Elicited Dopamine Redistribution from Vesicles to Cytosol in Human Dopaminergic SH-SY5Y Cells

Mitochondrial Complex I Inhibitor Rotenone-Elicited Dopamine Redistribution from Vesicles to Cytosol in Human Dopaminergic SH-SY5Y Cells

New insights into the intracellular distribution pattern of cationic amphiphilic drugs

Critical discussion on drug efflux in Mycobacterium tuberculosis

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