Rotenone-induced PC12 cell toxicity is caused by oxidative stress resulting from altered dopamine metabolism

Sai, Yan; Wu, Qiang; Le, Weidong; Feng, Yang; Liu, Yunpeng; Dong, Zhaojun

doi:10.1016/j.tiv.2008.04.019

Cited by 63 publications

(47 citation statements)

References 29 publications

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“…The reason for this phenomenon is presently unclear. A recent interesting study demonstrates that rotenone can increase MAO activity in PC 12 cells (Sai et al 2008). Therefore, the present results suggest that a significant increase in the striatal DOPAC levels in MPTP + rotenone (9 mg/kg)-treated mice may be due to the increase of MAO activity caused by rotenone, although further studies are needed to clarify our findings.…”

Section: Discussionsupporting

confidence: 49%

Chronic Administration with Rotenone does not Enhance MPTP Neurotoxicity in C57BL/6 Mice

et al. 2009

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Systematic administration of rotenone as one of pesticides is known to produce degeneration of nigral dopaminergic neurons and motor deficits in experimental animals. Here, we investigated to determine whether systematic administration of rotenone causes the increased susceptibility in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Rotenone was injected into MPTP-treated mice over a period of 4 weeks. Thereafter, we evaluated the effect of rotenone 1, 3, and 6 weeks after the cessation of treatment with rotenone. In the present study with HPLC analysis, rotenone did not enhance MPTP-induced dopaminergic neurotoxicity in mice. Furthermore, MPTP + rotenone (9 mg/kg)-treated mice exhibit a significant loss of motor activity 1 day after the cessation of treatment with rotenone, However, no significant change of motor activity was found in MPTP-treated and MPTP + rotenone (9 mg/kg)-treated animals 6 weeks after the cessation of treatment with 0.5% carboxymethyl cellulose or rotenone. Our Western blot analysis study demonstrated that the change of tyrosine hydroxylase and glial fibrillary acidic protein protein levels in MPTP-treated mice was similar than that in MPTP + rotenone-treated animals. These results suggest that rotenone did not enhance MPTP neurotoxicity in mice. Our findings suggest that rotenone is not a reliable model for PD. Thus, our findings provide further valuable information for the pathogenesis of PD for exposure to agricultural pesticides.

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Section: Discussionsupporting

confidence: 49%

Chronic Administration with Rotenone does not Enhance MPTP Neurotoxicity in C57BL/6 Mice

et al. 2009

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“…Moreover, inhibition of vesicular sequestration augments the toxicity of a variety of agents such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (46, 47) and 6-hydroxydopamine (48). Conversely, the pesticide and complex I inhibitor rotenone inhibits vesicular uptake (49,50), increases production of DOPAL (51), and evokes apoptosis via oxidation of cytosolic dopamine (52). Clinical significance.…”

Section: Figurementioning

confidence: 99%

Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases

Goldstein¹,

Holmes²,

Kopin³

et al. 2011

J. Clin. Invest.

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Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies -cytoplasmic inclusions containing α-synuclein protein aggregates -in the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH; also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons. We used 6-[ 18 F]-dopamine ( 18 F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal 18 F-DA was followed by assessment of arterial plasma levels of the 18 F-DA metabolite 18 F-dihydroxyphenylacetic acid ( 18 F-DOPAC). The ratio of myocardial 18 F-DA to arterial 18 F-DOPAC provided an index of vesicular uptake. Tracer concentrations were measured in patients with PD with or without orthostatic hypotension (PD+OH, PD-No-OH); in patients with pure autonomic failure (PAF, a Lewy body disease without parkinsonism); in patients with multiple system atrophy (MSA, a non-Lewy body synucleinopathy); and in normal controls. Patients with PD+OH or PAF had decreased vesicular 18 F-DA uptake and accelerated 18 F-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial 18 F-DA uptake. We conclude that sympathetic denervation in Lewy body diseases is associated with decreased vesicular uptake of neuronal catecholamines, suggesting that vesicular monoamine transport is impaired. Vesicular uptake may constitute a novel target for diagnosis, treatment, and prevention.

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“…While reserpine is more often used due to commercial availability, prolonged tetrabenazine administration leads to a reduction in dopamine neurons in the substantia nigra; the authors hypothesize that this is due to cytosolic dopamine build up and subsequent oxidative stress [171]. Additionally, genetic (A30P alpha-synuclein) and environmental contaminant (PCB and rotenone) models of degeneration show a dependence on dopamine for toxic effect [172][173][174]. These studies strongly suggest that VMAT2 activity prevents high levels of cytosolic dopamine, which can lead to oxidative stress and, if not halted, neuronal damage and death.…”

Section: Vesicular Transport and Neurotransmitter Toxicitymentioning

confidence: 99%

Protective Actions of the Vesicular Monoamine Transporter 2 (VMAT2) in Monoaminergic Neurons

2009

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Vesicular monoamine transporters (VMATs) are responsible for the packaging of neurotransmitters such as dopamine, serotonin, norepinephrine, and epinephrine into synaptic vesicles. These proteins evolved from precursors in the major facilitator superfamily of transporters and are among the members of the toxin extruding antiporter family. While the primary function of VMATs is to sequester neurotransmitters within vesicles, they can also translocate toxicants away from cytosolic sites of action. In the case of dopamine, this dual role of VMAT2 is combined-dopamine is more readily oxidized in the cytosol where it can cause oxidative stress so packaging into vesicles serves two purposes: neurotransmission and neuroprotection. Furthermore, the deleterious effects of exogenous toxicants on dopamine neurons, such as MPTP, can be attenuated by VMAT2 activity. The active metabolite of MPTP can be kept within vesicles and prevented from disrupting mitochondrial function thereby sparing the dopamine neuron. The highly addictive drug methamphetamine is also neurotoxic to dopamine neurons by using dopamine itself to destroy the axon terminals. Methamphetamine interferes with vesicular sequestration and increases the production of dopamine, escalating the amount in the cytosol and leading to oxidative damage of terminal components. Vesicular transport seems to resist this process by sequestering much of the excess dopamine, which is illustrated by the enhanced methamphetamine neurotoxicity in VMAT2-deficient mice. It is increasingly evident that VMAT2 provides neuroprotection from both endogenous and exogenous toxicants and that while VMAT2 has been adapted by eukaryotes for synaptic transmission, it is derived from phylogenetically ancient proteins that originally evolved for the purpose of cellular protection.

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Rotenone-induced PC12 cell toxicity is caused by oxidative stress resulting from altered dopamine metabolism

Cited by 63 publications

References 29 publications

Chronic Administration with Rotenone does not Enhance MPTP Neurotoxicity in C57BL/6 Mice

Chronic Administration with Rotenone does not Enhance MPTP Neurotoxicity in C57BL/6 Mice

Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases

Protective Actions of the Vesicular Monoamine Transporter 2 (VMAT2) in Monoaminergic Neurons

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