Mitochondrial toxin inhibition of [3H]dopamine uptake into rat striatal synaptosomes

Maragos, William F.; Zhu, Jun; Chesnut, M. Dathan; Dwoskin, Linda P.

doi:10.1016/s0006-2952(02)00910-3

Cited by 23 publications

(9 citation statements)

References 28 publications

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“…4). Rotenone, a pesticide and a specific inhibitor of the mitochondria complex I, can inhibit energy-producing mitochondrial enzymes and lead to the diminished production of ATP, consequently inhibiting [ 3 H]DA uptake into the rat striatal synaptosomes by noncompetitive inhibition of the DAT (Maragos et al, 2002). In the present study, neonatal LPS exposure enhanced rotenone-induced decreases in the [ 3 H]DA uptake in both striatum and SN (Fig.…”

Section: Discussionmentioning

confidence: 99%

Neonatal exposure to lipopolysaccharide enhances accumulation of α-synuclein aggregation and dopamine transporter protein expression in the substantia nigra in responses to rotenone challenge in later life

et al. 2013

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Brain inflammation in early life may enhance adult susceptibility to develop neurodegenerative disorders triggered by environmental toxins. Our previous studies show that perinatal lipopolysaccharide (LPS) exposure enhances adult susceptibility to rotenone-induced injury to the dopaminergic system in the substantia nigra (SN) of the adult rat brain. To further investigate the enhanced adult susceptibility by neonatal LPS exposure to rotenone neurotoxicity, we used our neonatal rat model of LPS exposure (1 mg/kg, intracerebral injection in postnatal day 5, P5, neonatal rats) to examine the protein levels of α-synuclein and dopamine transporters (DAT) in the adult rat. By P70, rats from the saline- or LPS-exposed group were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. The accumulation of α-synuclein aggregation and increment of DAT protein content were found in the SN of LPS-exposed rats. Neonatal LPS exposure enhanced rotenone-stimulated accumulation of α-synuclein aggregation and increment in DAT protein expression in the cytoplasmic compartment of the SN, and in the synaptosomal compartment of the striatum of adult rats. Rotenone treatment also resulted in reduction of [3H]dopamine uptake and mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. The current study suggests possible roles of α-synuclein aggregate and DAT distribution in the cytoplasm and synaptosome triggered by environmental toxins in later life in the development of neurodegenerative disorders. Our model may be useful in studying mechanisms involved in the pathogenesis of nonfamilial Parkinson's disease and for developing potential therapeutic treatments for this disease.

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Section: Discussionmentioning

confidence: 99%

Neonatal exposure to lipopolysaccharide enhances accumulation of α-synuclein aggregation and dopamine transporter protein expression in the substantia nigra in responses to rotenone challenge in later life

et al. 2013

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“…Indeed, oxidative and nitrative stress has been demonstrated to result in decreased levels of both DAT and VMAT2 by directly oxidizing or nitrating amino acid residues in both proteins (Park et al, 2002; Eyerman and Yamamoto, 2007). Interestingly, rotenone, a classic complex I inhibitor, has also been demonstrated to reduce both DAT and VMAT2 levels as a result of oxidative damage (Maragos et al, 2002; Watabe and Nakaki, 2008). Additionally, we observed increased neurotoxicity following mxc treatment as defined by increased GFAP levels, as has been observed in animals treated with the complex I inhibitor MPTP (Richardson et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Effects of the organochlorine pesticide methoxychlor on dopamine metabolites and transporters in the mouse brain

et al. 2009

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Pesticide exposure has been suggested as an increased risk factor in developing Parkinson's disease (PD). While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days. Following treatment, we observed a dose-related increase in protein carbonyl levels in nonsynaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16-31%), which were accompanied by decreased levels of the dopamine transporter (DAT; 35-48%) and the vesicular monoamine transporter 2 (VMAT2; 21-44%). Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggests that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly-exposed populations.

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“…Indeed, in vitro exposure of rat striatal synaptosomes to high concentrations (10-50 μM) of veratridine, a sodium channel activator, resulted in decreased dopamine uptake (Holz and Coyle, 1974). In addition, pyrethroids have been demonstrated to inhibit respiratory chain function in isolated mitochondria at submicromolar levels, which could lead to down-regulation of DAT function (Gassner et al, 1997;Maragos et al, 2002;Braguini et al, 2004). Although there are few studies reporting pyrethroid concentrations in the brain following systemic administration, Sheets et al (1994) reported that brain levels of deltamethrin were 0.023 μg/g and 0.145 μg/g following a single oral exposure to 4 or 80 mg/kg in adult rats.…”

Section: Discussionmentioning

confidence: 99%

Pyrethroid pesticide-induced alterations in dopamine transporter function

Elwan

Richardson

Guillot

et al. 2006

Toxicology and Applied Pharmacology

104

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Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DATmediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 μM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 μM) or 24 h (1, 5, and 10 μM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD. KeywordsDeltamethrin; Permethrin; Pyrethroid; Dopamine transporter; Parkinson's disease Parkinson's disease (PD) is a disabling neurodegenerative disorder characterized by the loss of nigrostriatal dopamine neurons and the formation of intraneuronal inclusions termed Lewy bodies (Olanow and Tatton, 1999). Although the exact etiology of PD is unknown, both genetic and environmental factors are thought to contribute to the pathogenesis of PD. While there are rare instances of genetically-linked PD, data from a recent comprehensive

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Mitochondrial toxin inhibition of [3H]dopamine uptake into rat striatal synaptosomes

Cited by 23 publications

References 28 publications

Neonatal exposure to lipopolysaccharide enhances accumulation of α-synuclein aggregation and dopamine transporter protein expression in the substantia nigra in responses to rotenone challenge in later life

Neonatal exposure to lipopolysaccharide enhances accumulation of α-synuclein aggregation and dopamine transporter protein expression in the substantia nigra in responses to rotenone challenge in later life

Effects of the organochlorine pesticide methoxychlor on dopamine metabolites and transporters in the mouse brain

Pyrethroid pesticide-induced alterations in dopamine transporter function

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