Lead exposure activates nuclear factor kappa B, activator protein-1, c-Jun N-terminal kinase and caspases in the rat brain

Ramesh, Govindarajan T.; Manna, Sunil K.; Aggarwal, Bharat B.; Jadhav, Arun L.

doi:10.1016/s0378-4274(01)00395-2

Cited by 52 publications

(26 citation statements)

References 44 publications

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“…An approximate 7-fold increase in cFOS expression in rats treated with 50 ppm lead and not challenged with amphetamine was found. This indicates that low-level lead treatment can induce cFOS and is consistent with the study by Ramesh et al (2001), which found that 3 months of exposure to 50 ppm lead caused an increase in striatal cFOS in rats. When rats treated with 50 ppm lead were challenged with amphetamine, the degree of cFOS activation was not significantly different from that of the untreated control group challenged with amphetamine.…”

Section: Discussionsupporting

confidence: 91%

“…D 1 receptor activation increases cAMP, resulting in the phosphorylation of the cAMP response element-binding protein (CREB) and the induction of cFOS in striatal neurons (Das et al, 1997). Recently, lead exposure has been shown to induce cFOS in the rat striatum (Ramesh et al, 2001). Because lead exposure has been shown to affect the midbrain DA system in animal lead exposure models, alter basal forebrain DA release and amphetamine-elicited forebrain DA release, and also induce cFOS expression in the forebrain, we sought to determine whether chronic lead exposure would alter the amphetamine-induced expression of the cFOS gene in the striatum.…”

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confidence: 99%

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Inorganic Lead Exposure in the Rat Activates Striatal cFOS Expression at Lower Blood Levels and Inhibits Amphetamine-Induced cFOS Expression at Higher Blood Levels

Lewis

Pitts

2004

J Pharmacol Exp Ther

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The impact of inorganic lead exposure on dopamine (DA) neurotransmission in the basal ganglia was examined. Amphetamine (AMPH)-induced cFOS immunoreactivity (cFOS-IR) in the striatum was determined after a 3-week exposure to lead acetate (0, 50, or 250 ppm). On the 21st day of lead exposure, rats were challenged with AMPH (4 mg/kg i.p.) or saline vehicle (Veh) and were assayed for presence of cFOS-IR. In the untreated control (Con) group, AMPH challenge (Con/AMPH) increased cFOS-IR expression by approximately 35-fold over Veh challenge (Con/Veh) (P Ͻ 0.01). In the Pb50/Veh group, cFOS-IR expression was approximately 7-fold greater than in the Con/Veh group (P Ͻ 0.05). Given that there was negligible cFOS-IR expression in the Con/Veh group, this indicates that the Pb50 exposure induced cFOS expression. The increase in cFOS-IR in the Pb50/AMPH was also significant (P Ͻ 0.01), but it was not different from the Con/AMPH (P Ͼ 0.20). Neither the Pb250/Veh group nor the Pb250/AMPH group had a significant increase in cFOS-IR relative to Con/Veh (P Ͼ 0.20). These results indicate that chronic 50 ppm lead exposure induced a low but statistically significantly level of cFOS gene activation and that it did not affect the AMPH-induced cFOS activation. However, chronic 250 ppm lead exposure inhibited AMPHinduced activation of cFOS in the striatum by about 89%. Therefore, lead is capable of both activating cFOS expression at low levels of exposure (mean blood lead level 21.6 Ϯ 1.9 g/dl) and inhibiting AMPH-induced cFOS expression at higher levels of exposure (mean blood lead level 47.4 Ϯ 2.6 g/dl).

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Inorganic Lead Exposure in the Rat Activates Striatal cFOS Expression at Lower Blood Levels and Inhibits Amphetamine-Induced cFOS Expression at Higher Blood Levels

Lewis

Pitts

2004

J Pharmacol Exp Ther

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“…In some of the experiments, the cells were treated with antioxidant N-acetyl-L-cysteine (50 M) along with 1 M arsenite for a period of 2 h. And then, nuclear extracts were prepared and activation of NF-B and AP-1 were analyzed by EMSA as previously described [63].…”

Section: Electrophoretic Mobility Shift Assays (Emsa)mentioning

confidence: 99%

Low levels of arsenite activates nuclear factor‐κB and activator protein‐1 in immortalized mesencephalic cells

Kumar

Manna

Wise

et al. 2005

J Biochem & Molecular Tox

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Degeneration of dopaminergic neurons is one of the major features of Parkinson's disease. Many redox-active metals such as iron and manganese have been implicated in neuronal degeneration characterized by symptoms resembling Parkinson's disease. Even though, arsenic, which is another redox-active metal, has been shown to affect the central monoaminergic systems, but its potential in causing dopaminergic cell degeneration has not been fully known. Hence, the present study was designed to investigate arsenic signaling especially that is mediated by reactive oxygen species and its effect on early transcription factors in dopamine producing mesencephalic cell line 1RB3AN27. These mesencephalic cells were treated with low concentrations of sodium arsenite (0.1, 0.5, 1, 5, and 10 microM) and incubated for different periods of time (0-4 h). Arsenite was cytotoxic at 5 and 10 microM concentrations only after 72-h incubation period. Arsenite, in a dose-dependent manner, induced generation of reactive oxygen species (ROS) and activation of early transcription factors such as nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) as shown by electro mobility shift assay. Incubation of antioxidants, either N-acetyl-L-cysteine (50 microM) or alpha-tocopherol (50 microM) with 1 microM arsenite, suppressed ROS generation. Arsenite at 1 microM concentration was sufficient for maximal activation of NF-kappaB and AP-1 activation. Time kinetics studies showed maximal activation of NF-kappaB by 1 microM concentration of arsenite was seen at 120 min and correlated with complete degradation of Ikappa Balpha at 60 min. Similarly, maximal activation of AP-1 by 1 microM concentration of arsenite occurred at 120 min. N-acetyl-L-cysteine at 50 microM concentration inhibited arsenite-induced NF-kappa B and AP-1. In addition, arsenite was shown to induce phosphorylation of extracellular signal regulated kinase (ERK) 1/2 at concentrations of 1 microM and above. These results suggest that arsenite, at low and subcytoxic concentrations, appears to induce oxidative stress leading to activation of early transcription factors whereas addition of antioxidant inhibited the activation of these factors.

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“…For example, some studies have found that lead exposure produces a particular vulnerability of mesolimbic DA systems and this can result in motor behavior alterations (Zuch et al, 1998;Cory-Slechta et al, 1998). Moreover, ex vivo and in vitro studies indicated that inorganic lead is distributed, among other nuclei, in the striatum and cerebral cortex (Moreira et al, 2001;Ramesh et al, 2001). Autoradiographic studies showed that lead exposure decreased the density of D2 receptors in the cerebral cortex (Ma et al, 1999), and it also has been shown a diminished evoked release of dopamine in synaptosomes isolated from the striatum of animals exposed to lead (Silbergeld, 1977;Sulkowski et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Motor behavior and brain enzymatic changes after acute lead intoxication on different strains of mice

2004

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Lead exposure activates nuclear factor kappa B, activator protein-1, c-Jun N-terminal kinase and caspases in the rat brain

Cited by 52 publications

References 44 publications

Inorganic Lead Exposure in the Rat Activates Striatal cFOS Expression at Lower Blood Levels and Inhibits Amphetamine-Induced cFOS Expression at Higher Blood Levels

Inorganic Lead Exposure in the Rat Activates Striatal cFOS Expression at Lower Blood Levels and Inhibits Amphetamine-Induced cFOS Expression at Higher Blood Levels

Low levels of arsenite activates nuclear factor‐κB and activator protein‐1 in immortalized mesencephalic cells

Motor behavior and brain enzymatic changes after acute lead intoxication on different strains of mice

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