Receptor alterations in manganese intoxicated monkeys

Eriksson, Håkan; Gillberg, Per‐Göran; Aquilonius, Sten–Magnus; Hedström, Karl‐Goran; Heilbronn, Edith

doi:10.1007/bf01973632

Cited by 82 publications

(41 citation statements)

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“…Concerning the mechanism of Mn-induced neurotoxicity, the effects of Mn intoxication on the expression of dopamine receptors in the striatum have been examined, but results have been controversial. For example, one study reported that Mn intoxication did not significantly alter DRD2 levels in the striatum of monkeys, 19) while another showed that striatal DRD2 levels markedly decreased in chronic Mn toxicity. 20) We described the behavioral changes and expression of dopamine D2-like receptors induced by acute Mn exposure in mice.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Motor Function and the Expression of Striatal Dopamine D2 Receptors in Manganese-Treated Mice

Nam

Kim

2008

Biological & Pharmaceutical Bulletin

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Manganese (Mn) exists in a number of physical and chemical forms in the environment, and is an essential trace metal, necessary for normal cellular functioning. 1) In the brain, Mn is a cofactor for some metalloprotein enzymes, including Mn-superoxide dismutase and glutamine synthetase.2,3) Although Mn is an essential element, excessive exposure to Mn can be toxic to the brain. Mn overload may lead to a neurological disorder similar to Parkinson's disease, called "manganism". 4,5) However, unlike Parkinson's disease, in which neurodegeneration occurs primarily in the substantia nigra pars compacta, Mn intoxication in human and animal models results in prominent neuronal loss and gliosis in the globus pallidus and striatum.6) The symptoms associated with Mn toxicity are neuropsychiatric and behavioral deficits, including poor motor coordination. 7)Although the mechanisms underlying Mn neurotoxicity remain unclear, research on the neurobiological consequences of Mn toxicity has largely focused on dopamine metabolism and associated behavioral alterations. Mn may alter the biochemical pathway involving brain dopamine systems in children with attention deficit hyperactivity disorder, 8) and alters dopamine levels in both neonatal and older rats. 9) These observations suggest that Mn may exert its neurotoxic effect(s), at least in part, by disturbing dopaminergic neurotransmission.The neurotransmitter dopamine plays important roles in many brain functions, including locomotor activity, cognition, emotion, positive reinforcement, food intake, and endocrine regulation.10) Dopamine biosynthesis is regulated by tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine. Moreover, dopamine affects neurons through dopamine receptors (DR) of two categories (D1-like and D2-like), according to pharmacological and biochemical properties. The D1-like subtype includes the D1 and D5 receptors, while the D2-like subtype consists of the D2, D3, and D4 receptors.11) The D1-like receptors interact with Gproteins that stimulate adenylate cyclase activity, while D2-like receptors inhibit adenylate cyclase activity.12) Most studies that have examined the effects of Mn neurotoxicity and dopamine receptors have focused on the D2 receptor, which is implicated in many of the behavioral alterations observed in subjects exposed to Mn. 13)We investigated whether acute exposure to Mn may change motor activity and the expression of TH and the dopamine D2-like receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) at the mRNA and protein level in the striatum of the mouse brain. MATERIALS AND METHODS Animals and TreatmentExperiments were approved by the Institutional Animal Care and Use Committee of Keimyung University, Korea. Experiments were conducted according to the NIH guidelines for the care and use of laboratory animals. Animals were housed in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-accredited facility, with free access to food and water.C57BL/6 mice (nϭ24, 8-week-old males, weighin...

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Section: Discussionmentioning

confidence: 99%

Abnormal Motor Function and the Expression of Striatal Dopamine D2 Receptors in Manganese-Treated Mice

Nam

Kim

2008

Biological & Pharmaceutical Bulletin

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“…The groups headed by Eriksson in Sweden (1992a) and by Guilarte in the United States (2006aStates ( , 2008, have used this approach extensively because not only is it quantitative, it also offers exquisite anatomical information with high resolution. Eriksson et al (1992a) performed receptor autoradiography studies in the basal ganglia of monkeys exposed to 0.1 g Mn/month for 26 months. They indicated that this dosing regimen was comparable with what workers might inhale in dusty environments.…”

Section: Behavioral Neuroimaging Neurochemical and Neuropathologicmentioning

confidence: 99%

Manganese and Parkinson's disease: a critical review and new findings

Guilarte

2011

Ciênc. saúde coletiva

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The goal of this review was to examine whether chronic Mn exposure produces dopamine neuron degeneration and PD or whether it has a distinct neuropathology and clinical presentation. I reviewed available clinical, neuroimaging, and neuropathological studies in humans and nonhuman primates exposed to Mn or other human conditions that result in elevated brain Mn concentrations. Human and nonhuman primate literature was examined to compare clinical, neuroimaging, and neuropathological changes associated with Mn-induced parkinsonism. Clinical, neuroimaging, and neuropathological evidence was used to examine whether Mn-induced parkinsonism involves degeneration of the nigrostriatal dopaminergic system as is the case in PD. The overwhelming evidence shows that Mn-induced parkinsonism does not involve degeneration of midbrain dopamine neurons and that l-dopa is not an effective therapy. New evidence is presented on a putative mechanism by which Mn may produce movement abnormalities. Confirmation of this hypothesis in humans is essential to make rational decisions about treatment, devise effective therapeutic strategies, and set regulatory guidelines.

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“…Only 6 papers reported group-average neurochemical endpoints of manganese treatment (Ulrich et al 1979a(Ulrich et al , 1979b(Ulrich et al , 1979cBird et al 1984;Eriksson et al 1992a;Neff et al 1969). Evaluation of motor effects was mostly qualitative with only two studies reporting quantitative tests to evaluate motor response (Eriksson et al 1992a;Newland and Weiss 1992).…”

Section: Parameter Values: Non-human Primate Studiesmentioning

confidence: 99%

“…Outcomes to the right of the vertical line were produced by MnO 2 exposure and almost all outcomes to the left by MnCl 2 exposure. Only Bird et al (1984), Eriksson et al 1992a, Neff et al (1969, Ulrich et al (1979aUlrich et al ( , 1979Ulrich et al ( b, 1979c) report average outcomes for more than one animal. Reported outcomes from other studies are from single animals.…”

Section: Figure Captionsmentioning

confidence: 99%

Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

Gwiazda

Lucchini

Smith

2007

Journal of Toxicology and Environmental Health, Part A

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The adequacy of existing animal studies to understand the effects of chronic low-level manganese exposures in humans is unclear. Here, a collection of subchronic to chronic rodent and non-human primate studies was evaluated to determine whether there is a consistent dose -response relationship among studies, whether there is a progression of effects with increasing dose, and whether these studies are adequate for evaluating the neurotoxicity of chronic low-level manganese exposures in humans. Neurochemical and behavioral effects were compared along the axis of estimated internal cumulative manganese dose, independent of the route of exposure. In rodents, motor effects emerged at cumulative doses below those where occupationally exposed humans start to show motor deficits. The main neurochemical effects in rodents were an increase in striatal GABA concentration throughout the internal cumulative dose range of 18 to 5300 mg Mn/Kg but a variable effect on striatal dopamine concentration emerging at internal cumulative doses above ~200 mg Mn/Kg. Monkey studies showed motor deficits and effects on the globus pallidus at relatively low doses and consistent harmful effects on both the globus pallidus and the caudate and putamen at higher doses (> 260 mg Mn/Kg). Internal cumulative manganese doses of animal studies extend more than two orders of magnitude (<1 to 5300 mg Mn/Kg) above the doses at which occupationally exposed humans show neurological dysfunction (10-15 mg Mn/Kg). Since the animal data indicate that manganese neurotoxicity may be different at low compared to elevated exposures, most existing animal model studies might be of 3 limited relevance for the risk assessment of chronic low-level manganese exposure to humans. 4

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Receptor alterations in manganese intoxicated monkeys

Cited by 82 publications

References 28 publications

Abnormal Motor Function and the Expression of Striatal Dopamine D2 Receptors in Manganese-Treated Mice

Abnormal Motor Function and the Expression of Striatal Dopamine D2 Receptors in Manganese-Treated Mice

Manganese and Parkinson's disease: a critical review and new findings

Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

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