Involvement of striatal lipid peroxidation and inhibition of calcium influx into brain slices in neurobehavioral alterations in a rat model of short-term oral exposure to manganese

Ávila, Daiana Silva; Gubert, Priscila; Fachinetto, Roselei; Wagner, Caroline; Aschner, Michael; Rocha, João Batista Teixeira da; Soares, Félix Alexandre Antunes

doi:10.1016/j.neuro.2008.08.004

Cited by 26 publications

(22 citation statements)

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“…While several studies have emphasized that excessive Mn concentrations in parenteral nutrition may lead to neurological disorders [6], [14], [20], [21], no in vivo studies have addressed the ability of Mn to interfere with intracellular signaling pathways in the developing CNS. To date, mechanisms implied in developmental Mn neurotoxicity have largely focused on oxidative stress, alterations in neurotransmitters and receptors, and behavioral abnormalities [6], [8], [9], [17], [36], [94]–[98].…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Manganese Exposure Modulates Erk, Akt and Darpp-32 in the Striatum of Developing Rats, and Impairs Their Motor Function

et al. 2012

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Manganese (Mn) is an essential metal for development and metabolism. However, exposures to high Mn levels may be toxic, especially to the central nervous system (CNS). Neurotoxicity is commonly due to occupational or environmental exposures leading to Mn accumulation in the basal ganglia and a Parkinsonian-like disorder. Younger individuals are more susceptible to Mn toxicity. Moreover, early exposure may represent a risk factor for the development of neurodegenerative diseases later in life. The present study was undertaken to investigate the developmental neurotoxicity in an in vivo model of immature rats exposed to Mn (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 (PN8) to PN12. Neurochemical analysis was carried out on PN14. We focused on striatal alterations in intracellular signaling pathways, oxidative stress and cell death. Moreover, motor alterations as a result of early Mn exposure (PN8-12) were evaluated later in life at 3-, 4- and 5-weeks-of-age. Mn altered in a dose-dependent manner the activity of key cell signaling elements. Specifically, Mn increased the phosphorylation of DARPP-32-Thr-34, ERK1/2 and AKT. Additionally, Mn increased reactive oxygen species (ROS) production and caspase activity, and altered mitochondrial respiratory chain complexes I and II activities. Mn (10 and 20 mg/kg) also impaired motor coordination in the 3 rd , 4 th and 5 th week of life. Trolox™, an antioxidant, reversed several of the Mn altered parameters, including the increased ROS production and ERK1/2 phosphorylation. However, Trolox™ failed to reverse the Mn (20 mg/kg)-induced increase in AKT phosphorylation and motor deficits. Additionally, Mn (20 mg/kg) decreased the distance, speed and grooming frequency in an open field test; Trolox™ blocked only the decrease of grooming frequency. Taken together, these results establish that short-term exposure to Mn during a specific developmental window (PN8-12) induces metabolic and neurochemical alterations in the striatum that may modulate later-life behavioral changes. Furthermore, some of the molecular and behavioral events, which are perturbed by early Mn exposure are not directly related to the production of oxidative stress.

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Section: Discussionmentioning

confidence: 99%

“…Additionally, Mn induces dopamine autoxidation, increasing the levels of toxic quinines [35]. Higher sensitivity of the striatum to Mn-induced oxidative stress [36], especially during development, has been noted [6]. Oxidative stress in the striatum is associated with impairment of motor activity [37].…”

Section: Introductionmentioning

confidence: 99%

In Vivo Manganese Exposure Modulates Erk, Akt and Darpp-32 in the Striatum of Developing Rats, and Impairs Their Motor Function

et al. 2012

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“…The negative effect of oxidative stress on CNS functionality has been repeatedly described for both metals. In Mn-exposed rats' brains, ROS generation and membrane lipid peroxidation was seen (Avila et al, 2008). For As, similar effects were described by Flora (2011) Each antioxidant used in this study had some counter effect on the electrophysiological and/or behavioral alterations induced by As and nano-Mn, but to a dissimilar extent.…”

Section: Discussionsupporting

confidence: 82%

Functional neurotoxicity of arsenic and manganese as environmental agents and the possible protective role of natural antioxidants

Sárközi¹

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SUMMARYOxidative stress apparently plays a major role in the effect of several toxicants, including heavy metals, of environmental or occupational origin. It means inequilibrium between metabolic reactions producing reactive oxygen and nitrogen species (ROS and RNS), and the capacity of enzymatic and non-enzymatic reactions to neutralize these. In itself, oxidative stress is a side effect of oxidative energy production, which can be caused by exposure to a number of environmental xenobiotics, metals and others. Non-neutralized ROS and other radicals damage the nervous system, liver, kidneys etc. Free radicals are more and more held responsible for various chronic non-communicable diseases, and for aging. The central and peripheral nervous system is prone to oxidative damage, due to highly active mitochondrial energy production, to abundance of (unsaturated) structural lipids, and to low antioxidant defence capacity in the brain; and ROS may constitute the final common pathway for several neurotoxicants because oxidative damage to membrane lipids may lead to alterations of the membrane-bound functions crucial to the functioning of neurons. In the present thesis, the relationships of neurotoxicity, oxidative stress and antioxidant protection are investigated in case of two heavy metals with public health importance, arsenic (As) and manganese (Mn). Arsenic used to have numerous practical applications most of which have been discontinued because of the health risks. Its modern applications e.g. in semiconductors, are apparently safe. Increased presence of As in certain rocks may lead to human exposure by As emissions from mining and smelting non-ferrous metal ores or from burning coal with higher As content, but most importantly via drinking water. The problem of As in drinking water has been quite serious in several regions. According to WHO, As is among the ten most important chemicals of major public health concern. Arsenic occurs in various oxidation states in inorganic or organic compounds. Inorganic arsenite (As III ) is more toxic that arsenate (As V ), and most of the organic arsenicals are practically nontoxic. Arsenite strongly binds to the -SH group of proteins, inactivating various enzymes including those in the citrate cycle and terminal oxidation, depleting ATP pool and promoting the generation of ROS in the cells. It also increases oxidative stress by depleting reduced glutathione and thioredoxin. The consequences of chronic exposure to inorganic arsenic include nervous system damage. Electrophysiological data on As neurotoxicity are scarce, but in As-exposed workers altered EEG, visual evoked potentials, and peripheral nerve activity were detected, together with signs of oxidative stress. Manganese (Mn) can have the oxidation states -3 to 7+, indicating its propensity to redox reactions. Mn and its compounds have numerous technical applications (steelmaking, welding, nanotechnology etc). It is an essential trace element, required for normal brain function, and acting as cofactor for several enzyme...

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“…It is well documented that DARPP-32 has important roles in the modulation of behavior and motor activity. [26][27][28][29] Due to the fact that the striatum is a major target of Mn neurotoxicity [30][31][32][33] and that this metal interferes markedly in dopaminergic and glutamatergic neurotransmission, 20,34-37 it is plausible therefore that Mn could interfere with the phosphorylation state of DARPP-32.…”

Section: Manganese May Alter Cell Signaling In the Striatummentioning

confidence: 99%

Effect of Manganese on Signaling Pathways

Peres¹,

Córdova²,

Lopes³

et al. 2014

Manganese in Health and Disease

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A complex intercellular and intracellular signaling network modulates the main neural functions. Regulation of protein kinases and protein phosphatases activities modify the phosphorylation state of target proteins that direct a diversity of cell fates, including gene expression, neural cell migration, differentiation or proliferation, cell survival or death, and synaptic plasticity. Regardless of all these aspects, modulation of intracellular signaling pathways by toxicants has only recently become part of the molecular toxicology research. Manganese (Mn) exposure causes a neurological syndrome, manganism, which resembles Parkinson's disease. The mechanisms of Mn neurotoxicity are not completely clear but may involve mitochondrial dysfunctions, induction of oxidative stress, and alterations in dopaminergic system, especially in the basal ganglia. The modulation of intracellular cell signaling elements by Mn and the cell fates of these effects is an issue that requires attention. In this chapter, we will present cell signaling pathways dependent of protein kinases (e.g. PKA, PKC, MAPKs, AKT, and GSK3β) and protein phosphatases (e.g. PP1 and PP2A) that have been reported to be altered in response to Mn exposure. Since only a few studies have addressed these aspects in vivo, a series of data obtained in vitro from cell cultures exposed to Mn will also be presented, aiming to help us identify the possible sites of Mn action in cell signaling networks involved in the patophysiology of Mn neurotoxicity.

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Involvement of striatal lipid peroxidation and inhibition of calcium influx into brain slices in neurobehavioral alterations in a rat model of short-term oral exposure to manganese

Cited by 26 publications

References 57 publications

In Vivo Manganese Exposure Modulates Erk, Akt and Darpp-32 in the Striatum of Developing Rats, and Impairs Their Motor Function

In Vivo Manganese Exposure Modulates Erk, Akt and Darpp-32 in the Striatum of Developing Rats, and Impairs Their Motor Function

Functional neurotoxicity of arsenic and manganese as environmental agents and the possible protective role of natural antioxidants

Effect of Manganese on Signaling Pathways

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