Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons

Malecki, Elise A.

doi:10.1016/s0361-9230(01)00456-7

Cited by 172 publications

(107 citation statements)

References 25 publications

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“…Mn is known to cause mitochondrial dysfunction (Gavin et al, 1990), including the inhibition of the enzymes of the tricarboxylic acid (TCA) cycle (Malthankar et al, 2004;Zheng et al, 1998) and a reduction in the activities of the electron transport chain (Malecki, 2001;Rama Rao and Norenberg, 2004), ultimately resulting in ATP depletion (Brouillet et al, 1993;Verity, 1999). Some of these mitochondrial events are significantly blocked by antioxidants (Chen and Liao, 2002), suggesting the involvement of oxidative stress in the mechanism of Mninduced mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Mn-SOD is critical in preventing or limiting apoptotosis and necrosis resulting from cellular damage caused by reactive oxygen species (ROS) (Raha and Robinson 2000;Halliwell 2001;Kitazawa et al, 2002;Milatovic et al, 2007). Changes in Mn-containing proteins have been observed in many neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and Parkinsonian-like syndrome (Frankel et al, 2000;Malecki 2001;Recette et al, 2001;Zelko et al, 2002;Olanow 2004;Petrozzi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Yin

Aschner

Santos³

et al. 2008

Brain Research

116

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Chronic exposure to excessive levels of Mn results in a movement disorder termed manganism, which resembles Parkinson's disease (PD). The pathogenic mechanisms underlying this disorder are not fully understood. Several lines of evidence implicate astrocytes as an early target of Mn neurotoxicity. In the present study, we investigated the effects of Mn on mitochondrial function. Primary astrocyte cultures were prepared from cerebral cortices of one-day-old Sprague-Dawley rats. We have examined the cellular toxicity of Mn and its effects on the phosphorylation of extracellular signalregulated kinase (ERK) and activation of the precursor protein of caspase-3. The potentiometric dye, tetramethylrhodamine ethyl ester (TMRE), was used to assess the effect of Mn on astrocytic mitochondrial inner membrane potential (ΔΨ m ). Our studies show that, in a concentration-dependent manner, Mn induces significant (p<0.05) activation of astrocyte caspase-3 and phosphorylated extracellular signal-regulated kinase (p-ERK). Mn treatment (1 and 6 hrs) also significantly (p<0.01) dissipates the ΔΨm in astrocytes as evidenced by a decrease in mitochondrial TMRE fluorescence. These results suggest that activations of astrocytic caspase-3 and ERK are involved in Mn-induced neurotoxicity via mitochondrial-dependent pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Yin

Aschner

Santos³

et al. 2008

Brain Research

116

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“…These findings indicate that PKCδ may be potentially correlated with neuronal degeneration in Parkinson's disease. Besides, some reports have suggested that the activation of PKCδ mediates the cytotoxic effects of the oxidative stress responses [18,20,21] induced by ultraviolet radiation [22] or environmental neurotoxins (such as MPP + and MMT) in dopaminergic neurons [1][2][3][4]23,24] .…”

Section: Discussionmentioning

confidence: 99%

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

et al. 2009

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Objective The present study aims to investigate the role of protein kinase C δ subtype (PKCδ) phosphorylation in the process of 6-hydroxydopamine (6-OHDA)-induced dopaminergic cell death, and demonstrate the molecular basis of neurological disorders, such as Parkinson's disease. Methods The pheochromocytoma (PC12) cell line was employed in the present study. Cells were treated with 2 μmol/L PKCδ inhibitor Rottlerin, 10 nmol/L protein kinase C α subtype (PKCα) inhibitor bisindolylmaleimide I, or 5 nmol/L Gö6976 that could specifically inhibit the calcium-dependent PKC isoforms, respectively. PKCδ activator phorbol-12-myristate-13-acetate (PMA, 100 nmol/L) was also used in this study. All these agents were added to the medium before cells were incubated with 6-OHDA. Cells with no treatment served as control. The cytotoxicity of 6-OHDA was determined by methyl thiazolyl tetrazolium (MTT) reduction assay and PKCδ phosphorylation levels in various groups were measured by western blotting. Results Bisindolylmaleimide I and Gö6976 exerted no significant attenuation on the cytotoxicity of 6-OHDA, nor any effects on PKCδ phosphorylation in PC12 cells. However, Rottlerin could inhibit the phosphorylation of PKCδ and attenuate 6-OHDA-induced cell death, and the cell viability was raised to 69.6±2.63% of that in control group (P < 0.05). In contrast, PMA induced a significant increase in PKCδ phosphorylation and also strengthened the cytotoxic effects of 6-OHDA. The cell viability of PMA-treated PC12 cells decreased to 49.8±5.06% of that in control group (P < 0.001). Conclusion Rottlerin can protect PC12 cells from cytotoxicity of 6-OHDA probably by inhibiting PKCδ phosphorylation. The results suggest that PKCδ may be a key regulator of neuron loss in Parkinson's disease.

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“…The negative effects on antioxidant enzyme mRNA levels caused by excessive Mn might be partially due to the Mn-induced mitochondrial dysfunction. In rat primary striatal neurons, Mn excess caused the mitochondrial dysfunction (Malecki, 2001). To our knowledge, mitochondrial dysfunction resulted in the increased generation of free radicals (Beal, 1998), which could impair the antioxidant system in fish (Tang et al, 2013).…”

Section: Mn Improved the Flesh Quality Of Fishmentioning

confidence: 99%

Nutritive values, flavor amino acids, healthcare fatty acids and flesh quality improved by manganese referring to up-regulating the antioxidant capacity and signaling molecules TOR and Nrf2 in the muscle of fish

Jiang

Tang

et al. 2016

Food Research International

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Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons

Cited by 172 publications

References 25 publications

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Mitochondrial-dependent manganese neurotoxicity in rat primary astrocyte cultures

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

Nutritive values, flavor amino acids, healthcare fatty acids and flesh quality improved by manganese referring to up-regulating the antioxidant capacity and signaling molecules TOR and Nrf2 in the muscle of fish

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