Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Chang, Chi Young; Song, Mi Jeon; Jeon, Sae Bom; Yoon, Hee Jung; Lee, Daekee; Kim, In Hoo; Suk, Kyungho; Choi, Dong‐Kug; Park, Eun Jung

doi:10.1016/j.ajpath.2011.04.033

Cited by 41 publications

(44 citation statements)

References 62 publications

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“…Administration of rotenone caused depletion of GSH in rat brains [61]. Microglia are activated by rotenone administration and once activated by rotenone, microglial cells increase the generation of reactive oxygen species [62]. In the present work, subcutaneous injection of rotenone caused increased oxidative stress in the whole brain as shown by significant reduction of GSH in brain and significant increase of malondialdehyde (MDA) which is a marker of lipid peroxidation.…”

Section: Discussionmentioning

confidence: 62%

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Ibrahim¹

2017

EJCBS

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Abstract:The nigrostriatal pathway is a dopaminergic pathway that connects the substantia nigra with the dorsal striatum.Loss of dopamine neurons in the substantia nigra is one of the main pathological features of Parkinson's disease, leading to a marked reduction in dopamine function in this pathway. This study aimed at evaluating the protective role of two antiinflammatory drugs, indomethacin and nimesulide separately or in combination with vitamin C against biochemical disturbances, brain damage and motor impairment in rotenone-induced mice model of Parkinson's disease. Animals were divided into 7 groups. 1 st received the vehicle (DEMSO); 2 nd received rotenone (1.5 mg/kg); 3 rd received rotenone then were left for two weeks recovery; 4 th rotenone + indomethacin (10 mg/kg); 5 th received rotenone + indomethacin in combination with vitamin C (25 mg/kg). 6 th received rotenone + nimesulide (10 mg/kg); group 7 received rotenone + nimesulide in combination with vitamin C. All treatments were given subcutaneously three times per week for one month. Rotenone treatment caused significant Increases in brain malondialdehyde (MDA), nitric oxide (NO), but induced significant decreases in brain reduced glutathione (GSH) level, acetylcholinesterase (AChE) activity, dopamine (DA), norepinephrine (NE) and serotonin (5-HT) levels. These changes lasted for two weeks after the termination of rotenone treatment. Histologically, Rotenone caused degeneration of neurons in striatum, cellular infiltration, atrophy, pyknosis, necrosis, as well as focal gliosis in cerebral cortex and pyknosis of pyramidal cells in the hippocampus. Furthermore, rotenone treatment caused a significant impairment in the motor function of the mice (stair test). Co-administration of indomethacin or nimesulide separately or in combination with vitamin C to rotenone treated mice resulted in alleviation of biochemical and motor activity but not the histological disturbances caused by rotenone treatment alone.

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Section: Discussionmentioning

confidence: 62%

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Ibrahim¹

2017

EJCBS

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“…50 Rotenone also causes microglial activation. [51][52][53] Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. 53 Nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide might be a factor mediating this microglia-enhanced rotenone neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…[51][52][53] Once activated by rotenone, microglia show increased production of reactive oxygen species, particularly HOCl. 53 Nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide might be a factor mediating this microglia-enhanced rotenone neurotoxicity. 52 In the present study, injection of rotenone resulted in increased oxidative stress in a number of brain areas including the cerebral cortex, striatum, hippocampus, and medulla, as shown by elevated levels of malondialdehyde, a marker of lipid peroxidation, which indicates increased free radical production with consequent attack on membrane lipids.…”

Section: Discussionmentioning

confidence: 99%

Rotenone-induced nigrostriatal toxicity is reduced by methylene blue

Abdel-Salam¹,

Omara²,

Youness³

et al. 2014

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This study investigated the effect of subcutaneously injected methylene blue on oxidative stress and nigrostriatal damage induced in the rat brain by systemic rotenone injection. Rotenone 1.5 mg/kg (injected subcutaneously three times per week) was given alone or in combination with methylene blue (5, 10, or 20 mg/kg subcutaneously daily) for 2 weeks. Brain concentrations of malondialdehyde, reduced glutathione, nitric oxide (nitrite), and acetylcholinesterase, paraoxonase 1 activity, and the antiapoptotic marker Bcl-2 (B-cell lymphoma 2) were determined. Histopathology, tyrosine hydroxylase immunoreactivity, tumor necrosis factor-alpha (TNF-α), and caspase-3 immunohistochemistry were also performed. Injection of rotenone resulted in increased oxidative stress in different regions of the brain. Substantial increases in malondialdehyde (by 59.6%-77.3%) and nitric oxide (by 43.7%-58.7%) were observed in the cortex, striatum, hippocampus, and medulla of rotenone-treated rats. Meanwhile, glutathione decreased by 24.3%-59.8% in these brain regions. Rotenone administration was associated with a significant decrease in paraoxonase 1 activity in the cerebral cortex, striatum, hippocampus, medulla, midbrain, and cerebellum (by 66%-73.6%). Further, acetylcholinesterase activity decreased by 44.4% in the cortex and Bcl-2 decreased in the striatum by 33.9% after rotenone injection. Rotenone induced a marked decrease in tyrosine hydroxylase immunoreactivity and increased both TNF-α and caspase-3 immunoreactivity in the striatum. These effects of rotenone were substantially reduced by coadministration of methylene blue, which resulted in significantly decreased malondialdehyde and nitrite and increased glutathione in different regions of the brain. In addition, there was increased paraoxonase 1 and acetylcholinesterase activity in response to treatment with methylene blue. Bcl-2 levels in the striatum increased significantly after the highest dose of methylene blue. Methylene blue also significantly decreased striatal expression of TNF-α and caspase-3 (apoptosis), and the degree of neuronal degeneration and gliosis in the striatum, substantia nigra, cortex, and hippocampus. Treatment with methylene blue resulted in an increased number of tyrosine hydroxylase-positive cells in the striatum, substantia nigra, and cerebral cortex, compared with the rotenone control group. The present findings suggest that treatment with methylene blue could prevent neuronal degeneration induced by rotenone injection in the rat brain. This effect may be mediated by inhibition of oxidative stress and apoptotic markers, and by enhancement of apoptotic markers and acetylcholinesterase activity.

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“…If validated, in keeping with studies demonstrating more pronounced rotenone-induced neuronal injury in myeloperoxidase-deficient mice, 29 and worsening cognitive decline in human participants with the myeloperoxidase AA genotype (leading to lower myeloperoxidase levels), 30 myeloperoxidase deficiency may promote ischemic neuronal injury. An alternative explanation is that chronically progressing large volumes of ischemic neuronal and glial injury, and the ensuing inflammatory response, promotes microglial senescence (the dysfunction and dystrophy of microglia with advancing age).…”

Section: -22mentioning

confidence: 99%

Inflammatory biomarkers, cerebral microbleeds, and small vessel disease

Shoamanesh¹,

Preis²,

Beiser³

et al. 2015

Neurology

182

155

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Objective: We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease.Methods: We performed a cross-sectional study relating a panel of 15 biomarkers, representing systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, monocyte chemotactic protein-1, tumor necrosis factor a, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), vascular inflammation (intercellular adhesion molecule 1, CD40 ligand, P-selectin, lipoproteinassociated phospholipase A 2 mass and activity, total homocysteine, and vascular endothelial growth factor), and oxidative stress (myeloperoxidase) to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease (CSVD) on MRI in 1,763 stroke-free Framingham offspring (mean age 60.2 6 9.1 years, 53.7% women). Results:We observed higher levels of circulating tumor necrosis factor receptor 2 and myeloperoxidase in the presence of cerebral microbleed (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.1-4.1 and OR 1.5, 95% CI 1.1-2.0, respectively), higher levels of osteoprotegerin (OR 1.1, 95% CI 1.0-1.2), intercellular adhesion molecule 1 (OR 1.7, 95% CI 1.1-2.5), and lipoproteinassociated phospholipase A 2 mass (OR 1.5, 95% CI 1.1-2.1), and lower myeloperoxidase (OR 0.8, 95% CI 0.7-1.0) in participants with greater white matter hyperintensity volumes and silent cerebral infarcts.Conclusions: Our study supports a possible role for inflammation in the pathogenesis of CSVD, but suggests that differing inflammatory pathways may underlie ischemic and hemorrhagic subtypes. If validated in other samples, these biomarkers may improve stroke risk prognostication and point to novel therapeutic targets to combat CSVD. Neurology ® 2015;84:825-832 GLOSSARY CAA 5 cerebral amyloid angiopathy; CI 5 confidence interval; CMB 5 cerebral microbleed; CSVD 5 cerebral small vessel disease; ICAM-1 5 intercellular adhesion molecule 1; ln 5 natural logarithm; Lp-PLA 2 5 lipoprotein-associated phospholipase A 2 ; OR 5 odds ratio; ROC 5 receiver operating characteristic; SCI 5 silent cerebral infarct; TNF-a 5 tumor necrosis factor a; TNFR2 5 tumor necrosis factor receptor 2; WMH 5 white matter hyperintensity.Cerebral small vessel disease (CSVD) assessed using brain MRI is characterized by 3 main findings that include cerebral microbleeds (CMBs), lacunes of presumed vascular origin (silent cerebral infarcts [SCIs]), and white matter hyperintensity (WMH). The vascular changes underlying ischemic and hemorrhagic CSVD likely include activation of the inflammatory cascade with endothelial failure and resulting neurovascular unit dysfunction.1-3 However, the specific mediators implicated in ischemic and hemorrhagic CSVD may differ.The Framingham Offspring Cohort provides a large, middle-age, community-based sample in which to investigate the association between systemic biomarkers of inflammation and MRI markers of CSVD. Given the complexity of i...

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Dual Functionality of Myeloperoxidase in Rotenone-Exposed Brain-Resident Immune Cells

Cited by 41 publications

References 62 publications

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

Rotenone-induced nigrostriatal toxicity is reduced by methylene blue

Inflammatory biomarkers, cerebral microbleeds, and small vessel disease

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