Free radicals in Parkinson's disease

Koutsilieri, Eleni; Scheller, Carsten; Grünblatt, Edna; Nara, Keinosuke; Li, J.; Riederer, Peter

doi:10.1007/s00415-002-1201-7

Cited by 104 publications

(55 citation statements)

References 49 publications

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“…The presence of toxins in the environment can cause damage to mitochondrial enzymes, leading to increased reactive oxygen species (Koutsilieri et al 2002). Stimulation of this pathway during the life appears to play an important role in the induction of molecular changes that modify the cellular adaptive responses, leading to a decreased function of several systems (Sapolsky 1992;McCann et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Kawamoto

Vasconcelos

Degaspari

et al. 2012

AGE

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Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study agerelated disorders and new anti-aging therapies.

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Section: Discussionmentioning

confidence: 99%

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Kawamoto

Vasconcelos

Degaspari

et al. 2012

AGE

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“…Earlier studies have demonstrated a significant increase in markers for oxidative stress in the brains of PD patients as compared to controls (Beal, 2003;Koutsilieri et al, 2002;Shavali et al, 2006). In many instances, oxidative stress occurs before appearance of clinical manifestations (Koutsilieri et al, 2002).…”

Section: Introductionmentioning

confidence: 98%

“…In many instances, oxidative stress occurs before appearance of clinical manifestations (Koutsilieri et al, 2002). In studies with cellular models, paraquat was shown to increase oxidative stress and neurotoxicity in PC12 cells, and polyphenolic antioxidants could ameliorate the cytotoxicity (Koutsilieri et al, 2002;Yang and Sun, 1998a;Yang and Sun, 1998b).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Miller

Sun

2007

Brain Research

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Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP + ), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCδ) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCδ inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCδ-and ERK-dependent pathways.

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“…Reactive oxygen species (ROS) generated from mitochondrial and/or extra-mitochondrial sources appear to be the main contributor of oxidative stress-mediated neurodegeneration in PD models (Koutsilieri et al, 2002;Tikka et al, 2002;Beal, 2003;Ischiropoulos and Beckman, 2003;Jenner, 2003;Kanthasamy et al, 2003;Greenamyre and Hastings, 2004;Love, 2004;Przedborski and Ischiropoulos, 2005). One of the well-recognized pathways responsible for generation of oxidative radicals is mitochondrial toxicity induced by accumulation of MPP + in the inner mitochondrial membrane, and the subsequent disruption of complex I in the electron transport chain (Cassarino et al, 1999;Fiskum et al, 2003;Kalivendi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

et al. 2007

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Oxidative stress is widely recognized as a key mediator of degenerative processes in Parkinson's disease (PD). Recently, we demonstrated that the dopaminergic toxin MPP + initiates oxidative stress to cause caspase-3-dependent apoptotic cell death in mesencephalic dopaminergic neuronal (N27) cells. In this study, we determined the source of reactive oxygen species (ROS) produced during MPP + -induced apoptotic cell death. In addition to mitochondria, plasma membrane NADPH oxidase is considered a major producer of ROS inside the cell. Here, we show that N27 cells express key NADPH oxidase subunits gp91 phox and p67 phox . We used structurally diverse NADPH oxidase inhibitors, aminoethyl-benzenesulfonylfluoride (AEBSF, 100-1000 μM), apocynin (100-1000 μM), and diphenylene iodonium (DPI, 3-30 μM), to inhibit intrinsic NADPH oxidase activity in N27 cells. Flow cytometric analysis using the ROS-sensitive dye hydroethidine revealed that AEBSF blocked 300 μM MPP + -induced ROS production for over 45 min in N27 cells, in a dose-dependent manner. Further treatment with DPI, apocynin, and SOD also blocked MPP + -induced ROS production. In Sytox cell death assays, co-treatment with AEBSF, apocynin, or DPI for 24 hr significantly suppressed MPP + -induced cytotoxic cell death. Similarly, co-treatment with these inhibitors also significantly attenuated MPP + -induced increases in caspase-3 enzymatic activity. Furthermore, quantitative DNA fragmentation ELISA assays revealed that AEBSF, DPI, and apocynin rescue N27 cells from MPP + -induced apoptotic cell death. Together, these results indicate for the first time that intracellular ROS generated by NAPDH oxidase are present within the mesencephalic neuronal cells, and are a key determinant of MPP + -mediated dopaminergic degeneration in in vitro models of dopaminergic degeneration. This study supports a critical role of NADPH oxidase in the oxidative damage in PD; targeting this enzyme may lead to novel therapies for PD.

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Free radicals in Parkinson's disease

Cited by 104 publications

References 49 publications

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

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