Mechanisms of L-DOPA-induced cytotoxicity in rat adrenal pheochromocytoma cells: implication of oxidative stress-related kinases and cyclic AMP

Jin, Chun Mei; Yang, Yoo Jung; Huang, Hai; Kai, Masahiro; Lee, M.K.

doi:10.1016/j.neuroscience.2010.07.039

Cited by 30 publications

(38 citation statements)

References 29 publications

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“…Recently, it was reported that a single treatment with nontoxic L‐DOPA (20 µM) induces transient ERK1/2 phosphorylation at 0.5–1 hr; however, toxic levels of L‐DOPA (100 and 200 µM) induced sustained ERK1/2 phosphorylation after 1–6 hr in PC12 cells (Jin et al, ). In this study, MT‐LD (10 and 20 µM) induced sustained ERK1/2 phosphorylation for 2–3 days in PC12 cells and embryonic rat midbrain primary cell cultures (Figs.…”

Section: Discussionmentioning

confidence: 99%

Multiple treatments with L‐3,4‐dihydroxyphenylalanine modulate dopamine biosynthesis and neurotoxicity through the protein kinase A‐transient extracellular signal‐regulated kinase and exchange protein activation by cyclic AMP‐sustained extracellular signal‐regulated kinase signaling pathways

Park

Shin

et al. 2014

J of Neuroscience Research

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Multiple treatments with L-3,4-dihydroxyphenylalanine (L-DOPA; 20 µM) induce neurite-like outgrowth and reduce dopamine biosynthesis in rat adrenal pheochromocytoma (PC) 12 cells. We therefore investigated the effects of multiple treatments with L-DOPA (MT-LD) on cell survival and death over a duration of 6 days by using PC12 cells and embryonic rat midbrain primary cell cultures. MT-LD (10 and 20 µM) decreased cell viability, and both types of cells advanced to the differentiation process at 4-6 days. MT-LD induced cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) phosphorylation and exchange protein activation by cAMP (Epac) expression at 1-3 days, which led to transient extracellular signal-regulated kinase (ERK1/2) phosphorylation in both cells. In these states, MT-LD activated cAMP-response element binding protein (CREB; Ser133) and tyrosine hydroxylase (Ser40) phosphorylation in PC12 cells, which led to an increase in intracellular dopamine levels. In contrast, MT-LD induced prolonged Epac expression at 4-5 days in both cells, which led to sustained ERK1/2 phosphorylation. In these states, the dopamine levels were decreased in PC12 cells. In addition, MT-LD induced c-Jun N-terminal kinase1/2 phosphorylation and cleaved caspase-3 expression at 4-6 days in both cells. These results suggest that MT-LD maintains cell survival via PKA-transient ERK1/2 activation, which stimulates dopamine biosynthesis. In contrast, at the later time period, MT-LD induces differentiation via both prolonged Epac and sustained ERK1/2 activation, which subsequently leads to the cell death process. Our data demonstrate that L-DOPA can cause neurotoxicity by modulating the Epac-ERK pathways in neuronal and PC12 cells.

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Section: Discussionmentioning

confidence: 99%

Multiple treatments with L‐3,4‐dihydroxyphenylalanine modulate dopamine biosynthesis and neurotoxicity through the protein kinase A‐transient extracellular signal‐regulated kinase and exchange protein activation by cyclic AMP‐sustained extracellular signal‐regulated kinase signaling pathways

Park

Shin

et al. 2014

J of Neuroscience Research

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“…The current standard of care for the treatment of PD is the administration of L-3,4-dihydroxyphenylalanine (L-DOPA), which in the short term relieves many of the symptoms of PD but has also been found to induce an oxidative stress response in DA-neurons [125–127]. It is believed that L-DOPA at high doses actually leads to cell death in neurons due to its activation of apoptosis through the ASK1 and MAP-K signaling pathways [127, 128]. Furthermore, higher levels of markers for oxidative stress were found in patients with PD, but the origin and response of these markers to L-DOPA therapy appear to be controversial [129].…”

Section: Therapy Utilizing L-dopamentioning

confidence: 99%

Oxidative Stress and Microglial Cells in Parkinson's Disease

Peterson

Flood

2012

Mediators of Inflammation

127

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Significant evidence has now been accumulated that microglial cells play a central role in the degeneration of DA neurons in animal models of PD. The oxidative stress response by microglial cells, most notably the activity of the enzyme NADPH oxidase, appears to play a central role in the pathology of PD. This oxidative stress response occurs in microglia through the activation of the ERK signaling pathway by proinflammatory stimuli, leading to the phosphorylation and translocation of the p47phoxand p67phoxcytosolic subunits, the activation of membrane-bound PHOX, and the production of ROS. Therapeutic anti-inflammatories which prevent DA neurodegeneration in PD, including anti-inflammatory cytokines, morphinan compounds, NADPH oxidase inhibitors, NF-κB inhibitors, andβ2-AR agonists, all function to inhibit the activation of the PHOX in microglial cells. These observations suggest a central role for the oxidative stress response in microglial cells as a mediator or regulator of DA neurodegeneration in PD.

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confidence: 51%

“…The NF-κB pathway expresses numerous pro-inflammatory mediators including AP-1, MEK, and JNK, and possibly MAX mutation-related tumors, which help to orchestrate and amplify oxidative stress responses and have a strong tumorigenesis activity. The present study of PHEOs suggested that the NF-κB pathway could exist in the places of adrenal PHEO cells [4].Angiogenesis is a key step for tumor growth and metastasis formation, this process of angiogenesis has showed correlation with oxidative stress. Basic fibroblast growth factors (bFGF) promote axon growth during the development and regeneration of the nervous system; it also promoted tumor aggressiveness and microenvironment, which is controlled migration, invasion, and tumorigenicity of tumor cells.…”

mentioning

confidence: 57%

Treatment of pheochromocytoma blockade of MAPK pathway inhibition in the NF-κB pathway and bFGF — Effect of statins on pheochromocytoma patients

Zhou

Liu

2015

International Journal of Cardiology

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Mechanisms of L-DOPA-induced cytotoxicity in rat adrenal pheochromocytoma cells: implication of oxidative stress-related kinases and cyclic AMP

Cited by 30 publications

References 29 publications

Oxidative Stress and Microglial Cells in Parkinson's Disease

Treatment of pheochromocytoma blockade of MAPK pathway inhibition in the NF-κB pathway and bFGF — Effect of statins on pheochromocytoma patients

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