Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway

Chen-Roetling, Jing; Li, Zhi; Chen, Mai; Awe, Olatilewa O.; Regan, Raymond F.

doi:10.1016/j.neuropharm.2009.01.022

Cited by 20 publications

(20 citation statements)

References 47 publications

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“…It was reported that basal HMOX activity was significantly inhibited by brief treatment of neuron/glia cell cultures with inhibitors of the MEK and ERK signaling pathways (19). While there are several potential ERK phosphorylation sites on HMOX1, many of these are not conserved among divergent species (Fig.…”

Section: Phosphorylationmentioning

confidence: 97%

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New Insights into Intracellular Locations and Functions of Heme Oxygenase-1

Dunn

Midwinter²,

Ni³

et al. 2014

Antioxidants & Redox Signaling

132

116

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Significance: Heme oxygenase-1 (HMOX1) plays a critical role in the protection of cells, and the inducible enzyme is implicated in a spectrum of human diseases. The increasing prevalence of cardiovascular and metabolic morbidities, for which current treatment approaches are not optimal, emphasizes the necessity to better understand key players such as HMOX1 that may be therapeutic targets. Recent Advances: HMOX1 is a dynamic protein that can undergo post-translational and structural modifications which modulate HMOX1 function. Moreover, trafficking from the endoplasmic reticulum to other cellular compartments, including the nucleus, highlights that HMOX1 may play roles other than the catabolism of heme. Critical Issues: The ability of HMOX1 to be induced by a variety of stressors, in an equally wide variety of tissues and cell types, represents an obstacle for the therapeutic exploitation of the enzyme. Any capacity to modulate HMOX1 in cardiovascular and metabolic diseases should be tempered with an appreciation that HMOX1 may have an impact on cancer. Moreover, the potential for heme catabolism end products, such as carbon monoxide, to amplify the HMOX1 stress response should be considered. Future Directions: A more complete understanding of HMOX1 modifications and the properties that they impart is necessary. Delineating these parameters will provide a clearer picture of the opportunities to modulate HMOX1 in human disease. Antioxid. Redox Signal. 20: 1723-1742.

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Section: Phosphorylationmentioning

confidence: 97%

“…More recently, HMOX1 phosphorylation at serine/threonine residues was detected in human brain samples (8,19). It was reported that basal HMOX activity was significantly inhibited by brief treatment of neuron/glia cell cultures with inhibitors of the MEK and ERK signaling pathways (19).…”

Section: Phosphorylationmentioning

confidence: 99%

New Insights into Intracellular Locations and Functions of Heme Oxygenase-1

Dunn

Midwinter²,

Ni³

et al. 2014

Antioxidants & Redox Signaling

132

116

View full text Add to dashboard Cite

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“…To assess the functional connection between ERK phosphorylation and increased excitability, a selective MEK1/2 inhibitor, U0126, was applied before acute DA administration in the slice preparation. U0126 is commonly used for in vitro physiology experiments and efficiently inhibits MEK (26). Because U0126 does not penetrate the blood-brain barrier, systemically active SL-327 was used in in vivo experiments described above (Fig.…”

Section: Repeated L-dopa Exposure Is Associated With Erk-dependent Inmentioning

confidence: 99%

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Ding¹,

Won²,

Britt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

172

192

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Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID.antagonist D opaminergic drugs are effective treatments for the motor symptoms of Parkinson disease (PD), but long-term therapy is limited by disabling abnormal involuntary movements, referred to as L-DOPA-induced dyskinesias (LID) (1). Thus, understanding the molecular and cellular mechanisms underlying LID will help identify more effective treatments for PD, and may also help elucidate the role of dopamine (DA) signaling in motor control.Several biochemical markers of LID have been studied in striatum using animal models. FosB/δFosB expression show a long-term temporal correlation with LID development in DA denervation PD models (2). The increased FosB expression persists over days or weeks and may contribute to the development of LID, but does not correlate with the L-DOPA-induced episodes of dyskinesia that follow each dose. To mediate expression of LID directly, cell signals should grow stronger with repeated L-DOPA treatment and show temporal correlation with acute dopaminergic stimulation. Acute administration of L-DOPA or dopamine agonists activates ERK1/2 by phosphorylation in striatal neurons of DA-denervated animals (3-7). In animals with unilateral 6-hydroxydopamine (6-OHDA) lesions, coadministration of inhibitors of ERK1/2 phosphorylation during repeated L-DOPA treatments reduce LID development (4,8). Studies on these molecular changes have focused on the predominant cell type in the striatum, medium spiny neurons (MSN). In addition, although the unilateral 6-OHDA lesion has been the standard model for the PD phenotype, and particularly for LID, the abrupt nature of the lesion and extreme depletion of dopaminergic afferents has posed limitations in behavioral and biochemical studies.In this study, we used both a unilateral 6-OHDA lesion model and a g...

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“…3B) also showed that 18 h-treatment with 4MC significantly induced the expression of HO-1 protein (14.4 ± 1.23-fold versus control cells). HO-1 has been observed to be present in various neuronal cells such as astrocytes (1,32), neurons (3,11), PC12 cells (18) and neuro 2A cells (10); but little is known about this enzyme in NS/PCs. To our the control group and 4MC-treated groups.…”

Section: Effects Of 4mc On Bdnf Mrna Expression and Differentiation Omentioning

confidence: 99%

4-Methylcatechol-induced heme oxygenase-1 exerts a protective effect against oxidative stress in cultured neural stem/progenitor cells via PI3 kinase/Akt pathway

et al. 2010

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ABSTRACT4-Methylcatechol (4MC), a stimulator of the synthesis of neurotrophin family members in various cells, was able to up-regulate the expression of heme oxygenase (HO)-1, a redox-sensitive inducible stress protein, in neural stem/progenitor cells (NS/PCs). RT-PCR analysis showed that 4MC induced HO-1 mRNA expression in a dose-and a time-dependent manner. The increase in HO-1 mRNA was followed by an increase in HO-1 protein content, which was confirmed by ELISA and Western blotting analysis. When NS/PCs were pretreated with 4MC before exposure to hydrogen peroxide (H 2 O 2 ), most of the cells were rescued from the H 2 O 2 -induced death. 4MC enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) and Akt in a time-dependent manner. Pretreatment of cultures with a selective inhibitor of PI3 kinase (PI3K)/Akt, but not with one of MAPK/ERK, inhibited both the 4MC-induced HO-1 expression and neuroprotective effect, demonstrating that PI3K/Akt signaling pathway played a significant role in 4MC-induced HO-1 induction and neuroprotection. Taken together, our results suggest that 4MC activates the expression of HO-1 through the PI3K/Akt signaling pathway and that the HO-1 protein inhibits the death of NS/PCs induced by oxidative stress.

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Heme oxygenase activity and hemoglobin neurotoxicity are attenuated by inhibitors of the MEK/ERK pathway

Cited by 20 publications

References 47 publications

New Insights into Intracellular Locations and Functions of Heme Oxygenase-1

New Insights into Intracellular Locations and Functions of Heme Oxygenase-1

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

4-Methylcatechol-induced heme oxygenase-1 exerts a protective effect against oxidative stress in cultured neural stem/progenitor cells via PI3 kinase/Akt pathway

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