p38 MAP Kinase Is Involved in Lipopolysaccharide‐Induced Dopaminergic Neuronal Cell Death in Rat Mesencephalic Neuron‐Glia Cultures

Jeohn, Gwang‐Ho; Cooper, Cynthia L.; Wilson, Belinda; Chang, Raymond Chuen‐Chung; Jang, Kyung-Jin; Kim, Hyoung‐Chun; Liu, Bin; Hong, Jau–Shyong

doi:10.1111/j.1749-6632.2002.tb04078.x

Cited by 56 publications

(48 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[21][22][23] Our previous study showed that JNK signaling plays a major role in the regulation of LPS-stimulated NO produc- tion and iNOS expression, and regulatory effect of the JNK signaling pathway on NO production was dependent on cellular ROS. 16) In the present study, compound #4 treatment significantly inhibited the NO production and iNOS expression, as well as ROS.…”

Section: Discussionmentioning

confidence: 99%

16α,17α-Epoxypregnenolone-20-oxime Prevent LPS-Induced NO Production and iNOS Expression in BV-2 Microglial Cells by Inhibiting JNK Phosphorylation

Sun

Jin

Han

et al. 2014

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The free radical nitric oxide (NO), a main member of neuroinflammatory cytokine and a gaseous molecule produced by activated microglia, has many physiological functions, including neuroinflammation. In the present study, we evaluated the effects of serial 16-dehydropregnenolone-3-acetate derivatives on lipopolysaccharide (LPS)-induced NO production and inducible nitric oxide synthase (iNOS) expression in BV-2 microglial cells. Among the six derivatives tested, the increases in NO production and iNOS expression observed in BV-2 microglial cells after LPS stimulation were significantly inhibited by treatment with 16α, 17α-epoxypregnenolone-20-oxime. Moreover, the inhibitory effect of 16α,17α-epoxypregnenolone-20-oxime on NO production was similar to that of S-methylisothiourea sulfate (SMT), an iNOS inhibitor. Further studies showed that 16α,17α-epoxypregnenolone-20-oxime inhibited c-Jun N-terminal kinase (JNK) phosphorylation but not inhibitor kappa B (IκB)-α degradation. Our data in LPS-stimulated microglia cells suggest that 16α,17α-epoxypregnenolone-20-oxime might be a candidate therapeutic for treatment of NO induced neuroinflammation and could be a novel iNOS inhibitor. Key words microglia; nitric oxide; neuroinflammationMicroglial cells, the tissue macrophages of the central nervous system (CNS), 1-3) play a crucial role in the recognition and phagocytic removal of apoptotic neurons. Microglial cell activation is regarded as a marker of brain injury development in many neuronal diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). 4,5) Neuron inflammation also accompanies neuron degeneration in these diseases. During neuroinflammation, microglias are activated and secrete various cytokines. Microglial cells respond to inflammatory agonists, such as bacterial lipopolysaccharide (LPS), the human immunodeficiency virus (HIV) coat protein gp120, and β-amyloidrelated peptides, by producing many inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β) and nitric oxide (NO). These microglial products are thought to be responsible for glia-mediated neurotoxicity. 6,7)The free radical NO, a gaseous molecule produced by activated microglia, has many physiological functions, including neuroinflammation. In the brain, NO serves as a neurotransmitter and a second messenger molecule mediating a variety of neuronal functions. 8) Deletion of Osteopontin (OPN) in mice increased thalamic neurodegeneration through regulation inducible nitric oxide synthase (iNOS) expression, 9) an enzyme that produces NO. The interactions of NO are not restricted to a single receptor, it can react with other inorganic molecules (such as oxygen, superoxide or transition metals), structures in DNA (pyrimidine bases), prosthetic groups (such as heme) and proteins (leading to S-nitrosylation of thiol groups, nitration of tyrosine residues or disruption of metal-sulfide clusters such as zinc-finger domains and ironsulfide complexes).10) In addition, a recent repor...

show abstract

Section: Discussionmentioning

confidence: 99%

16α,17α-Epoxypregnenolone-20-oxime Prevent LPS-Induced NO Production and iNOS Expression in BV-2 Microglial Cells by Inhibiting JNK Phosphorylation

Sun

Jin

Han

et al. 2014

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…We have previously reported that TNF-␣ in conjunction with IFN-␥ produced neurotoxicity in neuron-glia cultures (57) and that inhibition of iNOS activity and NO production prevents LPS-induced neurotoxicity, indicating that NO production is also involved in LPSinduced neurodegeneration (58). Moreover, we recently found that a systemic injection of TNF-␣ can cause neuronal death (59) and the production of superoxide (L. Qin and J.-S. Hong, unpublished observations) in the brain.…”

Section: Discussionmentioning

confidence: 99%

Microglia-Mediated Neurotoxicity Is Inhibited by Morphine through an Opioid Receptor-Independent Reduction of NADPH Oxidase Activity

Tan

Wei

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Recent studies have shown that morphine modulates the function of glia cells through both opioid receptor dependent and independent mechanisms. However, the mechanism by which morphine regulates neuronal disorders through the alteration of microglia activity remains unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that both l-morphine and its synthetic stereoenantiomer, d-morphine, an ineffective opioid receptor agonist, significantly reduced LPS- or 1-methyl-4-phenylpyridinium-induced dopaminergic neurotoxicity with similar efficacy, indicating a nonopioid receptor-mediated effect. In addition, using reconstituted neuron and glia cultures, subpicomolar concentrations of morphine were found to be neuroprotective only in the presence of microglia, and significantly inhibited the production of inflammatory mediators from LPS-stimulated microglia cells. Mechanistic studies showed that both l- and d- morphine failed to protect dopaminergic neurons in cultures from NADPH oxidase (PHOX) knockout mice and significantly reduced LPS-induced PHOX cytosolic subunit p47phox translocation to the cell membrane by inhibiting ERK phosphorylation. Taken together, our results demonstrate that morphine, even at subpicomolar concentrations, exerts potent anti-inflammatory and neuroprotective effects either through the inhibition of direct microglial activation by LPS or through the inhibition of reactive microgliosis elicited by 1-methyl-4-phenylpyridinium. Furthermore, our study reveals that inhibition of PHOX is a novel site of action for the mu-opioid receptor-independent effect of morphine.

show abstract

“…For example, neuronal p38, not JNK, has been reported (Ciesielski-Treska et al, 2001) to play a significant role in mediating neuron death induced by chromogranin A-activated microglia. In a study of rat mesencephalic glia-neuron co-cultures (Jeohn et al, 2002), it was reported that p38 of the glia, not of the neurons, is involved in LPS-induced dopaminergic neuron death. The MEK-ERK pathway in microglia has been found (Combs et al, 1999) to be important in mediating the neurotoxic effects of ␤-amyloid-stimulated microglia.…”

Section: Discussionmentioning

confidence: 99%

“…Our results in the present study showing that conditioned medium from activated glia does not induce neuron death are consistent with the neurotoxic substance(s) being short-lived, such as NO. In addition, there have been several studies linking MAPK activation with NO generation (Chan and Riches, 2001;Han et al, 2002;Jeohn et al, 2002;Park et al, 2002). However, our analysis of the ability of the MAPK inhibitors to suppress NO production in the glia-neuron co-culture reveals a more complicated scenario.…”

Section: Discussionmentioning

confidence: 99%

“…MAPK pathways are also known to play a role in neuronal death induced by neurotoxic agents such as ␤-amyloid protein (Morishima et al, 2001;Troy et al, 2001), NO (Cheng et al, 2001), or methylisothiazolinone (Du et al, 2002), or by neurotrophic factor deprivation (De Zutter and Davis, 2001). To date, few studies have been carried out on the role of MAPKs in mediating glial activation and glia-induced neuron death in an environment in which neurons and glia coexist (Combs et al, 1999;Ciesielski-Treska et al, 2001;Jeohn et al, 2002). In addition, no study has been reported that examines, under the same experimental conditions, the three major members of the MAPK signaling family (p38, JNK, ERK1/2) in both neurons and glia, and the relative quantitative contribution of these three MAPK pathways in mediating glia-induced neuron death.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38

Xie

Smith

Eldik

2003

Glia

150

108

View full text Add to dashboard Cite

Chronic glial activation in neurodegenerative diseases contributes to neuronal dysfunction and neuron loss through production of neuroinflammatory molecules. However, the molecular mechanisms, particularly the signal transduction pathways involved in glia-dependent neuron death, are poorly understood. As a first step to address this question, we used a neuron-glia co-culture system that allows diffusion of soluble molecules between glia and neurons to test the potential importance of mitogen-activated protein kinase (MAPK) signaling pathways in the glia-induced neuron death. Activation of glia in co-culture by lipopolysaccharide (LPS) induced apoptotic-like neuron death. The MAPKs tested (p38, JNK, ERK1/2) were activated in both glia and neurons following LPS treatment, suggesting their involvement in both glial activation and neuronal response to diffusible, glia-derived neurotoxic molecules. Inhibitors of p38 and JNK partially blocked neuron death in the LPS-treated co-culture, whereas an ERK1/2 pathway inhibitor did not protect neurons. These results show that p38 and JNK MAPKs, but not ERK1/2 MAPK, are important signal transduction pathways contributing to glia-induced neuron death.

show abstract

p38 MAP Kinase Is Involved in Lipopolysaccharide‐Induced Dopaminergic Neuronal Cell Death in Rat Mesencephalic Neuron‐Glia Cultures

Cited by 56 publications

References 58 publications

16α,17α-Epoxypregnenolone-20-oxime Prevent LPS-Induced NO Production and iNOS Expression in BV-2 Microglial Cells by Inhibiting JNK Phosphorylation

16α,17α-Epoxypregnenolone-20-oxime Prevent LPS-Induced NO Production and iNOS Expression in BV-2 Microglial Cells by Inhibiting JNK Phosphorylation

Microglia-Mediated Neurotoxicity Is Inhibited by Morphine through an Opioid Receptor-Independent Reduction of NADPH Oxidase Activity

Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38

Contact Info

Product

Resources

About