Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration

Kalehua, Audrey N.; Nagel, James; Whelchel, L.M; Gides, J.J; Pyle, Robert S.; Smith, Reed; Kusiak, John W.; Taub, Dennis D.

doi:10.1016/j.yexcr.2004.02.031

Cited by 90 publications

(65 citation statements)

References 67 publications

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“…Recent studies show that CCL2 and its receptor CCR2 are expressed in the normal hippocampus and that the levels of expression increase during neuroinflammatory conditions associated with CNS injury and disease (Banisadr et al, 2005a;Banisadr et al, 2005b;Galasso et al, 2000;Kalehua et al, 2004;Little et al, 2002;Sakurai-Yamashita et al, 2006;Sheehan et al, 2007;Szaflarski et al, 1998). These results implicate a role for CCL2 in the hippocampus, particularly during neuroinflammatory conditions.…”

Section: Discussionmentioning

confidence: 92%

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

Cho

Gruol

2008

Journal of Neuroimmunology

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Emerging evidence indicates that chemokines can regulate both the physiology and biochemistry of CNS neurons and glia. In the current study, Western blot analysis showed that in rat hippocampal neuronal/glial cultures the signal transduction pathway activated by CCL2, a chemokine expressed in the normal brain and at elevated levels during neuroinflammation, involves a G-protein coupled receptor, p38 MAPK as well as its immediate upstream kinase MKK3/6, and the downstream transcription factor CREB. ERK 1/2 and the transcription factors STAT1 and STAT3 do not play a prominent role. CCL2 also altered Ca 2+ influx and synaptic network activity in the hippocampal neurons. These results suggest an important role for p38 MAPK and CREB in hippocampal actions of CCL2.

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Section: Discussionmentioning

confidence: 92%

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

Cho

Gruol

2008

Journal of Neuroimmunology

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“…PCR data: three pools of three animals each were compared to same-sized control pools performing double measurements. *P B 0.05, **P B 0.01, ***P B 0.001 promote the survival and differentiation of hippocampal neurons [29,30]. Ccl2 via its receptor CCR2 plays also an important role in regulating the permeability of the bloodbrain-barrier which is reduced in CCR2 (-/-) mice being subjected to focal transient cerebral ischemia and which was correlated with reduced infarct sizes [31].…”

Section: Discussionmentioning

confidence: 99%

“…Low Ccl2 plasma levels are associated with survival in invasive pneumococcal disease and correlate with bacterial loads in blood and cerebrospinal fluid, disease presentation and outcome [26]. Intrahippocampal injections of Ccl2 or Cxcl2 (macrophage inflammatory protein-2, MIP-2) resulted in the apoptosis of hippocampal neurons, thus supporting a direct role of these chemokines in neuronal death [29]. Yet chemokine-activated astrocytes seemed to NS not significant ** Adjusted P B 0.01.…”

Section: Discussionmentioning

confidence: 99%

Endotoxin-induced gene expression differences in the brain and effects of iNOS inhibition and norepinephrine

et al. 2009

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Purpose: We studied gene expression differences in brain homogenate, hippocampus, somatosensory cortex and cerebellum of rats suffering from sepsis-associated delirium and analyzed the effects of norepinephrine and 1,400 W (specific inhibitor of the inducible nitric-oxide synthase). Methods: We applied microarray screenings to rat brain homogenate 1, 3 and 4.5 h after lipopolysaccharide (LPS, 5 mg/kg) or 0.9% NaCl treatment. Therapy groups were analyzed after 4.5 h. Validations and compartment specific investigations were carried out by real-time PCR. Results: Most striking gene expression differences were seen 4.5 h after LPS administration, especially within the hippocampus (chemokines and endothelial cellspecific molecule 1). Norepinephrine resulted in a discrete chemokine upregulation, while 1,400 W had hardly any effect. Conclusion: Strongest gene regulations were found within the hippocampus. Norepinephrine showed a tendency of having a proinflammatory influence, while 1,400 W had no clear-cut effect onto the gene expression level.

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“…A recent study found that trimethyltin induced hippocampal degeneration involved marked MCP-1 induction, without TNFα, IL-1, IL-6, or other proinflammatory cytokines (Little et al, 2002). Endogenous MCP-1 is also known to directly induce neuronal apoptosis (Kalehua et al, 2004). Thus, increased MCP-1 in alcoholic brains could directly cause neuronal damage, and could be one of the mechanisms contributing to alcohol-related neuronal loss and brain atrophy (Brooks, 2000;Harper et al, 2003;Ikegami et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Increased MCP-1 and microglia in various regions of the human alcoholic brain

Crews

2008

Experimental Neurology

446

413

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Cytokines and microglia have been implicated in anxiety, depression, neurodegeneration as well as the regulation of alcohol drinking and other consumatory behaviors, all of which are associated with alcoholism. Studies using animal models of alcoholism suggest that microglia and proinflammatory cytokines contribute to alcoholic pathologies (Crews et al., 2006). In the current study, human postmortem brains from moderate drinking controls and alcoholics obtained from the New South Wales Tissue Resource Center were used to study the cytokine, monocyte chemoattractant protein 1 (MCP-1,CCL2) and microglia markers in various brain regions. Since MCP-1 is a key proinflammatory cytokine induced by chronic alcohol treatment of mice, and known to regulate drinking behavior in mice, MCP-1 protein levels from human brain homogenate were measured using ELISA, and indicated increased MCP-1 concentration in ventral tegmental area (VTA), substantia nigra (SN), hippocampus and amygdala of alcoholic brains as compared with controls. Immunohistochemistry was further performed to visualize human microglia using ionized calcium binding adaptor protein-1 (Iba-1), and Glucose transporter-5 (GluT 5 ). Alcoholics were found to have brain region-specific increases in microglial markers. In cingulate cortex, both Iba-1 and GluT 5 were increased in alcoholic brains relative to controls. Alternatively, no detectable change was found in amygdala nuclei. In VTA and midbrain, only GluT 5 , but not Iba-1 was increased in alcoholic brains. These data suggest that the enhanced expression of MCP-1 and microglia activities in alcoholic brains could contribute to ethanol-induced pathogenesis.

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Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration

Cited by 90 publications

References 67 publications

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

Endotoxin-induced gene expression differences in the brain and effects of iNOS inhibition and norepinephrine

Increased MCP-1 and microglia in various regions of the human alcoholic brain

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