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Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats.

Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK - J Neuroinflammation (2011)

Bottom Line: Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells).We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset.This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Division, Pharmacology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. erik.a.johnson1@us.army.mil

ABSTRACT

Background: Exposure to the nerve agent soman (GD) causes neuronal cell death and impaired behavioral function dependent on the induction of status epilepticus (SE). Little is known about the maturation of this pathological process, though neuroinflammation and infiltration of neutrophils are prominent features. The purpose of this study is to quantify the regional and temporal progression of early chemotactic signals, describe the cellular expression of these factors and the relationship between expression and neutrophil infiltration in damaged brain using a rat GD seizure model.

Methods: Protein levels of 4 chemokines responsible for neutrophil infiltration and activation were quantified up to 72 hours in multiple brain regions (i.e. piriform cortex, hippocampus and thalamus) following SE onset using multiplex bead immunoassays. Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells). Lastly, neutrophil infiltration into these brain regions was quantified and correlated to the expression of these chemokines.

Results: We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset. CXCL1 expression originated from neurons and endothelial cells while MIP-1α was expressed by neurons and microglia. Lastly, the expression of these chemokines directly preceded and positively correlated with significant neutrophil infiltration in the brain. These data suggest that following GD-induced SE, a strong chemotactic response originating from various brain cells, recruits circulating neutrophils to the injured brain.

Conclusions: A strong induction of neutrophil attractant chemokines occurs following GD-induced SE resulting in neutrophil influx into injured brain tissues. This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

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MIP-1α Increases in Rat Brain after GD-induced SE. MIP-1α concentrations significantly increase in the hippocampus, piriform cortex and thalamus following GD-induced SE. MIP-1α concentrations peak at 24 hours after seizure onset in both the hippocampus (solid black line) and piriform cortex (solid gray line). In the thalamus (open gray line), there is a double peak at 12 and 48 hours after seizure onset. Data are given as pg/ml of tissue lysate reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (# p < 0.05, ## p < 0.01 hippocampus; ** p < 0.01 piriform cortex; $ p < 0.05, $$ p < 0.01 thalamus).
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Figure 3: MIP-1α Increases in Rat Brain after GD-induced SE. MIP-1α concentrations significantly increase in the hippocampus, piriform cortex and thalamus following GD-induced SE. MIP-1α concentrations peak at 24 hours after seizure onset in both the hippocampus (solid black line) and piriform cortex (solid gray line). In the thalamus (open gray line), there is a double peak at 12 and 48 hours after seizure onset. Data are given as pg/ml of tissue lysate reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (# p < 0.05, ## p < 0.01 hippocampus; ** p < 0.01 piriform cortex; $ p < 0.05, $$ p < 0.01 thalamus).

Mentions: Significant concentration increases were observed for MIP-1α protein in all three brain regions following GD-induced seizure (Figure 3). MIP-1α concentrations significantly increased in the hippocampus at 6 hours (152 ± 42 pg/ml), peaked at 24 hours (247 ± 90 pg/ml) and then rapidly decreased by 48 hours after SE onset compared to vehicle controls (2.06 ± 0.05 pg/ml). In the piriform cortex, MIP-1α concentrations significantly increased at 3 hours (149 ± 14 pg/ml), peaked at 24 hours (200 ± 34 pg/ml) and remained elevated through the 72-hour endpoint (139 ± 22 pg/ml) compared to vehicle controls (<1.94 pg/ml, MinDC). The pattern in the thalamus was different still, where a double peak was observed at 12 hours (245 ± 28 pg/ml) and 48 hours (248 ± 22 pg/ml) compared to controls (18 ± 11 pg/ml).


Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats.

Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK - J Neuroinflammation (2011)

MIP-1α Increases in Rat Brain after GD-induced SE. MIP-1α concentrations significantly increase in the hippocampus, piriform cortex and thalamus following GD-induced SE. MIP-1α concentrations peak at 24 hours after seizure onset in both the hippocampus (solid black line) and piriform cortex (solid gray line). In the thalamus (open gray line), there is a double peak at 12 and 48 hours after seizure onset. Data are given as pg/ml of tissue lysate reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (# p < 0.05, ## p < 0.01 hippocampus; ** p < 0.01 piriform cortex; $ p < 0.05, $$ p < 0.01 thalamus).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104356&req=5

Figure 3: MIP-1α Increases in Rat Brain after GD-induced SE. MIP-1α concentrations significantly increase in the hippocampus, piriform cortex and thalamus following GD-induced SE. MIP-1α concentrations peak at 24 hours after seizure onset in both the hippocampus (solid black line) and piriform cortex (solid gray line). In the thalamus (open gray line), there is a double peak at 12 and 48 hours after seizure onset. Data are given as pg/ml of tissue lysate reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (# p < 0.05, ## p < 0.01 hippocampus; ** p < 0.01 piriform cortex; $ p < 0.05, $$ p < 0.01 thalamus).
Mentions: Significant concentration increases were observed for MIP-1α protein in all three brain regions following GD-induced seizure (Figure 3). MIP-1α concentrations significantly increased in the hippocampus at 6 hours (152 ± 42 pg/ml), peaked at 24 hours (247 ± 90 pg/ml) and then rapidly decreased by 48 hours after SE onset compared to vehicle controls (2.06 ± 0.05 pg/ml). In the piriform cortex, MIP-1α concentrations significantly increased at 3 hours (149 ± 14 pg/ml), peaked at 24 hours (200 ± 34 pg/ml) and remained elevated through the 72-hour endpoint (139 ± 22 pg/ml) compared to vehicle controls (<1.94 pg/ml, MinDC). The pattern in the thalamus was different still, where a double peak was observed at 12 hours (245 ± 28 pg/ml) and 48 hours (248 ± 22 pg/ml) compared to controls (18 ± 11 pg/ml).

Bottom Line: Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells).We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset.This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Division, Pharmacology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. erik.a.johnson1@us.army.mil

ABSTRACT

Background: Exposure to the nerve agent soman (GD) causes neuronal cell death and impaired behavioral function dependent on the induction of status epilepticus (SE). Little is known about the maturation of this pathological process, though neuroinflammation and infiltration of neutrophils are prominent features. The purpose of this study is to quantify the regional and temporal progression of early chemotactic signals, describe the cellular expression of these factors and the relationship between expression and neutrophil infiltration in damaged brain using a rat GD seizure model.

Methods: Protein levels of 4 chemokines responsible for neutrophil infiltration and activation were quantified up to 72 hours in multiple brain regions (i.e. piriform cortex, hippocampus and thalamus) following SE onset using multiplex bead immunoassays. Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells). Lastly, neutrophil infiltration into these brain regions was quantified and correlated to the expression of these chemokines.

Results: We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset. CXCL1 expression originated from neurons and endothelial cells while MIP-1α was expressed by neurons and microglia. Lastly, the expression of these chemokines directly preceded and positively correlated with significant neutrophil infiltration in the brain. These data suggest that following GD-induced SE, a strong chemotactic response originating from various brain cells, recruits circulating neutrophils to the injured brain.

Conclusions: A strong induction of neutrophil attractant chemokines occurs following GD-induced SE resulting in neutrophil influx into injured brain tissues. This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

Show MeSH
Related in: MedlinePlus