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Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system.

Soulet D, Rivest S - J. Cell Biol. (2003)

Bottom Line: This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells.In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion.Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, Canada G1V 4G2.

ABSTRACT
The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

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Related in: MedlinePlus

Inhibition of ODC prevents cerebral damages and increases survival rate of mice that received a systemic administration with the GC receptor inhibitor RU486 before the intracerebral LPS infusion. A–D are from mice killed 3 d after the intracerebral LPS infusion (2.5 μg/1 μl sterile saline solution) and the systemic treatment with RU486 (50 mg/kg per 100 μl DMSO). Animals had free access to tap water (A and B) or DFMO (2% in drinking water, C and D) for a period of 2 d before the intracerebral LPS injection. Please note the degenerating area in the brain of the mouse that had only access to tap water before RU486 and LPS insults (A and B), and that DFMO essentially abolished these effects (C and D). Nissl stain and fluorochrome Fluoro-Jade B (green area) were used to label the degenerating neurons. E depicts the survival curve of mice in response to the different treatments. Some treatments are represented by the same color because the survival rate was identical among these groups of mice. Please note that most mice died after being injected with RU486 and LPS (red line), whereas the majority of mice that were treated with the inhibitor of ODC survived to the insults. 100% signifies no death; n represents the total number of mice used for a given treatment. cc, corpus callosum; CPu, caudate putamen.
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fig7: Inhibition of ODC prevents cerebral damages and increases survival rate of mice that received a systemic administration with the GC receptor inhibitor RU486 before the intracerebral LPS infusion. A–D are from mice killed 3 d after the intracerebral LPS infusion (2.5 μg/1 μl sterile saline solution) and the systemic treatment with RU486 (50 mg/kg per 100 μl DMSO). Animals had free access to tap water (A and B) or DFMO (2% in drinking water, C and D) for a period of 2 d before the intracerebral LPS injection. Please note the degenerating area in the brain of the mouse that had only access to tap water before RU486 and LPS insults (A and B), and that DFMO essentially abolished these effects (C and D). Nissl stain and fluorochrome Fluoro-Jade B (green area) were used to label the degenerating neurons. E depicts the survival curve of mice in response to the different treatments. Some treatments are represented by the same color because the survival rate was identical among these groups of mice. Please note that most mice died after being injected with RU486 and LPS (red line), whereas the majority of mice that were treated with the inhibitor of ODC survived to the insults. 100% signifies no death; n represents the total number of mice used for a given treatment. cc, corpus callosum; CPu, caudate putamen.

Mentions: To determine whether the ability of polyamines to alter the inflammatory response may be associated with functional consequences on the neuronal integrity, mice received a single systemic injection with the glucocorticoid (GC) receptor inhibitor RU486 before an intracerebral bolus of LPS. This treatment is known to cause an exaggerated inflammatory reaction due to the lack of inhibitory feedback of GCs on microglial cells, which ultimately leads to neurodegeneration (Nadeau and Rivest, 2003). Anatomical signs of brain damages were detected 3 d after the dual treatment combining intracerebral LPS and systemic RU486 (Fig. 7, A and B). Infusion of the endotoxin alone directly into the brain parenchyma failed to provoke neurodegeneration despite the robust and transient innate immune reaction (Nadeau and Rivest, 2002; unpublished data). Indeed, brain damages took place only in mice that received RU486 before the intracerebral LPS insult (Fig. 7 A, white area into the dotted-line circle). The fluorochrome Fluoro-Jade B (FJB) was also used to determine the extent of the neurodegenerating area, which can be visualized by the FJB green staining (Fig. 7 B). Pretreatment with DFMO essentially abolished the effects of the combined injections of RU486 and LPS (Fig. 7, C and D). Indeed, the brain of mice that had free access to DFMO for a period of 2 d before LPS and RU486 insults did not exhibit any signs of neurodegeneration except for the tract made by the infusion cannula.


Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system.

Soulet D, Rivest S - J. Cell Biol. (2003)

Inhibition of ODC prevents cerebral damages and increases survival rate of mice that received a systemic administration with the GC receptor inhibitor RU486 before the intracerebral LPS infusion. A–D are from mice killed 3 d after the intracerebral LPS infusion (2.5 μg/1 μl sterile saline solution) and the systemic treatment with RU486 (50 mg/kg per 100 μl DMSO). Animals had free access to tap water (A and B) or DFMO (2% in drinking water, C and D) for a period of 2 d before the intracerebral LPS injection. Please note the degenerating area in the brain of the mouse that had only access to tap water before RU486 and LPS insults (A and B), and that DFMO essentially abolished these effects (C and D). Nissl stain and fluorochrome Fluoro-Jade B (green area) were used to label the degenerating neurons. E depicts the survival curve of mice in response to the different treatments. Some treatments are represented by the same color because the survival rate was identical among these groups of mice. Please note that most mice died after being injected with RU486 and LPS (red line), whereas the majority of mice that were treated with the inhibitor of ODC survived to the insults. 100% signifies no death; n represents the total number of mice used for a given treatment. cc, corpus callosum; CPu, caudate putamen.
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Related In: Results  -  Collection

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fig7: Inhibition of ODC prevents cerebral damages and increases survival rate of mice that received a systemic administration with the GC receptor inhibitor RU486 before the intracerebral LPS infusion. A–D are from mice killed 3 d after the intracerebral LPS infusion (2.5 μg/1 μl sterile saline solution) and the systemic treatment with RU486 (50 mg/kg per 100 μl DMSO). Animals had free access to tap water (A and B) or DFMO (2% in drinking water, C and D) for a period of 2 d before the intracerebral LPS injection. Please note the degenerating area in the brain of the mouse that had only access to tap water before RU486 and LPS insults (A and B), and that DFMO essentially abolished these effects (C and D). Nissl stain and fluorochrome Fluoro-Jade B (green area) were used to label the degenerating neurons. E depicts the survival curve of mice in response to the different treatments. Some treatments are represented by the same color because the survival rate was identical among these groups of mice. Please note that most mice died after being injected with RU486 and LPS (red line), whereas the majority of mice that were treated with the inhibitor of ODC survived to the insults. 100% signifies no death; n represents the total number of mice used for a given treatment. cc, corpus callosum; CPu, caudate putamen.
Mentions: To determine whether the ability of polyamines to alter the inflammatory response may be associated with functional consequences on the neuronal integrity, mice received a single systemic injection with the glucocorticoid (GC) receptor inhibitor RU486 before an intracerebral bolus of LPS. This treatment is known to cause an exaggerated inflammatory reaction due to the lack of inhibitory feedback of GCs on microglial cells, which ultimately leads to neurodegeneration (Nadeau and Rivest, 2003). Anatomical signs of brain damages were detected 3 d after the dual treatment combining intracerebral LPS and systemic RU486 (Fig. 7, A and B). Infusion of the endotoxin alone directly into the brain parenchyma failed to provoke neurodegeneration despite the robust and transient innate immune reaction (Nadeau and Rivest, 2002; unpublished data). Indeed, brain damages took place only in mice that received RU486 before the intracerebral LPS insult (Fig. 7 A, white area into the dotted-line circle). The fluorochrome Fluoro-Jade B (FJB) was also used to determine the extent of the neurodegenerating area, which can be visualized by the FJB green staining (Fig. 7 B). Pretreatment with DFMO essentially abolished the effects of the combined injections of RU486 and LPS (Fig. 7, C and D). Indeed, the brain of mice that had free access to DFMO for a period of 2 d before LPS and RU486 insults did not exhibit any signs of neurodegeneration except for the tract made by the infusion cannula.

Bottom Line: This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells.In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion.Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, Canada G1V 4G2.

ABSTRACT
The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

Show MeSH
Related in: MedlinePlus