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Lipopolysaccharide potentiates hyperthermia-induced seizures.

Eun BL, Abraham J, Mlsna L, Kim MJ, Koh S - Brain Behav (2015)

Bottom Line: Prolonged febrile seizures (FS) have both acute and long-lasting effects on the developing brain.Because FS are often associated with peripheral infection, we aimed to develop a preclinical model of FS that simulates fever and immune activation in order to facilitate the implementation of targeted therapy after prolonged FS in young children.By simulating fever, a regulated increase in body temperature from an immune challenge, we developed a more clinically relevant animal model of prolonged FS.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Korea University College of Medicine Seoul, Korea.

ABSTRACT

Background: Prolonged febrile seizures (FS) have both acute and long-lasting effects on the developing brain. Because FS are often associated with peripheral infection, we aimed to develop a preclinical model of FS that simulates fever and immune activation in order to facilitate the implementation of targeted therapy after prolonged FS in young children.

Methods: The innate immune activator lipopolysaccharide (LPS) was administered to postnatal day 14 rat (200 μg/kg) and mouse (100 μg/kg) pups 2-2.5 h prior to hyperthermic seizures (HT) induced by hair dryer or heat lamp. To determine whether simulation of infection enhances neuronal excitability, latency to seizure onset, threshold temperature and total number of seizures were quantified. Behavioral seizures were correlated with electroencephalographic changes in rat pups. Seizure-induced proinflammatory cytokine production was assessed in blood samples at various time points after HT. Seizure-induced microglia activation in the hippocampus was quantified using Cx3cr1(GFP/+) mice.

Results: Lipopolysaccharide priming increased susceptibility of rats and mice to hyperthemic seizures and enhanced seizure-induced proinflammatory cytokine production and microglial activation.

Conclusions: Peripheral inflammation appears to work synergistically with hyperthermia to potentiate seizures and to exacerbate seizure-induced immune responses. By simulating fever, a regulated increase in body temperature from an immune challenge, we developed a more clinically relevant animal model of prolonged FS.

No MeSH data available.


Related in: MedlinePlus

Experimental protocol for induction of infection-associated febrile seizures. (A) Rats were injected with lipopolysaccharide (LPS) (200 μg/kg, i.p.) 2.5 h prior to induction of hyperthermic seizures, using a hair dryer (Experiment 1) or heat lamp (Experiment 2). Blood cytokine levels were assayed at 0, 3, and 24 h after hyperthermic seizures. (B) Mice were injected with lipopolysaccharide (LPS) (100 μg/kg, i.p.) 2 h prior to induction of hyperthermic seizures using a heat lamp (Experiment 3). Blood cytokine levels were assayed at 0, 2, 4, and 24 h after hyperthermic seizures.
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fig01: Experimental protocol for induction of infection-associated febrile seizures. (A) Rats were injected with lipopolysaccharide (LPS) (200 μg/kg, i.p.) 2.5 h prior to induction of hyperthermic seizures, using a hair dryer (Experiment 1) or heat lamp (Experiment 2). Blood cytokine levels were assayed at 0, 3, and 24 h after hyperthermic seizures. (B) Mice were injected with lipopolysaccharide (LPS) (100 μg/kg, i.p.) 2 h prior to induction of hyperthermic seizures using a heat lamp (Experiment 3). Blood cytokine levels were assayed at 0, 2, 4, and 24 h after hyperthermic seizures.

Mentions: To allow direct comparisons between a well-established experimental FS model and our model of infection-associated FS, hyperthermic seizures (HT) were induced using a hairdryer according to the protocol developed in laboratory of Dr. Tallie Baram (Dube et al. 2005). A total of 68 P14 male Long Evans rat pups were used. Animals were randomly divided into four groups: (1) LPS-normothermia (LPS only), (2) LPS-hyperthemia (LPS-HT), (3) PBS-hyperthemia (HT only), and (4) normothermia controls. LPS only and LPS-HT animals were primed with LPS (Escherichia coli, serotype 0127:B8; Sigma Chemicals Co., St. Louis, MO; 200 μg/kg, i.p.) 2.5 h prior to induction of hyperthermia to simulate fever (Fig.1A). An additional group of rat pups (n = 3 HT; 3 LPS + HT) were implanted with EEG head mounts on P10 and monitored during seizure induction via a tethered data acquisition system on P14 in order to confirm the electrographic correlates of behavioral seizures.


Lipopolysaccharide potentiates hyperthermia-induced seizures.

Eun BL, Abraham J, Mlsna L, Kim MJ, Koh S - Brain Behav (2015)

Experimental protocol for induction of infection-associated febrile seizures. (A) Rats were injected with lipopolysaccharide (LPS) (200 μg/kg, i.p.) 2.5 h prior to induction of hyperthermic seizures, using a hair dryer (Experiment 1) or heat lamp (Experiment 2). Blood cytokine levels were assayed at 0, 3, and 24 h after hyperthermic seizures. (B) Mice were injected with lipopolysaccharide (LPS) (100 μg/kg, i.p.) 2 h prior to induction of hyperthermic seizures using a heat lamp (Experiment 3). Blood cytokine levels were assayed at 0, 2, 4, and 24 h after hyperthermic seizures.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4559014&req=5

fig01: Experimental protocol for induction of infection-associated febrile seizures. (A) Rats were injected with lipopolysaccharide (LPS) (200 μg/kg, i.p.) 2.5 h prior to induction of hyperthermic seizures, using a hair dryer (Experiment 1) or heat lamp (Experiment 2). Blood cytokine levels were assayed at 0, 3, and 24 h after hyperthermic seizures. (B) Mice were injected with lipopolysaccharide (LPS) (100 μg/kg, i.p.) 2 h prior to induction of hyperthermic seizures using a heat lamp (Experiment 3). Blood cytokine levels were assayed at 0, 2, 4, and 24 h after hyperthermic seizures.
Mentions: To allow direct comparisons between a well-established experimental FS model and our model of infection-associated FS, hyperthermic seizures (HT) were induced using a hairdryer according to the protocol developed in laboratory of Dr. Tallie Baram (Dube et al. 2005). A total of 68 P14 male Long Evans rat pups were used. Animals were randomly divided into four groups: (1) LPS-normothermia (LPS only), (2) LPS-hyperthemia (LPS-HT), (3) PBS-hyperthemia (HT only), and (4) normothermia controls. LPS only and LPS-HT animals were primed with LPS (Escherichia coli, serotype 0127:B8; Sigma Chemicals Co., St. Louis, MO; 200 μg/kg, i.p.) 2.5 h prior to induction of hyperthermia to simulate fever (Fig.1A). An additional group of rat pups (n = 3 HT; 3 LPS + HT) were implanted with EEG head mounts on P10 and monitored during seizure induction via a tethered data acquisition system on P14 in order to confirm the electrographic correlates of behavioral seizures.

Bottom Line: Prolonged febrile seizures (FS) have both acute and long-lasting effects on the developing brain.Because FS are often associated with peripheral infection, we aimed to develop a preclinical model of FS that simulates fever and immune activation in order to facilitate the implementation of targeted therapy after prolonged FS in young children.By simulating fever, a regulated increase in body temperature from an immune challenge, we developed a more clinically relevant animal model of prolonged FS.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Korea University College of Medicine Seoul, Korea.

ABSTRACT

Background: Prolonged febrile seizures (FS) have both acute and long-lasting effects on the developing brain. Because FS are often associated with peripheral infection, we aimed to develop a preclinical model of FS that simulates fever and immune activation in order to facilitate the implementation of targeted therapy after prolonged FS in young children.

Methods: The innate immune activator lipopolysaccharide (LPS) was administered to postnatal day 14 rat (200 μg/kg) and mouse (100 μg/kg) pups 2-2.5 h prior to hyperthermic seizures (HT) induced by hair dryer or heat lamp. To determine whether simulation of infection enhances neuronal excitability, latency to seizure onset, threshold temperature and total number of seizures were quantified. Behavioral seizures were correlated with electroencephalographic changes in rat pups. Seizure-induced proinflammatory cytokine production was assessed in blood samples at various time points after HT. Seizure-induced microglia activation in the hippocampus was quantified using Cx3cr1(GFP/+) mice.

Results: Lipopolysaccharide priming increased susceptibility of rats and mice to hyperthemic seizures and enhanced seizure-induced proinflammatory cytokine production and microglial activation.

Conclusions: Peripheral inflammation appears to work synergistically with hyperthermia to potentiate seizures and to exacerbate seizure-induced immune responses. By simulating fever, a regulated increase in body temperature from an immune challenge, we developed a more clinically relevant animal model of prolonged FS.

No MeSH data available.


Related in: MedlinePlus