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Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model.

Sato SM, Woolley CS - Elife (2016)

Bottom Line: We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity.Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures.These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Northwestern University, Evanston, United States.

ABSTRACT
Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE.

No MeSH data available.


Related in: MedlinePlus

Comparison of manual and 3x, 5x, and 10x baseline thresholds.(A) Raw EEG, (B) normalized EEG amplitude, and (C) normalized β-low γ (10–50 Hz) power from a representative vehicle-treated rat. The colored bars above the traces indicate seizures detected manually (A), or using 3x, 5x, or 10x baseline threshold (B, C), as indicated on the right. While there were differences in sensitivity to minor seizures (e.g., 1st seizure at ~200 s) and the ability to resolve seizures during the merging phase (4000–7200 s), the effects of systemic fadrozole to suppress seizures were detected with all thresholds tested. (D, E) Systemic administration of fadrozole attenuated seizure progression, so that the fadrozole-treated rats spent significantly less time in seizure during the 2nd hr of testing, whether seizures were detected based on an increase in EEG amplitude (3x: F1,19=15.93, p<0.01; 10x: F1,19=5.79, p<0.05, D) or an increase in β-low γ power (3x: F1,19=20.97, p<0.001; 10x: F1,19=12.62, p<0.01, E) and regardless of the threshold used. *p<0.05 and **p<0.01 for the 2nd hr between vehicle- and fadrozole-treated rats, post-hoc unpaired t-tests. Statistics for 5x baseline threshold data are reported in the Results.DOI:http://dx.doi.org/10.7554/eLife.12917.005
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fig1s2: Comparison of manual and 3x, 5x, and 10x baseline thresholds.(A) Raw EEG, (B) normalized EEG amplitude, and (C) normalized β-low γ (10–50 Hz) power from a representative vehicle-treated rat. The colored bars above the traces indicate seizures detected manually (A), or using 3x, 5x, or 10x baseline threshold (B, C), as indicated on the right. While there were differences in sensitivity to minor seizures (e.g., 1st seizure at ~200 s) and the ability to resolve seizures during the merging phase (4000–7200 s), the effects of systemic fadrozole to suppress seizures were detected with all thresholds tested. (D, E) Systemic administration of fadrozole attenuated seizure progression, so that the fadrozole-treated rats spent significantly less time in seizure during the 2nd hr of testing, whether seizures were detected based on an increase in EEG amplitude (3x: F1,19=15.93, p<0.01; 10x: F1,19=5.79, p<0.05, D) or an increase in β-low γ power (3x: F1,19=20.97, p<0.001; 10x: F1,19=12.62, p<0.01, E) and regardless of the threshold used. *p<0.05 and **p<0.01 for the 2nd hr between vehicle- and fadrozole-treated rats, post-hoc unpaired t-tests. Statistics for 5x baseline threshold data are reported in the Results.DOI:http://dx.doi.org/10.7554/eLife.12917.005

Mentions: Figure 1B and C show representative recordings of electrographic seizures throughout the 2 hr seizure monitoring period. Vehicle-treated rats showed the expected progression of seizure activity, beginning with individual seizures that evolved to merging seizures (Treiman et al., 1990) with high EEG amplitude and increased power. In contrast, fadrozole-treated rats showed much lower seizure activity, particularly during the 2nd hr when vehicle rats typically experienced merging seizures. Thus fadrozole suppressed seizure escalation. The effects of fadrozole were the same in males and females (all p values >0.30) so data were combined. The seizure-induced increase in EEG amplitude during the 2nd hr was 46% lower on average in fadrozole-treated compared to vehicle-treated rats (time x drug: F1,19=10.36, p<0.01, Figure 1D) and the time animals spent in seizures based on a 5x baseline threshold of EEG amplitude was 73% lower in the 2nd hr (time x drug: F1,19=20.88, p<0.001, Figure 1E). In addition to EEG amplitude, fadrozole also significantly attenuated the seizure-induced increase in EEG power in the δ-θ (1–10 Hz, F1,19=21.50, p<0.001) and β-low γ (10–50 Hz, F1,19=8.08, p=0.01) frequency ranges over the entire 2 hr testing period (Figure 1F). Additional analyses revealed that the effect on power was more prominent during the 2nd hr of seizure testing, when normalized power was significantly lower in all frequency ranges examined (time x drug: δ-θ: F1,19=20.86, p<0.001; β-low γ: F1,19=20.22, p<0.001; ripple (100–200 Hz): F1,19=5.96, p<0.05, not shown). We focused further analyses on β-low γ power because this is known to be sensitive to KA both in vitro (Fisahn et al., 2004) and in vivo (Medvedev et al., 2000; Lévesque et al., 2009) and may contribute to the spread of seizures to other brain regions (Finnerty and Jefferys, 2000; Lévesque et al., 2009). The seizure-induced increase in β-low γ power in fadrozole-treated rats was 59% lower during the 2nd hr (Figure 1G) and time in seizure based on a threshold of 5x baseline β-low γ power was 44% lower in the 2nd hr (time x drug: F1,19=16.87, p<0.01, Figure 1H). The same results for time in seizure were obtained using 3x or 10x baseline thresholds of EEG amplitude or β-low γ power (Figure 1—figure supplement 2). These results demonstrated that inhibition of extra-gonadal aromatase suppressed electrographic seizure activity in the hippocampus.


Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model.

Sato SM, Woolley CS - Elife (2016)

Comparison of manual and 3x, 5x, and 10x baseline thresholds.(A) Raw EEG, (B) normalized EEG amplitude, and (C) normalized β-low γ (10–50 Hz) power from a representative vehicle-treated rat. The colored bars above the traces indicate seizures detected manually (A), or using 3x, 5x, or 10x baseline threshold (B, C), as indicated on the right. While there were differences in sensitivity to minor seizures (e.g., 1st seizure at ~200 s) and the ability to resolve seizures during the merging phase (4000–7200 s), the effects of systemic fadrozole to suppress seizures were detected with all thresholds tested. (D, E) Systemic administration of fadrozole attenuated seizure progression, so that the fadrozole-treated rats spent significantly less time in seizure during the 2nd hr of testing, whether seizures were detected based on an increase in EEG amplitude (3x: F1,19=15.93, p<0.01; 10x: F1,19=5.79, p<0.05, D) or an increase in β-low γ power (3x: F1,19=20.97, p<0.001; 10x: F1,19=12.62, p<0.01, E) and regardless of the threshold used. *p<0.05 and **p<0.01 for the 2nd hr between vehicle- and fadrozole-treated rats, post-hoc unpaired t-tests. Statistics for 5x baseline threshold data are reported in the Results.DOI:http://dx.doi.org/10.7554/eLife.12917.005
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Related In: Results  -  Collection

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fig1s2: Comparison of manual and 3x, 5x, and 10x baseline thresholds.(A) Raw EEG, (B) normalized EEG amplitude, and (C) normalized β-low γ (10–50 Hz) power from a representative vehicle-treated rat. The colored bars above the traces indicate seizures detected manually (A), or using 3x, 5x, or 10x baseline threshold (B, C), as indicated on the right. While there were differences in sensitivity to minor seizures (e.g., 1st seizure at ~200 s) and the ability to resolve seizures during the merging phase (4000–7200 s), the effects of systemic fadrozole to suppress seizures were detected with all thresholds tested. (D, E) Systemic administration of fadrozole attenuated seizure progression, so that the fadrozole-treated rats spent significantly less time in seizure during the 2nd hr of testing, whether seizures were detected based on an increase in EEG amplitude (3x: F1,19=15.93, p<0.01; 10x: F1,19=5.79, p<0.05, D) or an increase in β-low γ power (3x: F1,19=20.97, p<0.001; 10x: F1,19=12.62, p<0.01, E) and regardless of the threshold used. *p<0.05 and **p<0.01 for the 2nd hr between vehicle- and fadrozole-treated rats, post-hoc unpaired t-tests. Statistics for 5x baseline threshold data are reported in the Results.DOI:http://dx.doi.org/10.7554/eLife.12917.005
Mentions: Figure 1B and C show representative recordings of electrographic seizures throughout the 2 hr seizure monitoring period. Vehicle-treated rats showed the expected progression of seizure activity, beginning with individual seizures that evolved to merging seizures (Treiman et al., 1990) with high EEG amplitude and increased power. In contrast, fadrozole-treated rats showed much lower seizure activity, particularly during the 2nd hr when vehicle rats typically experienced merging seizures. Thus fadrozole suppressed seizure escalation. The effects of fadrozole were the same in males and females (all p values >0.30) so data were combined. The seizure-induced increase in EEG amplitude during the 2nd hr was 46% lower on average in fadrozole-treated compared to vehicle-treated rats (time x drug: F1,19=10.36, p<0.01, Figure 1D) and the time animals spent in seizures based on a 5x baseline threshold of EEG amplitude was 73% lower in the 2nd hr (time x drug: F1,19=20.88, p<0.001, Figure 1E). In addition to EEG amplitude, fadrozole also significantly attenuated the seizure-induced increase in EEG power in the δ-θ (1–10 Hz, F1,19=21.50, p<0.001) and β-low γ (10–50 Hz, F1,19=8.08, p=0.01) frequency ranges over the entire 2 hr testing period (Figure 1F). Additional analyses revealed that the effect on power was more prominent during the 2nd hr of seizure testing, when normalized power was significantly lower in all frequency ranges examined (time x drug: δ-θ: F1,19=20.86, p<0.001; β-low γ: F1,19=20.22, p<0.001; ripple (100–200 Hz): F1,19=5.96, p<0.05, not shown). We focused further analyses on β-low γ power because this is known to be sensitive to KA both in vitro (Fisahn et al., 2004) and in vivo (Medvedev et al., 2000; Lévesque et al., 2009) and may contribute to the spread of seizures to other brain regions (Finnerty and Jefferys, 2000; Lévesque et al., 2009). The seizure-induced increase in β-low γ power in fadrozole-treated rats was 59% lower during the 2nd hr (Figure 1G) and time in seizure based on a threshold of 5x baseline β-low γ power was 44% lower in the 2nd hr (time x drug: F1,19=16.87, p<0.01, Figure 1H). The same results for time in seizure were obtained using 3x or 10x baseline thresholds of EEG amplitude or β-low γ power (Figure 1—figure supplement 2). These results demonstrated that inhibition of extra-gonadal aromatase suppressed electrographic seizure activity in the hippocampus.

Bottom Line: We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity.Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures.These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Northwestern University, Evanston, United States.

ABSTRACT
Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE.

No MeSH data available.


Related in: MedlinePlus