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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

Acute intra-hippocampal aromatase inhibition suppresses electrographic seizures in gonadectomized rats.(A) Representative time-synched behavioral (top) and electrographic seizures (bottom) following KA. (B) Magnified views of early (left) and middle (right) electrographic seizures and accompanying seizure behaviors. (C, D) Mild limbic seizures (Racine 0: staring (str), and 1–2: chewing and head-waving (C-HW)) showed higher correlation with normalized hippocampal EEG amplitude (C) and β-low γ power (D) than convulsive seizure behaviors (Racine 3: forelimb clonus (FLC), 4: rearing, 5: falling) (**p<0.001 between each behavior, post-hoc Newman-Keuls pairwise comparisons, vehicle: n=11, blue; fadrozole: n=10, orange). Intra-hippocampal infusion of fadrozole did not alter these relationships. (E) Mean ± SEM normalized power spectrogram plotted in 1 Hz bins for δ-θ (1–10 Hz), β-low γ (10–50 Hz), and ripple (100–200 Hz) frequency ranges for vehicle and fadrozole rats showing the seizure-induced increase in power in the β-low γ range in both groups. (F) Fadrozole attenuated the seizure-induced increase in power in the β-low γ range (*p<0.05, unpaired t-test) but not the δ-θ or ripple ranges. (G) Representative normalized power spectrum from one vehicle- (top) and one fadrozole- (bottom) treated rat. Teal bars above heat maps indicate seizures detected by 5x baseline power in the β-low γ range as the threshold. (H) Fadrozole decreased time that power in the β-low γ range exceeded 5x baseline (*p<0.05, unpaired t-test).DOI:http://dx.doi.org/10.7554/eLife.12917.012
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fig5: Acute intra-hippocampal aromatase inhibition suppresses electrographic seizures in gonadectomized rats.(A) Representative time-synched behavioral (top) and electrographic seizures (bottom) following KA. (B) Magnified views of early (left) and middle (right) electrographic seizures and accompanying seizure behaviors. (C, D) Mild limbic seizures (Racine 0: staring (str), and 1–2: chewing and head-waving (C-HW)) showed higher correlation with normalized hippocampal EEG amplitude (C) and β-low γ power (D) than convulsive seizure behaviors (Racine 3: forelimb clonus (FLC), 4: rearing, 5: falling) (**p<0.001 between each behavior, post-hoc Newman-Keuls pairwise comparisons, vehicle: n=11, blue; fadrozole: n=10, orange). Intra-hippocampal infusion of fadrozole did not alter these relationships. (E) Mean ± SEM normalized power spectrogram plotted in 1 Hz bins for δ-θ (1–10 Hz), β-low γ (10–50 Hz), and ripple (100–200 Hz) frequency ranges for vehicle and fadrozole rats showing the seizure-induced increase in power in the β-low γ range in both groups. (F) Fadrozole attenuated the seizure-induced increase in power in the β-low γ range (*p<0.05, unpaired t-test) but not the δ-θ or ripple ranges. (G) Representative normalized power spectrum from one vehicle- (top) and one fadrozole- (bottom) treated rat. Teal bars above heat maps indicate seizures detected by 5x baseline power in the β-low γ range as the threshold. (H) Fadrozole decreased time that power in the β-low γ range exceeded 5x baseline (*p<0.05, unpaired t-test).DOI:http://dx.doi.org/10.7554/eLife.12917.012

Mentions: The results with systemic inhibition of aromatase demonstrated that extra-gonadal estrogen synthesis during seizures contributes to the escalation of seizures from mild to severe. Coupled with results from microdialysis showing seizure-induced E2 synthesis in the hippocampus, this suggests that E2 synthesized in the hippocampus may be acutely seizure-promoting. To test this possibility, we first bilaterally infused fadrozole (10 µg/side, n=10) or vehicle (30% β-cyclodextrin in saline, n=11) into the dorsal hippocampus 20 min before KA (10 mg/kg, i.p.) and monitored seizures for 2 hrs. We used pre-treatment in this experiment because of difficulties associated with intra-hippocampal infusion after the onset of seizures and to avoid the possibility that infusions would disrupt EEG recording. Figure 5A shows data from a representative vehicle-infused animal, demonstrating the same pattern of hippocampal electrographic activity and accompanying behavioral seizures as in non-infused animals (Figure 1, 2). Also as seen previously, increased EEG activity in the hippocampus often corresponded to behaviors characteristic of mild limbic seizures (Figure 5B) and the relationship between electrographic seizure activity was stronger for mild limbic than convulsive seizure behaviors (amplitude: F4,94=44.02, p<0.001, Figure 5C; power: F4,94=21.13, p<0.001, Figure 5D). In contrast to systemic fadrozole, however, intra-hippocampal fadrozole did not affect the strength of cross-correlation between EEG amplitude (Figure 5C) or power (Figure 5D) and seizure behaviors.10.7554/eLife.12917.012Figure 5.Acute intra-hippocampal aromatase inhibition suppresses electrographic seizures in gonadectomized rats.


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

Sato SM, Woolley CS - Elife (2016)

Acute intra-hippocampal aromatase inhibition suppresses electrographic seizures in gonadectomized rats.(A) Representative time-synched behavioral (top) and electrographic seizures (bottom) following KA. (B) Magnified views of early (left) and middle (right) electrographic seizures and accompanying seizure behaviors. (C, D) Mild limbic seizures (Racine 0: staring (str), and 1–2: chewing and head-waving (C-HW)) showed higher correlation with normalized hippocampal EEG amplitude (C) and β-low γ power (D) than convulsive seizure behaviors (Racine 3: forelimb clonus (FLC), 4: rearing, 5: falling) (**p<0.001 between each behavior, post-hoc Newman-Keuls pairwise comparisons, vehicle: n=11, blue; fadrozole: n=10, orange). Intra-hippocampal infusion of fadrozole did not alter these relationships. (E) Mean ± SEM normalized power spectrogram plotted in 1 Hz bins for δ-θ (1–10 Hz), β-low γ (10–50 Hz), and ripple (100–200 Hz) frequency ranges for vehicle and fadrozole rats showing the seizure-induced increase in power in the β-low γ range in both groups. (F) Fadrozole attenuated the seizure-induced increase in power in the β-low γ range (*p<0.05, unpaired t-test) but not the δ-θ or ripple ranges. (G) Representative normalized power spectrum from one vehicle- (top) and one fadrozole- (bottom) treated rat. Teal bars above heat maps indicate seizures detected by 5x baseline power in the β-low γ range as the threshold. (H) Fadrozole decreased time that power in the β-low γ range exceeded 5x baseline (*p<0.05, unpaired t-test).DOI:http://dx.doi.org/10.7554/eLife.12917.012
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fig5: Acute intra-hippocampal aromatase inhibition suppresses electrographic seizures in gonadectomized rats.(A) Representative time-synched behavioral (top) and electrographic seizures (bottom) following KA. (B) Magnified views of early (left) and middle (right) electrographic seizures and accompanying seizure behaviors. (C, D) Mild limbic seizures (Racine 0: staring (str), and 1–2: chewing and head-waving (C-HW)) showed higher correlation with normalized hippocampal EEG amplitude (C) and β-low γ power (D) than convulsive seizure behaviors (Racine 3: forelimb clonus (FLC), 4: rearing, 5: falling) (**p<0.001 between each behavior, post-hoc Newman-Keuls pairwise comparisons, vehicle: n=11, blue; fadrozole: n=10, orange). Intra-hippocampal infusion of fadrozole did not alter these relationships. (E) Mean ± SEM normalized power spectrogram plotted in 1 Hz bins for δ-θ (1–10 Hz), β-low γ (10–50 Hz), and ripple (100–200 Hz) frequency ranges for vehicle and fadrozole rats showing the seizure-induced increase in power in the β-low γ range in both groups. (F) Fadrozole attenuated the seizure-induced increase in power in the β-low γ range (*p<0.05, unpaired t-test) but not the δ-θ or ripple ranges. (G) Representative normalized power spectrum from one vehicle- (top) and one fadrozole- (bottom) treated rat. Teal bars above heat maps indicate seizures detected by 5x baseline power in the β-low γ range as the threshold. (H) Fadrozole decreased time that power in the β-low γ range exceeded 5x baseline (*p<0.05, unpaired t-test).DOI:http://dx.doi.org/10.7554/eLife.12917.012
Mentions: The results with systemic inhibition of aromatase demonstrated that extra-gonadal estrogen synthesis during seizures contributes to the escalation of seizures from mild to severe. Coupled with results from microdialysis showing seizure-induced E2 synthesis in the hippocampus, this suggests that E2 synthesized in the hippocampus may be acutely seizure-promoting. To test this possibility, we first bilaterally infused fadrozole (10 µg/side, n=10) or vehicle (30% β-cyclodextrin in saline, n=11) into the dorsal hippocampus 20 min before KA (10 mg/kg, i.p.) and monitored seizures for 2 hrs. We used pre-treatment in this experiment because of difficulties associated with intra-hippocampal infusion after the onset of seizures and to avoid the possibility that infusions would disrupt EEG recording. Figure 5A shows data from a representative vehicle-infused animal, demonstrating the same pattern of hippocampal electrographic activity and accompanying behavioral seizures as in non-infused animals (Figure 1, 2). Also as seen previously, increased EEG activity in the hippocampus often corresponded to behaviors characteristic of mild limbic seizures (Figure 5B) and the relationship between electrographic seizure activity was stronger for mild limbic than convulsive seizure behaviors (amplitude: F4,94=44.02, p<0.001, Figure 5C; power: F4,94=21.13, p<0.001, Figure 5D). In contrast to systemic fadrozole, however, intra-hippocampal fadrozole did not affect the strength of cross-correlation between EEG amplitude (Figure 5C) or power (Figure 5D) and seizure behaviors.10.7554/eLife.12917.012Figure 5.Acute intra-hippocampal aromatase inhibition suppresses electrographic seizures in gonadectomized rats.

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