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

Sato, Satoru M.; Woolley, Catherine S.

doi:10.7554/elife.12917

Cited by 61 publications

(74 citation statements)

References 86 publications

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“…Oestradiol can potentiate NMDA receptor activity through sex‐specific mechanisms, with oestradiol increasing release and sensitivity to glutamate in males (Oberlander & Woolley, ). Further, seizures can induce neurosteroid oestradiol synthesis, which in turn escalates seizure activity (Sato & Woolley, ). Testosterone aromatase activity can be downregulated in the presence of increased magnesium (Balthazart et al .…”

Section: Discussionmentioning

confidence: 99%

Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep

Bennet

Galinsky

Draghi

et al. 2018

The Journal of Physiology

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Seizures are common in newborns after asphyxia at birth and are often refractory to anti-seizure agents. Magnesium sulphate (MgSO ) has anticonvulsant effects and is increasingly given to women in preterm labour for potential neuroprotection. There is limited information on its effects on perinatal seizures. We examined the hypothesis that MgSO infusion would reduce fetal seizures after asphyxia in utero. Preterm fetal sheep at 0.7 gestation (104 days, term = 147 days) were given intravenous infusions of either saline (n = 14) or MgSO (n = 12, 160 mg bolus + 48 mg h infusion over 48 h). Fetuses underwent umbilical cord occlusion (UCO) for 25 min, 24 h after the start of infusion. The start time for seizures did not differ between groups, but MgSO significantly reduced the total number of seizures (P < 0.001), peak seizure amplitude (P < 0.05) and seizure burden (P < 0.005). Within the saline-asphyxia group, male fetuses had significantly more seizures than females (P < 0.05). Within the MgSO -asphyxia group, although both sexes had fewer seizures than the saline-asphyxia group, the greatest effect of MgSO was on male fetuses, with reduced numbers of seizures (P < 0.001) and seizure burden (P < 0.005). Only 1 out of 6 MgSO males had seizures on the second day post-UCO compared to 5 out of 6 MgSO female fetuses (P = 0.08). Finally, seizures showed a circadian profile with peak seizures between 04.00 and 06.00 h on the first and second day post-UCO. Collectively, these results suggest that MgSO may have utility in treating perinatal seizures and has sexually dimorphic effects.

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Section: Discussionmentioning

confidence: 99%

Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep

Bennet

Galinsky

Draghi

et al. 2018

The Journal of Physiology

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“…From this recent evidence, it is now clear that rapid estrogen signaling plays a key role in hypothalamic feedback in rhesus monkeys (Kenealy et al, 2013), seizure proliferation in the rat hippocampus (Sato and Woolley, 2016), and gonadotropin feedback in quail preoptic area (Ubuka et al, 2014). As this technique is applied to other species and systems, we will begin to better understand the prevalence and specifics of neurotransmitter-like effects of estrogens underlying a variety of behaviors in a wide range of systems and species.…”

Section: Neurotransmitter-like Effects Of Steroids Estrogens In Birdsmentioning

confidence: 99%

Actions of Steroids: New Neurotransmitters

et al. 2016

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Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain. IntroductionAt one time, the actions of steroid hormones were thought to mediate physiological changes through changes in gene transcription over an extended time course. This incomplete picture of steroid action has been filled in by the additional understanding that these compounds can have rapid, extragenomic, membrane-initiated actions. It has been known for decades that steroid hormones can have acute actions (within minutes) on physiology (Szego and Davis, 1967), the activity of neurons (Kelly et al., 1976), and the expression of behavior (Hayden-Hixson and Ferris, 1991). More recently, data demonstrate that steroids can and do function in ways that are "neurotransmitter-like," as they are synthesized at precise spatial locations within neural circuits and can act within minutes as local neuromodulators to rapidly regulate cognitive functions and behaviors (Balthazart and Ball,

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“…EEG power has been used as a proxy to determine seizure burden on acute induced seizures ( 28, 29 ). EEG power suppression was examined to evaluate efficacy of LM intervention (for example 10min EEG seizure trace see S2A-D).…”

Section: Resultsmentioning

confidence: 99%

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

Kipnis

Sullivan

Carter

et al. 2019

Preprint

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34Refractory neonatal seizures do not respond to first-line anti-seizure medications (ASMs) 35 like phenobarbital (PB), a positive allosteric modulator for GABAA receptors, the most widely 36 used ASM to treat neonatal seizures. GABAA receptor-mediated inhibition is dependent upon 37 neuronal chloride regulation. The electroneutral cation-chloride transporter KCC2 mediates 38 neuronal chloride extrusion; an age-dependent increase of KCC2 expression enables the shift of 39 GABAergic signaling from depolarizing to hyperpolarizing. BDNF-TrkB activation following 40 excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. This 41 study investigated the efficacy of partial and full TrkB agonists; LM22A-4 (LM), HIOC and 42 Deoxygedunin (DG) respectively, on PB-refractory seizures, post-ischemic TrkB-pathway 43 activation, and KCC2 membrane stability in a P7 CD-1 mouse model of refractory neonatal 44 seizures. Anti-seizure efficacy was determined by quantifying seizure burdens with continuous 45 video-EEG. LM rescued PB-refractory seizures in a sexually dimorphic manner. LM anti-seizure 46 efficacy was associated with a significant reduction in the post-ischemic phosphorylation of 47 TrkB at Y816, a site known to mediate post-ischemic KCC2 hypofunction via PLCγ1 activation. 48 LM additionally rescued ischemia-induced pKCC2-S940 dephosphorylation preserving its 49 membrane stability. HIOC and DG, two novel full TrkB agonists, also rescued PB-refractoriness 50 and post-ischemic TrkB-PLCγ1 pathway activation. Additionally, chemogenetic inactivation of 51 TrkB significantly reduced post-ischemic neonatal seizure burdens at P7. Developmental 52 expression profiles of TrkB and KCC2 in naïve pups identified developmental differences that 53 may underlie the sex-dependent variance in anti-seizure efficacy. These results support a novel 54 role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures. 55 56 65 (KCC2) in a mouse model of acute neonatal ischemia associated with phenobarbital (PB)-66 refractory seizures (5). 67The electroneutral cation-chloride transporter KCC2 is the primary neuronal Clextruder 68 and enables hyperpolarizing GABAergic inhibition in the brain. The residue Ser940 (S940) on 69 the C-terminus of KCC2 is associated with its membrane stability and chloride extrusion 70 capacity (6, 7). The developmental switch in GABAergic signaling from depolarizing to 71 hyperpolarizing (8) is enabled by an age-dependent increase of KCC2 expression (9). In the 72 neonatal period, KCC2 expression is low and GABA is depolarizing (8-10). In addition, KCC2 73 is susceptible to degradation following excitotoxic injury (2, 11, 12). In our characterized CD-1 74 mouse model of ischemic neonatal seizures, KCC2 underwent degradation and 75 dephosphorylation of residue S940 (5). This rendered the ASM PB inefficacious (5), as PB is a 76 positive allosteric modulator of GABAA receptors (13). Prevention of BDNF-TrkB mediated 77 KCC2 hypofunction rescued PB-refractori...

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

Cited by 61 publications

References 86 publications

Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep

Time and sex dependent effects of magnesium sulphate on post‐asphyxial seizures in preterm fetal sheep

Actions of Steroids: New Neurotransmitters

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

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