Loss of neurosteroid-mediated protection following stress during fetal life

Hirst, Jonathan J.; Cumberland, Angela; Shaw, Julia C.; Bennett, Greer A.; Kelleher, Meredith A.; Walker, David W.; Palliser, Hannah K.

doi:10.1016/j.jsbmb.2015.09.012

Cited by 32 publications

(26 citation statements)

References 67 publications

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“…The suppression of EEG power and fetal movement, which may reflect inhibition of synaptic activity due to increased local cytokine production [46][47][48], were associated with significantly elevated circulating IL-6 levels and neuroinflammation that are characteristic of preterm brain injury. Further, both inflammation and hypotension can trigger active EEG suppression through the release of inhibitory neuromodulators, such as adenosine and neurosteroids such as allopregnanolone [49][50][51]. Although in the present study, systemic hypotension and EEG suppression were not associated with reduced carotid artery perfusion, there was an increase in circulating lactate within the first 6 h after the first high dose LPS bolus, suggesting impaired oxidative phosphorylation at that time.…”

Section: Discussioncontrasting

confidence: 63%

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Galinsky

Dhillon

Dean

et al. 2020

J Neuroinflammation

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Background: Increased circulating levels of tumor necrosis factor (TNF) are associated with greater risk of impaired neurodevelopment after preterm birth. In this study, we tested the hypothesis that systemic TNF inhibition, using the soluble TNF receptor Etanercept, would attenuate neuroinflammation in preterm fetal sheep exposed to lipopolysaccharide (LPS). Methods: Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive saline (control; n = 7), LPS infusion (100 ng/kg i.v. over 24 h then 250 ng/kg/24 h for 96 h plus 1 μg LPS boluses at 48, 72, and 96 h, to induce inflammation; n = 8) or LPS plus two i.v. infusions of Etanercept (2 doses, 5 mg/kg infused over 30 min, 48 h apart) started immediately before LPS-exposure (n = 8). Sheep were killed 10 days after starting infusions, for histology. Results: LPS boluses were associated with increased circulating TNF, interleukin (IL)-6 and IL-10, electroencephalogram (EEG) suppression, hypotension, tachycardia, and increased carotid artery perfusion (P < 0.05 vs. control). In the periventricular and intragyral white matter, LPS exposure increased gliosis, TNFpositive cells, total oligodendrocytes, and cell proliferation (P < 0.05 vs control), but did not affect myelin expression or numbers of neurons in the cortex and subcortical regions. Etanercept delayed the rise in circulating IL-6, prolonged the increase in IL-10 (P < 0.05 vs. LPS), and attenuated EEG suppression, hypotension, and tachycardia after LPS boluses. Histologically, Etanercept normalized LPS-induced gliosis, and increase in TNF-positive cells, proliferation, and total oligodendrocytes. Conclusion: TNF inhibition markedly attenuated white matter gliosis but did not affect mature oligodendrocytes after prolonged systemic inflammation in preterm fetal sheep. Further studies of long-term brain maturation are now needed.

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Section: Discussioncontrasting

confidence: 63%

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Galinsky

Dhillon

Dean

et al. 2020

J Neuroinflammation

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“…More precise titration is needed to identify the lowest dose required to achieve the maximal effects. Hirst et al ( 57 ) reported that some of the P 4 is converted to cortisol, a hormone that could be detrimental to brain development. Thus, we need to consider the combined effects of possible P 4 metabolites as well as the diverse effects of steroids.…”

Section: Discussionmentioning

confidence: 99%

Progesterone as a Postnatal Prophylactic Agent for Encephalopathy Caused by Prenatal Hypoxic Ischemic Insult

et al. 2018

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Brain damage caused by hypoxic ischemic insult during the perinatal period causes hypoxic ischemic encephalopathies (HIEs). Therapeutic hypothermia is indicated for HIE, but because the therapeutic burden is large for its limited therapeutic effectiveness, another strategy is needed. Progesterone (P4) plays a neuroprotective role through the actions of its metabolite, allopregnanolone (Allo), on P4 receptor, γ-aminobutyric acid type A receptors or both. We examined the therapeutic potential of P4 using a newborn rat model of HIE. Fetal rats were exposed to transient ischemic hypoxia by 30-minute bilateral uterine artery clamping on gestational day 18. After spontaneous birth, newborn pups were subcutaneously injected with P4 (0.10 or 0.01 mg), medroxyprogesterone acetate (MPA; 0.12 mg), or Allo (0.10 mg) through postnatal days (PDs) 1 to 9. Brain damage in the rats was assessed using the rotarod test at PD50. The HIE insult reduced the rats’ ability in the rotarod task, which was completely reversed by P4 and Allo, but not by MPA. Histological examination revealed that the HIE insult decreased neuronal (the cortex and the hippocampal CA1 region) and oligodendroglial cell density (the corpus callosum) through PD0 to PD50. The axon fiber density and myelin sheath thickness in the corpus callosum were also reduced at PD50. The time-course study revealed that P4 restored oligodendroglial cells by PD5, which was followed by neuroprotective action of P4 that lasted long over the injection period. These results suggest that P4 protects the neonatal brain from HIE insult via restoration of oligodendroglial cells.

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“…When the ALLO level decreases, it brings about overexcitability in the neurons and increases the risk of brain damage secondary to hypoxia. Following birth (both normal and preterm) the neurosteroid level is found to be lower, which is particularly unfavourable for a preterm (104). Age-dependent effect was also evident for DOC which exhibited clear cut anticonvulsant effects in neonatal, infant, weanling and juvenile rats against PTZ-induced convulsions (87).…”

Section: Neurosteroids and Seizure Activity In The Pediatric Populatimentioning

confidence: 99%

Neurosteroids and Seizure Activity

2020

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Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline-pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3betamethylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebocontrolled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.

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Loss of neurosteroid-mediated protection following stress during fetal life

Cited by 32 publications

References 67 publications

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Tumor necrosis factor inhibition attenuates white matter gliosis after systemic inflammation in preterm fetal sheep

Progesterone as a Postnatal Prophylactic Agent for Encephalopathy Caused by Prenatal Hypoxic Ischemic Insult

Neurosteroids and Seizure Activity

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