Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs

Shaw, Julia C.; Dyson, Rebecca M.; Palliser, Hannah K.; Gray, Charles M.; Berry, Mary J.; Hirst, Jonathan J.

doi:10.1038/s41390-018-0185-7

Cited by 26 publications

(32 citation statements)

References 37 publications

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“…In our studies, the distance travelled, and time spent mobile in open field testing is markedly higher than the control, which is consistent with findings reported in the mouse . This hyperactive type behaviour returned to normal in response to GABA A receptor stimulation by ganaxolone following preterm birth . Our guinea pig model parallels clinical studies with premature‐born male children, who show an increased incidence of disorders related to hyperactivity …”

Section: Evidence For Imbalance Following Perinatal Compromisesupporting

confidence: 91%

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Shaw

Crombie

Zakár

et al. 2019

J Neuroendocrinology

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Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA‐synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.

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Section: Evidence For Imbalance Following Perinatal Compromisesupporting

confidence: 91%

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Shaw

Crombie

Zakár

et al. 2019

J Neuroendocrinology

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“…Following preterm birth, the brain is left extremely vulnerable as it is deprived of essential supplies from the placenta including steroids, enzymes and nutrients and at the same time is prematurely exposed to stimulating environments such as hyperoxia and associated damage [ 29 ]. Steroid hormones have been long implicated in neuroprotection and so are some of the major steroid hormone precursor molecules such as DHEA and the neuroactive steroid Allopregnanolone, which are being increasingly investigated for their pharmacological importance [ 23 , 30 ]. Even though DHEA is one of the major secretory products of the human adrenal gland, the concentration of DHEA has been found to be particularly high in the brain.…”

Section: Discussionmentioning

confidence: 99%

Fetal Zone Steroids and Estrogen Show Sex Specific Effects on Oligodendrocyte Precursor Cells in Response to Oxidative Damage

Sunny

Hammer

Ittermann

et al. 2021

IJMS

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Oxygen causes white matter damage in preterm infants and male sex is a major risk factor for poor neurological outcome, which speculates the role of steroid hormones in sex-based differences. Preterm birth is accompanied by a drop in 17β-estradiol (E2) and progesterone along with increased levels of fetal zone steroids (FZS). We performed a sex-based analysis on the FZS concentration differences in urine samples collected from preterm and term infants. We show that, in preterm urine samples, the total concentration of FZS, and in particular the 16α-OH-DHEA concentration, is significantly higher in ill female infants as compared to males. Since we previously identified Nup133 as a novel target protein affected by hyperoxia, here we studied the effect of FZS, allopregnanolone (Allo) and E2 on differentiation and Nup133 signaling using mouse-derived primary oligodendrocyte progenitor cells (OPCs). We show that the steroids could reverse the effect of hyperoxia-mediated downregulation of Nup133 in cultured male OPCs. The addition of FZS and E2 protected cells from oxidative stress. However, E2, in presence of 16α-OH-DHEA, showed a negative effect on male cells. These results assert the importance of sex-based differences and their potential implications in preterm stress response.

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“…Thus, in pre-term neonates, there is a decrease in allopregnanolone concentration associated with hypomyelination (Shaw et al, 2015). Animal studies using guinea pig pre-term neonates (Shaw et al, 2019) show positive effects on myelination with an allopregnanolone analog acting on GABA A Rs. Neurosteroid replacement has been suggested as a viable therapeutic option to improve myelination in this condition, as neurosteroids may help prevent neurodevelopmental disorders associated with pre-term birth (Shaw et al, 2019).…”

Section: Direct Modulation Of Gabaergic and Glutamatergic Receptors By Cholesterolmentioning

confidence: 99%

Dysregulation of Neuronal Nicotinic Acetylcholine Receptor–Cholesterol Crosstalk in Autism Spectrum Disorder

Vallés

Barrantes

2021

Front. Mol. Neurosci.

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Autism spectrum disorder (ASD) is a set of complex neurodevelopmental diseases that include impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior, restricted range of interests, and altered sensory processing. The underlying causes of the core symptoms remain unclear, as are the factors that trigger their onset. Given the complexity and heterogeneity of the clinical phenotypes, a constellation of genetic, epigenetic, environmental, and immunological factors may be involved. The lack of appropriate biomarkers for the evaluation of neurodevelopmental disorders makes it difficult to assess the contribution of early alterations in neurochemical processes and neuroanatomical and neurodevelopmental factors to ASD. Abnormalities in the cholinergic system in various regions of the brain and cerebellum are observed in ASD, and recently altered cholesterol metabolism has been implicated at the initial stages of the disease. Given the multiple effects of the neutral lipid cholesterol on the paradigm rapid ligand-gated ion channel, the nicotinic acetylcholine receptor, we explore in this review the possibility that the dysregulation of nicotinic receptor-cholesterol crosstalk plays a role in some of the neurological alterations observed in ASD.

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Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs

Abstract: Ganaxolone improved neurobehavioural outcomes in males suggesting that neonatal treatment may be an option for reducing preterm-associated neurodevelopmental impairment. However, dosing studies are required to reduce the burden of unwanted side effects.

Cited by 26 publications

References 37 publications

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long‐term effects on offspring behaviour

Fetal Zone Steroids and Estrogen Show Sex Specific Effects on Oligodendrocyte Precursor Cells in Response to Oxidative Damage

Dysregulation of Neuronal Nicotinic Acetylcholine Receptor–Cholesterol Crosstalk in Autism Spectrum Disorder

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