Neonatal Estradiol Stimulation Prevents Epilepsy in Arx Model of X-Linked Infantile Spasms Syndrome

Olivetti, Pedro R.; Maheshwari, Atul; Noebels, Jeffrey L.

doi:10.1126/scitranslmed.3007231

Cited by 60 publications

(77 citation statements)

References 66 publications

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“…In search of alternative therapy, the effects of estrogen, a neuroprotective hormone, were explored. Daily postnatal treatment of Arx (GCG)10+7 mutant mice for one week with the neurosteroid 17β-estradiol (E2), restored the decreased forebrain interneuron numbers, reduced neonatal spasms, and prevented seizures in adults [19]. E2 treatment was ineffective when administered to adults, indicating a critical, neonatal window in which E2 corrects pathological processes and modifies disease (Figure 2) [19].…”

Section: Estradiol Rescue Of Arx Mutations In Catastrophic Epilepsiesmentioning

confidence: 99%

“…Daily postnatal treatment of Arx (GCG)10+7 mutant mice for one week with the neurosteroid 17β-estradiol (E2), restored the decreased forebrain interneuron numbers, reduced neonatal spasms, and prevented seizures in adults [19]. E2 treatment was ineffective when administered to adults, indicating a critical, neonatal window in which E2 corrects pathological processes and modifies disease (Figure 2) [19]. E2 acts on ERα and ERβ receptors located on the plasma membrane or in the cytoplasm, which then activate downstream pathways via transcriptional regulation or non-genomic mediated signaling [20].…”

Section: Estradiol Rescue Of Arx Mutations In Catastrophic Epilepsiesmentioning

confidence: 99%

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Early rescue of interneuron disease trajectory in developmental epilepsies

Siehr

Noebels

2016

Current Opinion in Neurobiology

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The discovery of over 150 monogenic epilepsies and advances in early genetic diagnoses have launched a search for molecular strategies and developmental timetables to reverse or even prevent the course of these debilitating brain disorders. Orthologous rodent models of key disease genes are providing important examples of the range of targets, and serve as valuable test systems for perinatal therapeutic approaches. While gene-specific analyses of single rare ‘orphan’ diseases are each narrow in scope, they illuminate downstream pathways converging onto interneurons, and treatments that strengthen inhibition during cortical maturation may provide broad protection against these seemingly disparate gene errors. Several genes, even those linked to malformations, show promise for postnatal correction before the onset of their clinical phenotype.

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Section: Estradiol Rescue Of Arx Mutations In Catastrophic Epilepsiesmentioning

confidence: 99%

Section: Estradiol Rescue Of Arx Mutations In Catastrophic Epilepsiesmentioning

confidence: 99%

Early rescue of interneuron disease trajectory in developmental epilepsies

Siehr

Noebels

2016

Current Opinion in Neurobiology

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“…Quinidine, a partial antagonist of KCNT1 has been used to treat children with this encephalopathy (Bearden et al 2014). Neonatal estradiol has been shown to have neuroprotective effects that alter the disease trajectory and prevent infantile spasms and seizures in the ARX model of catastrophic epilepsy (Olivetti et al 2014). Greater effort in developing drugs that target the genetic mutation is likely to lead to more personalized treatments.…”

Section: Novel Therapeuticsmentioning

confidence: 99%

The Epilepsy Spectrum: Targeting Future Research Challenges

Holmes

Noebels

2016

Cold Spring Harb Perspect Med

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There have been tremendous recent advances in our understanding of the biological underpinnings of epilepsy and associated comorbidities that justify its representation as a spectrum disorder. Advances in genetics, electrophysiology, and neuroimaging have greatly improved our ability to differentiate, diagnose, and treat individuals with epilepsy. However, we have made little overall progress in preventing epilepsy, and the number of patients who are cured remains small. Likewise, the comorbidities of epilepsy are often underdiagnosed or not adequately treated. In this article, we suggest a few areas in which additional research will likely pay big dividends for patients and their families.T he pace of recent advances in epilepsy has been explosive, driven by our increasing understanding of the disorder's inextricable links to development, excitability, and plasticity in the central nervous system, and by the steady emergence of techniques to analyze these properties at high resolution in both human and animal models. As shown in Figure 1, there has been a near doubling in published articles dealing with epilepsy over the last 15 years. Experimental research has produced a threefold increase in peer-reviewed papers since 1970. Subareas within epilepsy research that have shown nearly exponential increases in activity include genetic models, epileptogenesis, comorbidities, and mortality.Although it is gratifying that epilepsy is now receiving the attention it deserves based on its prevalence, the new knowledge comes at a cost; the more we learn about the complex biology of epilepsy, the further away we appear to be from the therapeutic goalposts. Despite our advances in more precisely defining seizure phenotypes, isolating causative genes, and developing specific therapies, much more work needs to be done before we can hope to prevent epilepsy in vulnerable populations, reduce comorbidities associated with epilepsy, and effectively eliminate seizures without causing adverse side effects. However, clinical heterogeneity and molecular complexity are features of all human disease, and serve to position the field of epilepsy research alongside that of cancer in allowing the opportunity to make steady inroads in curing certain forms (Noebels 2015). In the future, rather than measuring our progress by the prevalence of the disorder as a whole, we will be monitoring research progress within the many

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“…Based on existing reports that estradiol may promote cell proliferation, neuronal migration, and differentiation (McCarthy 2008), a follow-up study investigated the therapeutic effects of neonatal estradiol administration in the Arx (GCG)10þ7 mouse (Table 4) (Olivetti et al 2014). Neonatal estradiol administration before the onset of spasms (PN3-10) restored the number of calbindin and NPY interneurons in the cerebral cortex, as well as cholinergic striatal neurons, and prevented spasms and subsequent epilepsy in their model.…”

Section: Animal Models Of Early-life Epilepsymentioning

confidence: 99%

Neonatal and Infantile Epilepsy: Acquired and Genetic Models

Galanopoulou

Moshé

2015

Cold Spring Harb Perspect Med

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The incidence of seizures and epilepsies is particularly high during the neonatal and infantile periods. We will review selected animal models of early-life epileptic encephalopathies that have addressed the dyscognitive features of frequent interictal spikes, the pathogenesis and treatments of infantile spasms (IS) or Dravet syndrome, disorders with mammalian target of rapamycin (mTOR) dysregulation, and selected early-life epilepsies with genetic defects. Potentially pathogenic mechanisms in these conditions include interneuronopathies in IS or Dravet syndrome and mTOR dysregulation in brain malformations, tuberous sclerosis, and related genetic disorders, or IS of acquired etiology. These models start to generate the first therapeutic drugs, which have been specifically developed in immature animals. However, there are challenges in translating preclinical discoveries into clinically relevant findings. The advances made so far hold promise that the new insights may potentially have curative or disease-modifying potential for many of these devastating conditions. T he neonatal and infantile periods show relatively high age-adjusted incidence of epilepsy compared with other ages of life (Hauser et al. 1993). The etiology of newly diagnosed epilepsies at these ages also is distinct, showing greater representation of epilepsies of unknown, genetic, or congenital etiologies (Hauser et al. 1993). The semiology and syndromic phenotypes of epilepsies that first appear in this early life period are also distinct and often more fulminant, appearing with evident neurodevelopmental problems or regression (e.g., epileptic encephalopathies) or characteristic seizure types (e.g., infantile spasms [IS], multifocal clonic seizures) ( Table 1). In addition, the treatments for epilepsies of these age groups can be specialized, as is the case with the use of hormonal therapies (e.g., adrenocorticotropic hormone [ACTH] in certain epileptic encephalopathies). Given the serious repercussions for the development of these neonates and infants and the importance of finding better therapies with disease-modifying potential, several efforts have been made to create animal models of these conditions to increase our understanding and ability to treat them. Here, we will review selected animal models, genetic or induced, that address epilepsies and epileptic encephalopathies characteristic of neonates and infants.

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Neonatal Estradiol Stimulation Prevents Epilepsy in Arx Model of X-Linked Infantile Spasms Syndrome

Cited by 60 publications

References 66 publications

Early rescue of interneuron disease trajectory in developmental epilepsies

Early rescue of interneuron disease trajectory in developmental epilepsies

The Epilepsy Spectrum: Targeting Future Research Challenges

Neonatal and Infantile Epilepsy: Acquired and Genetic Models

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