A potential effect of ganaxolone in an animal model of infantile spasms

Yum, Mi‐Sun; Lee, Minyoung; Ko, Tae‐Sung; Velı́šek, Libor

doi:10.1016/j.eplepsyres.2014.08.015

Cited by 32 publications

(20 citation statements)

References 22 publications

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“…To facilitate this analysis, a rat model of IS was developed using betamethasone and NMDA to prime and trigger the IS-like state, along with scoring criteria to assess seizure severity [85]. In this setting, a preclinical study explored the potential for GX to address IS-like disease manifestations [86]. GX doses of 25 and 50 mg/kg significantly delayed and decreased the severity of NMDA-induced spasms, whether primed with betamethasone or not, and minimized observable behavioral changes associated with repeated spasm bouts, such as alterations in exploratory behavior.…”

Section: Infantile Spasmsmentioning

confidence: 99%

Clinical Potential of Neurosteroids for CNS Disorders

Reddy

Estes

2016

Trends in Pharmacological Sciences

153

164

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Summary Neurosteroids are key endogenous molecules in the brain that affect many neural functions. Here, we describe recent advances in NIH-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus, brain injury, Fragile X syndrome, and chemical neurotoxicity. The neurosteroid field has entered a new era, as many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends.

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Section: Infantile Spasmsmentioning

confidence: 99%

Clinical Potential of Neurosteroids for CNS Disorders

Reddy

Estes

2016

Trends in Pharmacological Sciences

153

164

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“…Most importantly, the effects of rapamycin on naïve rats (as done in the NMDA model) are different compared to those in subjects with epilepsy (as in the multiple-hit model) (Raffo et al 2011). More recently, pretreatment with ganaxolone, a neuroactive steroid, delayed and reduced NMDA spasms in the prenatal betamethasone model (Yum et al 2014). The therapeutic relevance of ganaxolone in IS is currently unclear because the effect on spasms or flurothyl seizures was only observed with high doses that can produce motor impairment (Liptakova et al 2000; Yum et al 2014).…”

Section: West Syndrome and Infantile Spasmsmentioning

confidence: 99%

“…More recently, pretreatment with ganaxolone, a neuroactive steroid, delayed and reduced NMDA spasms in the prenatal betamethasone model (Yum et al 2014). The therapeutic relevance of ganaxolone in IS is currently unclear because the effect on spasms or flurothyl seizures was only observed with high doses that can produce motor impairment (Liptakova et al 2000; Yum et al 2014). In a multicenter open label, add-on clinical trial of ganaxolone in infants with refractory IS, 33% of the infants responded with at least 50% reduction in spasms but only one of the 15 patients became spasm-free (Kerrigan et al 2000).…”

Section: West Syndrome and Infantile Spasmsmentioning

confidence: 99%

“…: intraperitoneally; s.c.: subcutaneously; U: units. Reproduced from (Galanopoulou 2013) in a modified form with permission from Elsevier. 1 (Velisek et al 2007) 2 (Wang et al 2012c) 3 (Wang et al 2012b) 4 (Kabova et al 1999) 5 (Kubova and Mares 2010) 6 (Velisek and Mares 1995) 7 (Chachua et al 2011) 8 (Yum et al 2012) 9 (Cortez et al 2009) 10 (Yum et al 2014) …”

Section: Highlightsmentioning

confidence: 99%

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Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

Galanopoulou

Moshé

2015

Neurobiology of Disease

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Early onset and infantile epileptic encephalopathies (EIEEs) are usually associated with medically intractable or difficult to treat epileptic seizures and prominent cognitive, neurodevelopmental and behavioral consequences. EIEEs have numerous etiologies that contribute to the inter- and intra-syndromic phenotypic variability. Etiologies include structural and metabolic or genetic etiologies although a significant percentage is of unknown cause. The need to better understand their pathogenic mechanisms and identify better therapies has driven the development of animal models of EIEEs. Several rodent models of infantile spasms have emerged that recapitulate various aspects of the disease. The acute models manifest epileptic spasms after induction and include the NMDA rat model, the NMDA model with prior prenatal betamethasone or perinatal stress exposure, and the γ-butyrolactone induced spasms in a mouse model of Down syndrome. The chronic models include the tetrodotoxin rat model, the aristaless related homeobox X-linked (Arx) mouse models and the multiple-hit rat model of infantile spasms. We will discuss the main features and findings from these models on target mechanisms and emerging therapies. Genetic models have also provided interesting data on the pathogenesis of Dravet syndrome and proposed new therapies for testing. The genetic associations of many of the EIEEs have also been tested in rodent models as to their pathogenicity. Finally, several models have tested the impact of subclinical epileptiform discharges on brain function. The impact of these advances in animal modeling for therapy development will be discussed.

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“…Additionally, intravenous methylprednisolone pulse therapy appeared effective in a small trial . Ganaxolone, a neurosteroid GABA A agonist, is an emerging neonatal anticonvulsant, which may benefit patients with IS . In the future, the optimal dosage route, and combination regimen of hormone therapy must be determined through clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of corticosteroids versus adrenocorticotropic hormone for infantile spasms: a systematic review and meta‐analysis

Chang

Chen

et al. 2019

Ann Clin Transl Neurol

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ObjectiveTo compare the therapeutic effectiveness of oral corticosteroids with that of adrenocorticotrophic hormone for infantile spasms.MethodsPubMed, Embase, Scopus, and the Cochrane library were searched to retrieve studies published before December 2018 to identify pediatric patients with a diagnosis of infantile spasms. The interventions of oral corticosteroids and adrenocorticotrophic hormone were compared. We included only randomized controlled trials that reported the cessation of spasms as treatment response. The primary outcome was clinical spasm cessation on day 13 or 14. The secondary outcomes were the resolution of hypsarrhythmia, side effects, continued spasm control, spasm relapse rate, and subsequent epilepsy rate. Following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, the study‐level quality assessment was conducted using the Cochrane risk‐of‐bias tool.ResultsAfter extensive review, 39 articles were included for meticulous evaluation. Five randomized controlled trials with a total of 239 individuals were eligible for further analysis. No significant difference was detected between the corticosteroids and adrenocorticotrophic hormone in the cessation of clinical spasms (odds ratio [OR]: 0.54; 95% confidence interval [CI]: 0.16 to 1.81; P = 0.32). The subgroups of high‐dose prednisolone versus adrenocorticotrophic hormone and low‐dose prednisone versus adrenocorticotrophic hormone also exhibited no significant difference. Furthermore, the two subgroups did not differ in terms of hypsarrhythmia resolution, side effects, relapse rate, or subsequent epilepsy rate.InterpretationThis meta‐analysis suggests that high‐dose prednisolone is not inferior to adrenocorticotrophic hormone and that it be considered a safe and effective alternative treatment.

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A potential effect of ganaxolone in an animal model of infantile spasms

Cited by 32 publications

References 22 publications

Clinical Potential of Neurosteroids for CNS Disorders

Clinical Potential of Neurosteroids for CNS Disorders

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

Effectiveness of corticosteroids versus adrenocorticotropic hormone for infantile spasms: a systematic review and meta‐analysis

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