Neurosteroids and infantile spasms: The deoxycorticosterone hypothesis

Rogawski, Michael A.; Reddy, Doodipala Samba

doi:10.1016/s0074-7742(02)49014-9

Cited by 41 publications

(27 citation statements)

References 84 publications

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“…In an open-label, add-on trial, spasm frequency was reduced at least 50 % in 33 % of subjects (Class IV) [63][64][65]. The drug was well tolerated, but showed only modest and non-significant effectiveness.…”

Section: Different Forms Of Corticosteroidsmentioning

confidence: 99%

Recent Advances in the Pharmacotherapy of Infantile Spasms

Riikonen

2014

CNS Drugs

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Adrenocorticotrophic hormone (ACTH), oral corticosteroids and vigabatrin are now first-line treatments for infantile spasms in the US and Europe. There is now increased knowledge regarding the role of ACTH, corticosteroids and vigabatrin (e.g. efficacy, doses, side effects, treatment in specific aetiological subtypes of infantile spasms), and other antiepileptic drugs (i.e. topiramate, valproate, zonisamide, sulthiame, levetiracetam, lamotrigine, pyridoxine, ganaxolone), as well as adjunctive flunarizine and novel drugs not yet in clinical use for infantile spasms (i.e. pulse rapamycin and melanocortin receptor agonists). The existence of a latent period, weeks to months following a precipitating brain insult, raises the possibility of preventive interventions. Recent experimental data emerging from animal models of infantile spasms have provided optimism that new and innovative treatments can be developed, and knowledge that drug treatment can affect long-term cognitive outcome is increasing. The aim of this article is to review recent developments in the pharmacotherapy of infantile spasms and to highlight the practical implications of the latest research.

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Section: Different Forms Of Corticosteroidsmentioning

confidence: 99%

Recent Advances in the Pharmacotherapy of Infantile Spasms

Riikonen

2014

CNS Drugs

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“…Hence, the concept of endogenous steroid synthesis in the brain, neurosteroidogenesis, was formed. Since that time, the function for these compounds began to be uncovered, and the mechanisms and receptors through which these compounds mediated their action also began to be studied Belelli and Lambert, 2005;Compagnone and Mellon, 2000;Costa and Paul, 1991;Mensah-Nyagan et al, 1999;Puia et al, 2003;Rupprecht, 2003;Rupprecht and Holsboer, 1999a) and functions for these compounds in human diseases was also proposed (Backstrom et al, 2003;Barbaccia, 2004;Belelli et al, 2006;Bernardi et al, 2004;Brinton and Wang, 2006;Campbell, 2006;Charalampopoulos et al, 2006;Guarneri et al, 2003;Matsumoto et al, 2005;Mellon and Griffin, 2002;Morrow et al, 2001;Reddy, 2002;Rogawski and Reddy, 2002;Rupprecht and Holsboer, 1999b;Stoffel-Wagner, 2003;Uzunova et al, 2006). These references are merely a partial list of review articles written about neurosteroids and their functions, indicating the breadth of research on this topic.…”

Section: Introductionmentioning

confidence: 99%

Neurosteroid regulation of central nervous system development

Mellon

2007

Pharmacology & Therapeutics

183

114

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Neurosteroids are a relatively new class of neuroactive compounds, brought to prominence in the past two decades. Despite knowing of their presence in the nervous system of various species for over twenty years and knowing of their functions as GABA A and NMDA ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of four distinct neurosteroids -pregnenolone, progesterone, allopregnanolone and dehydroepiandrosterone.

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“…Over the past decade, the identification of the steroids found in the brains of many species has demonstrated a remarkable similarity. Functions associated with these neuroactive compounds has also been identified (reviewed in (Backstrom, et al, 2003,Barbaccia, 2004,Belelli, et al, 2006,Belelli and Lambert, 2005,Bernardi, et al, 2004,Brinton and Wang, 2006,Compagnone and Mellon, 2000,Finn, et al, 2004,Guarneri, et al, 2003,Mensah-Nyagan, et al, 2001,Reddy, 2002,Reddy, 2004,Rogawski and Reddy, 2002,Rupprecht and Holsboer, 1999,Schumacher, et al, 2004,Stoffel-Wagner, 2003,Tsutsui and Mellon, 2006,Tsutsui, et al, 2004,Uzunova, et al, 2005,Vallee, et al, 2001. However, it is still unknown if these compounds are essential for life.…”

Section: Introductionmentioning

confidence: 99%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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Neurosteroids and infantile spasms: The deoxycorticosterone hypothesis

Cited by 41 publications

References 84 publications

Recent Advances in the Pharmacotherapy of Infantile Spasms

Recent Advances in the Pharmacotherapy of Infantile Spasms

Neurosteroid regulation of central nervous system development

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

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