Neurosteroid Replacement Therapy for Catamenial Epilepsy

Reddy, Doodipala Samba; Rogawski, Michael A.

doi:10.1201/9781420085594-c28

Cited by 21 publications

(36 citation statements)

References 60 publications

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“…Synthetic neurosteroids that augment tonic inhibition may provide a rational treatment strategy for controlling catamenial seizures at low doses that do not cause significant GABAergic side effects. Such neurosteroid replacement therapy may prevent seizure occurrence in women with epilepsy (Reddy and Rogawski, 2009).…”

Section: Discussionmentioning

confidence: 99%

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Reddy

Gould²,

Gangisetty³

2012

J Pharmacol Exp Ther

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Catamenial epilepsy is caused by fluctuations in progesteronederived GABA A receptor-modulating anticonvulsant neurosteroids, such as allopregnanolone, that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy by using the neurosteroid-withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (midluteal phase) and increases during their withdrawal (perimenstrual periods) in close association with GABA A receptor plasticity. A chronic seizure condition was created by using the hippocampus kindling model in female mice. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Elevated neurosteroid exposure reduced seizure expression in fully kindled mice. Fully kindled mice subjected to neurosteroid withdrawal showed increased generalized seizure frequency and intensity and enhanced seizure susceptibility. They also showed reduced benzodiazepine sensitivity and enhanced neurosteroid potency, similar to the clinical catamenial seizure phenotype. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the ␣4 and ␦ subunits of GABA A receptors in the hippocampus. These findings demonstrate that endogenous neurosteroids protect against seizure susceptibility and their withdrawal, such as that which occurs during menstruation, leads to exacerbation of seizure activity. This is possibly caused by specific changes in GABA A receptor-subunit plasticity and function, therefore providing a novel mouse model of human perimenstrual catamenial epilepsy that can be used for the investigation of disease mechanisms and new therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Reddy

Gould²,

Gangisetty³

2012

J Pharmacol Exp Ther

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“…Despite the metabolism by microsomal enzyme, the information available to date indicates that ganaxolone will have low drug-drug interactions. 4,24 Therefore, it could be administered easily with concomitant antiepileptic drugs. However, clinical trials having large sample size and with randomized, controlled and double blind study design are needed before its use in clinical practice.…”

Section: Neurosteroidsmentioning

confidence: 99%

Neuroactive steroids and their role in epilepsy

Patil

Jadhav

Doifode

et al. 2012

Int J Basic Clin Pharmacol

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“…Finally, there is substantial evidence that GABA-receptor agonists, such as the neurosteroid allopregnanolone and a related analog, ganaxolone, possess significant antiseizure activity (49,50). It would be valuable to have these agents subjected to clinical trials for fragile X syndrome and, in particular, for the associated seizures.…”

Section: Clinical Correlations and Prospects For Therapeutic Intervenmentioning

confidence: 99%

Origins of Epilepsy in Fragile X Syndrome

Hagerman

Stafstrom

2009

Epilepsy Curr

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Fragile X syndrome is the leading heritable form of cognitive impairment and the leading known monogenic disorder associated with autism. Roughly one-quarter of children with this disorder have seizures, most of which are relatively benign and are resolved beyond childhood. Because of the prevalence of fragile X syndrome, numerous animal models have been developed and electrophysiological studies have taken place to investigate its pathogenesis. The investigations have yielded a wealth of information regarding the synaptic dysfunction that underlies the hyperexcitability and epileptiform features associated with this disorder.Fragile X syndrome is the most common heritable form of cognitive impairment and the principal single-gene disorder associated with autism currently known (1,2). The disorder arises when a CGG-repeat tract in the 5 noncoding region of the fragile X mental retardation 1 (FMR1) gene exceeds approximately 200 repeats (i.e., the full mutation range), at which point the gene becomes hypermethylated and transcriptionally silent (3). The absence of the FMR1 protein, FMRP, is responsible for the syndrome's clinical phenotype (4-7). The frequency of full mutation alleles in the general population is approximately 1 in 2,500 (8,9). Physical features of fragile X syndrome typically include prominent ears, long face, higharched palate, macroorchidism, and hyperextensibility of finger joints. Approximately 85% of males and 25% of females experience cognitive impairment (IQ < 70); however, nearly all patients present with behavioral dysregulation, with males tending to present with attention deficit hyperactivity disorder and FMRP is an RNA-binding protein that is believed to have multiple functions, including involvement in the dendritic transport of various mRNA species (11) and the translational regulation of mRNAs whose protein products are involved in synaptic development, function, and plasticity (12). Among known targets of FMRP-coupled translational downregulation are: 1) the microtubule-associated protein 1B (MAP1B), which is important for modulating microtubule-coupled growth of dendritic spines and for dendritic arborization (13,14), and 2) Arc, which plays a role in the internalization of subunits of AMPA (15,16) and GABA A (17) receptors.One important characteristic of fragile X syndrome is the cooccurrence of seizures in 10 to 20 percent of individuals with full mutations (18,19). Seizure patterns on EEG typically reflect features of benign focal epilepsy of childhood (especially benign childhood epilepsy with centrotemporal spikes, also known as benign Rolandic epilepsy). In the study by Berry-Kravis involving 16 children with fragile X syndrome and epilepsy, 12 children exhibited partial seizures, with 10 of the 12 having an EEG with centrotemporal spikes (19). In addition, 23% of the children who did not have seizures displayed abnormal patterns on EEG, typically centrotemporal spikes. For most individuals, seizures are readily controlled and tend to disappear in adolescence. Therefore, ...

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Neurosteroid Replacement Therapy for Catamenial Epilepsy

Cited by 21 publications

References 60 publications

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Neuroactive steroids and their role in epilepsy

Origins of Epilepsy in Fragile X Syndrome

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