A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2012 Mar 22

PMID 22434675

Citations 30

Authors

Doodipala Samba Reddy

Jordan Gould

O Gangisetty

Affiliations

Soon will be listed here.

Abstract

Catamenial epilepsy is caused by fluctuations in progesterone-derived 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 α4 and δ 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.

Citing Articles

Kindling Models of Epileptogenesis for Developing Disease-Modifying Drugs for Epilepsy.

Reddy D, Vadassery A, Ramakrishnan S, Singh T, Clossen B, Wu X Curr Protoc. 2024; 4(10):e70020.

PMID: 39436626 PMC: 11498896. DOI: 10.1002/cpz1.70020.

Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.

Reddy D, Singh T, Ramakrishnan S, Huber M, Wu X J Pharmacol Exp Ther. 2023; 388(2):399-415.

PMID: 38071567 PMC: 10801736. DOI: 10.1124/jpet.123.001819.

Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic.

Reddy D J Pharmacol Exp Ther. 2023; 388(2):273-300.

PMID: 37977814 PMC: 10801762. DOI: 10.1124/jpet.123.001816.

Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.

Reddy D, Mbilinyi R, Estes E Psychopharmacology (Berl). 2023; 240(9):1841-1863.

PMID: 37566239 PMC: 10471722. DOI: 10.1007/s00213-023-06427-2.

Towards understanding the biology of premenstrual dysphoric disorder: From genes to GABA.

Hantsoo L, Payne J Neurosci Biobehav Rev. 2023; 149:105168.

PMID: 37059403 PMC: 10176022. DOI: 10.1016/j.neubiorev.2023.105168.

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