Chapter 7 7 Neurosteroids-Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy

Neurosteroids such as allopregnanolone are positive allosteric modulators of γ‐aminobutyric acid (GABA)A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids may be endogenous regulators of seizure susceptibility, for example, in catamenial epilepsy. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of refractory partial seizures and infantile spasms have been encouraging. Neurosteroids and analogs such as ganaxolone show promise in the treatment of diverse forms of epilepsy. For an expanded treatment of this topic see Jasper’s basic mechanisms of the epilepsies. 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado‐Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).

[1]  H. E. Edwards Epileptic Seizures: Do They Cause Reproductive Dysfunction? , 2000 .

[2]  F. Holsboer,et al.  Progesterone receptor-mediated effects of neuroactive steroids , 1993, Neuron.

[3]  M. Motta,et al.  The 5alpha-reductase in the central nervous system: expression and modes of control. , 1998, The Journal of steroid biochemistry and molecular biology.

[4]  G. Biggio,et al.  Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress. , 1996, Neuroendocrinology.

[5]  I. Módy,et al.  Activation of GABAA Receptors: Views from Outside the Synaptic Cleft , 2007, Neuron.

[6]  O. Snead Ganaxolone, a selective, high‐affinity steroid modulator of the γ‐aminobutyric acid‐A receptor, exacerbates seizures in animal models of absence , 1998, Annals of neurology.

[7]  K. Grant,et al.  Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior , 2006, Dialogues in clinical neuroscience.

[8]  Alastair M. Hosie,et al.  Neurosteroid binding sites on GABA(A) receptors. , 2007, Pharmacology & therapeutics.

[9]  T. Tomson,et al.  Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII) , 2015, Epilepsy Research.

[10]  M. Rogawski,et al.  Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model , 2010, Epilepsy Research.

[11]  M. Avoli,et al.  Jasper's basic mechanisms of the epilepsies , 2012 .

[12]  S. Imaoka,et al.  Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brain. , 2004, Endocrinology.

[13]  A. Herzog Altered reproductive endocrine regulation in men with epilepsy: Implications for reproductive function and seizures , 2002, Annals of neurology.

[14]  R. Citraro,et al.  Effects of some neurosteroids injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy , 2006, Neuropharmacology.

[15]  David E Reichert,et al.  Mutations of the GABA-A Receptor α1 Subunit M1 Domain Reveal Unexpected Complexity for Modulation by Neuroactive Steroids , 2008, Molecular Pharmacology.

[16]  R. B. Carter,et al.  Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice. , 2003, European journal of pharmacology.

[17]  K. Furukawa,et al.  Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice , 2008, Pharmacology Biochemistry and Behavior.

[18]  M. Hill,et al.  Neuroactive pregnanolone isomers during pregnancy. , 2005, The Journal of clinical endocrinology and metabolism.

[19]  Doodipala Samba Reddy,et al.  Pharmacology of endogenous neuroactive steroids. , 2003, Critical reviews in neurobiology.

[20]  J. Schramm,et al.  Serum androgens return to normal after temporal lobe epilepsy surgery in men , 2000, Neurology.

[21]  S. Paul,et al.  Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. , 1986, Science.

[22]  L. Stein,et al.  Comparative behavioral characterization of the neuroactive steroids 3α-OH,5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents , 1995, Psychopharmacology.

[23]  D. Reddy Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3α-androstanediol and 17β-estradiol , 2004, Neuroscience.

[24]  K. Laxer,et al.  Assessment of Ganaxolone's Anticonvulsant Activity Using a Randomized, Double‐Blind, Presurgical Trial Design , 2000, Epilepsia.

[25]  D. Peričić,et al.  Anticonvulsive Effect of Swim Stress in Mice , 2000, Pharmacology Biochemistry and Behavior.

[26]  Gerhard Rammes,et al.  Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders , 2010, Nature Reviews Drug Discovery.

[27]  M. Brunet,et al.  Effects of long-term antiepileptic therapy on the catabolism of testosterone. , 1995, Pharmacology & toxicology.

[28]  M. Bolger,et al.  Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one , 1989 .

[29]  N. Geschwind,et al.  Reproductive endocrine disorders in men with partial seizures of temporal lobe origin. , 1986, Archives of neurology.

[30]  J. Data,et al.  Ganaxolone: a novel positive allosteric modulator of the GABA(A) receptor complex for the treatment of epilepsy. , 1999, Expert opinion on investigational drugs.

[31]  Chengsan Sun,et al.  Endogenous neurosteroid synthesis modulates seizure frequency , 2010, Annals of neurology.