Endogenous neurosteroid synthesis modulates seizure frequency

Lawrence, Courtney; Martin, Brandon S.; Sun, Chengsan; Williamson, John

doi:10.1002/ana.21989

Cited by 58 publications

(69 citation statements)

References 17 publications

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“…Withdrawal of neurosteroids had led to decreased seizure threshold and increased seizure activity ). This paradigm was also verified in female epileptic rats with spontaneous seizures (Reddy and Zeng, 2007;Lawrence et al, 2010). Although rat models are useful for investigating therapies for catamenial epilepsy , there is currently no mouse model that recapitulates neuroendocrine and clinical features of catamenial epilepsy for use in molecular and genetic investigations.…”

Section: Introductionmentioning

confidence: 89%

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: Introductionmentioning

confidence: 89%

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Reddy

Gould²,

Gangisetty³

2012

J Pharmacol Exp Ther

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“…On the other hand, the treatment with FIN may induce alternative metabolic pathways in the progesterone metabolism, such as 3␣ reduction, 20␣ reduction, and 21 hydroxylation. These effects of FIN on neurosteroid metabolism were found to modulate the emotional state (43), exacerbate lithium-and pilocarpine-induced seizures (34), in-crease formalin-induced pain in rats (42), and alter the ethanol intake pattern in C57BL/6J mice (20). In addition, 5␣-reductase inhibitors exert antipsychotic-like properties in rats and are proposed as a putative novel target in the management of psychotic disorders (11,47).…”

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confidence: 99%

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Mladenović

Hrnčić

Petronijević

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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(HE). This study evaluated the effects of finasteride, inhibitor of neurosteroid synthesis, on motor, EEG, and cellular changes in rat brain in thioacetamide-induced HE. Male Wistar rats were divided into the following groups: 1) control; 2) thioacetamide-treated group, TAA (300 mg·kg Ϫ1 ·day Ϫ1 ); 3) finasteride-treated group, FIN (50 mg·kg Ϫ1 ·day Ϫ1 ); and 4) group treated with FIN and TAA (FIN ϩ TAA). Daily doses of TAA and FIN were administered in three subsequent days intraperitoneally, and in the FIN ϩ TAA group FIN was administered 2 h before every dose of TAA. Motor and reflex activity was determined at 0, 2, 4, 6, and 24 h, whereas EEG activity was registered about 24 h after treatment. The expressions of neuronal (NeuN), astrocytic [glial fibrilary acidic protein (GFAP)], microglial (Iba1), and oligodendrocyte (myelin oligodendrocyte glycoprotein) marker were determined 24 h after treatment. While TAA decreased all tests, FIN pretreatment (FIN ϩ TAA) significantly improved equilibrium, placement test, auditory startle, head shake reflex, motor activity, and exploratory behavior vs. the TAA group. Vital reflexes (withdrawal, grasping, righting and corneal reflex) together with mean EEG voltage were significantly higher (P Ͻ 0.01) in the FIN ϩ TAA vs. the TAA group. Hippocampal NeuN expression was significantly lower in TAA vs. control (P Ͻ 0.05). Cortical Iba1 expression was significantly higher in experimental groups vs. control (P Ͻ 0.05), whereas hippocampal GFAP expression was increased in TAA and decreased in the FIN ϩ TAA group vs. control (P Ͻ 0.05). Finasteride improves motor and EEG changes in TAA-induced HE and completely prevents the development of hepatic coma. motor tests; electroencephalography; cellular markers HEPATIC ENCEPHALOPATHY (HE) represents a clinical syndrome characterized by neurological and psychiatric disturbances that develop as a result of acute or chronic liver failure (21). Various mechanisms are involved in the pathogenesis of HE, including changes in neurotransmission (17), oxidative stress, bioenergetic failure, mitochondrial permeability transition (49), inflammatory response, and immune dysfunction (14, 52), due to accumulation of various toxins in the organism, principally ammonia (4).Changes in glutamatergic and GABAergic transmission have an important role in the development of HE (13, 16). Both acute and chronic liver failure were found to be associated with increased GABAergic activity due to increased neurosteroid synthesis. Neurosteroids are steroid compounds, synthesized in mitochondria of glial cells and neurons from cholestrol (2). Cholesterol is taken up into mitochondria via the activation of translocator protein (TSPO), a multimeric complex that spans both outer and inner mitochondrial membrane. Ammonia and manganese, toxins accumulated in HE, and proinflammatory cytokines upregulate components of TSPO and increase cholesterol uptake into the mitochondrion (2, 4). Cholesterol serves as a substrate for increased synthesis of neurosteroids, including all...

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“…In addition, allopregnanolone protects against seizures induced by GABA A receptor antagonists as pentylenetetrazol [23][24][25], bicuculline and picrotoxin [26], and is also effective against pilocarpine and kainate [27], as well as against amygdala kindling seizures [28] and stimulationinduced discharges (but not motor alterations) in immature rats [29]. Blockade of endogenous neurosteroid synthesis exacerbated the frequency of seizures induced by pilocarpine, and allopregnanolone protected against this effect [30], but in a genetic model of absence epilepsy the effect of the neurosteroid increased or decreased spike discharges depending on the site of focal injection [31]. These data, in addition to our previous results in vitro, showing that allopregnanolone protected against the 4-AP-induced epileptiform discharges in hippocampal slices [15], made us expect that it should be a protector against the excitotoxic action of 4-AP in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Allopregnanolone Potentiates the Glutamate-Mediated Seizures Induced by 4-Aminopyridine in Rat Hippocampus in vivo

Salazar

Tapia

2011

Neurochem Res

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Excitatory and inhibitory neurotransmission in the central nervous system can be modulated by neurosteroids. We previously found that in rat hippocampal slices allopregnanolone (3α-hydroxy-5α-pregnan-20-one), a positive GABA(A) receptor modulator, suppresses the epileptic discharges induced by 4-aminopyridine (4-AP), a convulsant K(+) channel blocker that stimulates glutamate release. Here, we tested the action of allopregnanolone on the epileptogenic and excitotoxic effects of the intrahippocampal administration of 4-AP in vivo. Drugs were perfused by a microdialysis cannula-electrode in the dorsal hippocampus and the EEG was recorded. Extracellular levels of aspartate, glutamate and GABA were analyzed by HPLC in the microdialysis fractions, and 24 h after the experiment the hippocampus was studied histologically. 4-AP induced intense epileptic discharges, increased the extracellular levels of aspartate, glutamate, and GABA by 383, 420, and 245%, respectively, and produced a notable neurodegeneration in CA1 and CA3 areas. Allopregnanolone administration alone did not affect the electrical activity, amino acids levels or cellular morphology, but when co-infused with 4-AP incremented 55-77% the duration of the epileptic discharges, and potentiated 32-49% the release of glutamate in comparison with 4-AP alone. The 4-AP-induced neurodegeneration was not modified by allopregnanolone. The NMDA receptor antagonist MK-801 protected against the epilepsy and neurodegeneration produced by 4-AP, and allopregnanolone did not affect this protection. We conclude that, differently from the observations in vitro, allopregnanolone potentiated the stimulatory effect of 4-AP on glutamate release and that this may explain the potentiation of the epileptogenic effect of 4-AP in vivo.

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Endogenous neurosteroid synthesis modulates seizure frequency

Cited by 58 publications

References 17 publications

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Allopregnanolone Potentiates the Glutamate-Mediated Seizures Induced by 4-Aminopyridine in Rat Hippocampus in vivo

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