Tolerance to the anticonvulsant activity of midazolam and allopregnanolone in a model of picrotoxin seizures

Czlonkowska, A; Krząścik, Paweł; Sienkiewicz-Jarosz, Halina; Siemiątkowski, Marek; Szyndler, Janusz; Maciejak, Piotr; Bidziński, Andrzej; Płaźnik, Adam

doi:10.1016/s0014-2999(01)01183-9

Cited by 31 publications

(26 citation statements)

References 18 publications

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“…Long-term exposure of cultured cortical neurons to allopregnanolone induces a significant decrease in the abundance of ␣2, ␣3, ␤2, and ␤3 subunit mRNAs (Yu et al, 1996). The modifications in the GABA A receptor gene expression induced by chronic exposure to allopregnanolone are consistent with the evidence that this steroid gives tolerance to its anticonvulsant activity (Czlonkowska et al, 2001). Given that chronic treatment of cerebellar granule cells with ganaxolone had no effect on the amounts of any of the ␣ or ␥ subunit mRNAs examined, such treatment would not be expected to affect GABA A receptor sensitivity to positive modulators or to lead to the development of tolerance.…”

Section: Discussionsupporting

confidence: 75%

“…This hypothesis, however, is rather improbable because progesterone by itself is not capable of modifying the GABA A gene expression (Follesa et al, 2000). Indeed, our results may explain the differences between these two steroids in the development of tolerance to their anticonvulsant activities (Reddy and Rogawski, 2000;Czlonkowska et al, 2001). …”

Section: Effects Of Ganaxolone On Gaba a Receptor Gene Expression 1017mentioning

confidence: 70%

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Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Mascia

Biggio

Mancuso

et al. 2002

J Pharmacol Exp Ther

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The effects of ganaxolone, a synthetic analog of the endogenous neuroactive steroid allopregnanolone, on the function and expression of GABA A receptors were determined. Electrophysiological recordings demonstrated that ganaxolone potentiated with a potency and efficacy similar to those of allopregnanolone the Cl Ϫ currents evoked by GABA at recombinant human GABA A receptors (comprising ␣1␤2␥2L or ␣2␤2␥2L subunit assemblies) expressed in Xenopus oocytes. Exposure of cultured rat cerebellar granule cells to 1 M ganaxolone for 5 days had no effect on the abundance of mRNAs encoding the ␣1, ␣2, ␣3, ␣4, ␣5, ␥2L, or ␥2S subunits of the GABA A receptor. Withdrawal of ganaxolone after such long-term treatment, however, induced an increase in the abundance of ␣2, ␣4, and ␣5 subunit mRNAs and a decrease in the amounts of ␣1, ␥2L, and ␥2S subunit mRNAs. These changes were maximal 3 to 6 h after drug withdrawal and were reversible, being no longer apparent after 24 h. These results suggest that long-term exposure of cerebellar granule cells to ganaxolone does not affect the sensitivity of the GABA A receptor to several positive modulators. Nevertheless, the reduction in the amounts of the ␣1 and ␥2 subunit mRNAs together with the increase in the abundance of the ␣4 subunit mRNA induced by abrupt discontinuation of long-term treatment with ganaxolone suggest that withdrawal of this drug might result in a reduced response to classic benzodiazepines.GABA A receptor is the main type of inhibitory receptor in the brain and is a member of the superfamily of ligand-gated ion channels that includes the strychnine-sensitive glycine receptor, the 5-hydroxytryptamine 3 subtype of the serotonin receptor, and the nicotinic acetylcholine receptor (Betz, 1990). The binding of GABA to GABA A receptors induces the opening of an intrinsic Cl Ϫ channel with consequent hyperpolarization of the cell. The subunit composition of the pentameric GABA A receptors determines their specific physiological and pharmacological properties (Rudolph et al., 2001). The GABA A receptor is a prominent target of certain neuroactive steroids, which act as potent endogenous allosteric (positive or negative) modulators of receptor activity (ParkChung et al., 1999). Such compounds are also thought to be of potential therapeutic benefit. Indeed, neuroactive steroids have been used as intravenous anesthetics and have been shown to exert anxiolytic, hypnotic, anticonvulsant, and antiepileptic effects in animals or humans (Gasior et al., 1999).Ganaxolone (3␣-hydroxy-3␤-methyl-5␣-pregnan-20-one) is a synthetic compound that is structurally related to the endogenous neurosteroid allopregnanolone (3␣-hydroxy-5␣-pregnan-20-one) (Gasior et al., 1999). Like its endogenous analog, ganaxolone is a potent anticonvulsive and antiepileptic agent; however, it is more stable than allopregnanolone as a result of its ␤-methyl group, which prevents its metabolism and oxidation of the 3␣-hydroxy moiety (Carter et al., 1997 (Carter et al., 1997). In addition, ganaxolone is mor...

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Section: Discussionsupporting

confidence: 75%

Section: Effects Of Ganaxolone On Gaba a Receptor Gene Expression 1017mentioning

confidence: 70%

Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Mascia

Biggio

Mancuso

et al. 2002

J Pharmacol Exp Ther

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“…However, this remains to be confirmed in further investigations. To our knowledge, the present study is the first one to report acute pharmacodynamic tolerance development for alphaxalone, although for chronic treatment (more than 1-day administration), tolerance has been reported for minaxolone (Marshall et al, 1997) and allopregnanolone (Czlonkowska et al, 2001).…”

Section: Discussionmentioning

confidence: 70%

“…Furthermore, synergy has been detected between pregnanolone and flurazepam in an EEG threshold model (Norberg et al, 1999). On the other hand, upon chronic treatment, neuroactive steroids have been shown to reduce the anticonvulsant activity of benzodiazepines (Czlonkowska et al, 2001).…”

mentioning

confidence: 99%

“…Furthermore, understanding of this interaction may provide information on the role of potent endogenous neuroactive steroids, which are derived from progesterone and deoxycorticosterone and might influence the effects of benzodiazepines (Majewska, 1992). Finally, it could be important for the optimization of the eventual treatment of e.g., epilepsy, anxiety, and sleep disorders with combinations of GABA A receptor modulators (Gasior et al, 1999;Czlonkowska et al, 2001).…”

mentioning

confidence: 99%

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Mechanism-Based Modeling of the Pharmacodynamic Interaction of Alphaxalone and Midazolam in Rats

Visser¹,

Huntjens²,

Graaf³

et al. 2003

J Pharmacol Exp Ther

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The objective of the present investigation was to characterize the pharmacodynamic interaction between the synthetic neuroactive steroid alphaxalone and the benzodiazepine midazolam. The time course of the electroencephalographic (EEG) effect (11.5-30 Hz) was determined in rats in conjunction with plasma concentrations. Alphaxalone was administered as a continuous intravenous infusion of 0, 1.2, 2.2, or 5.2 mg over 360 min. Midazolam was administered as a 5-min intravenous bolus infusion of 4 mg⅐kg Ϫ1 . The pharmacokinetic profiles of both drugs were described by a two-compartment model. No pharmacokinetic interaction was observed. The EEG effect versus time profiles of midazolam and alphaxalone, when administered separately and in combination, were modeled on the basis of the recently proposed mechanism-based pharmacokinetic/pharmacodynamic model for GABA A receptor modulators, which contains separate expressions to describe the drug-receptor interaction and the stimulus-response relationship. The pharmacodynamic interaction between alphaxalone and midazolam was best characterized using an independent drug-drug interaction model without an expression for allosteric modulation of the effect of midazolam by alphaxalone. The final model contained an exponential expression to account for acute functional adaptation to the EEG effect upon continuous infusion of alphaxalone. The mechanism-based analysis showed that this functional adaptation is best explained by a change in the system-specific stimulus-response relationship, rather than the drug-receptor activation process. It is concluded that the pharmacodynamic interaction between alphaxalone and midazolam in vivo is best described using an independent interaction model without allosteric modulation.Recently, a mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for the electroencephalographic (EEG) effects of a wide array of GABA A receptor modulators, including neuroactive steroids, benzodiazepines, imidazopyridines, cyclopyrrolones, and ␤-carbolines (Visser et al., 2002a(Visser et al., ,b, 2003a. A unique feature of this model is that it contains separate expressions for the characterization of 1) the receptor activation process and 2) the signal-transduction process. In this specific model, the receptor activation process is described by a hyperbolic function, whereas the biphasic transducer function is described by a parabolic equation (Fig. 1). It has been shown that a single unique transducer function can describe the effects of the different GABA A modulators. In this paradigm, neuroactive steroids and benzodiazepines differ in their ability to activate the receptor. It has also been shown that the model can account for the additive effects upon activation of two distinct GABA A receptor subtypes by zolpidem in vivo (Visser et al., 2003b).The objective of the present investigation was to determine whether the mechanism-based PK/PD model could be used to characterize the effect of neuroactive steroids and benzodiazepines whe...

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Neurosteroid Perturbation and Neuropsychiatric Symptoms in Schizophrenia: From the Mechanisms to the Treatment

Michele

Caltagirone

Spalletta

2008

Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders

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Tolerance to the anticonvulsant activity of midazolam and allopregnanolone in a model of picrotoxin seizures

Cited by 31 publications

References 18 publications

Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Mechanism-Based Modeling of the Pharmacodynamic Interaction of Alphaxalone and Midazolam in Rats

Neurosteroid Perturbation and Neuropsychiatric Symptoms in Schizophrenia: From the Mechanisms to the Treatment

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Tolerance to the anticonvulsant activity of midazolam and allopregnanolone in a model of picrotoxin seizures

Cited by 31 publications

References 18 publications

Changes in GABAA Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Changes in GABAA Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Mechanism-Based Modeling of the Pharmacodynamic Interaction of Alphaxalone and Midazolam in Rats

Neurosteroid Perturbation and Neuropsychiatric Symptoms in Schizophrenia: From the Mechanisms to the Treatment

Contact Info

Product

Resources

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Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells

Changes in GABA_A Receptor Gene Expression Induced by Withdrawal of, but Not by Long-Term Exposure to, Ganaxolone in Cultured Rat Cerebellar Granule Cells