11-Deoxycortisol impedes GABAergic neurotransmission and induces drug-resistant status epilepticus in mice

Kaminski, Rafal M. and Fu, Zhanyan and Venkatesan, Kumar and Mazzuferi, Manuela and Leclercq, Karine and Seutin, Vincent and Vicini, Stefano (2011) 11-Deoxycortisol impedes GABAergic neurotransmission and induces drug-resistant status epilepticus in mice. Neuropharmacology, 60 (8). pp. 1098-1108. ISSN 00283908

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Official URL: http://dx.doi.org/10.1016/j.neuropharm.2010.09.021

Abstract

Systemic injection of high doses of 11-deoxycortisol succinate had been reported to induce status epilepticus in rats and cats that was associated with paroxysmal epileptiform activity refractory to first generation antiepileptic drugs (AEDs). Using patch clamp recordings we have investigated the mechanisms of 11-deoxycortisol-induced excitability and we have discovered that this molecule accelerates the decay time of the inhibitory postsynaptic currents (IPSCs) mediated by GABAA receptors, both in neuronal cultures and in hippocampal slices. In addition, it reduces the amplitude and frequency of IPSCs. Thus, 11-deoxycortisol action on GABAergic neurotransmission may be one of the underlying causes of convulsive seizures that had been observed in rats. In the present study, we have reproduced the ability of 11-deoxycortisol to induce convulsive seizures after intravenous infusion in mice. The threshold dose of 11-deoxycortisol necessary for seizure induction was also determined (0.95 mmol/kg). Furthermore, we have established that these seizures are completely refractory to several AEDs such as phenytoin (up to 100 mg/kg), carbamazepine (up to 56 mg/kg), and valproate (up to 300 mg/kg). Levetiracetam and diazepam afforded only limited protection at high doses, 540 and 3e10 mg/kg, respectively. Interestingly, long-lasting seizures induced by 11-deoxycortisol in mice were not associated with typical neuropathological changes observed in other models of status epilepticus. We propose that 11-deoxycortisolinduced seizures may be an advantageous experimental model of drug-resistant epilepsy. Finally, better understanding of the pro-epileptic properties of 11-deoxycortisol is very important, because this endogenous steroid precursor may play a role in the pathophysiology of epilepsy. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’

Item Type: Article
Subjects: Pharmaceutical Sciences
Divisions: College of Pharmacy > Pharmaceutical Sciences
Depositing User: Dr KUMAR Venkatesan
Date Deposited: 04 Jun 2017 11:04
Last Modified: 04 Jun 2017 11:04
URI: http://eprints.kku.edu.sa/id/eprint/772

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