11-Deoxycortisol impedes GABAergic neurotransmission and induces drug-resistant status epilepticus in mice.
11-Deoxycortisol impedes GABAergic neurotransmission and induces drug-resistant status epilepticus in mice.
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DOI：
10.1016/j.neuropharm.2010.09.021
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发表时间：
2011-06
影响因子：
4.7
通讯作者：
Vicini, Stefano
中科院分区：
文献类型：
--
作者：
Kaminski, Rafal M.;Fu, Zhanyan;Venkatesan, Kumar;Mazzuferi, Manuela;Leclercq, Karine;Seutin, Vincent;Vicini, Stefano
据报道，全身注射高剂量琥珀酸11-脱氧皮质醇可诱导大鼠和猫癫痫持续状态，与第一代抗癫痫药物（AED）难治的阵发性癫痫样活动相关。使用膜片钳记录，我们已经调查了11-脱氧皮质醇诱导的兴奋性的机制，我们已经发现，这种分子加速衰减时间的抑制性突触后电流（IPSC）介导的GABAA受体，无论是在神经元培养物和海马切片。此外，它降低了IPSC的幅度和频率。因此，11-脱氧皮质醇对GABA能神经传递的作用可能是在大鼠中观察到的惊厥发作的根本原因之一。在本研究中，我们复制了11-脱氧皮质醇静脉输注后诱导小鼠惊厥发作的能力。还确定了癫痫发作诱导所需的11-脱氧皮质醇的阈值剂量（0.95 mmol/kg）。此外，我们已经确定这些癫痫发作对几种AED完全难治，如苯妥英（高达100 mg/kg）、卡马西平（高达56 mg/kg）和丙戊酸盐（高达300 mg/kg）。左乙拉西坦和地西泮分别在540和3-10 mg/kg的高剂量下仅提供有限的保护。有趣的是，11-脱氧皮质醇在小鼠中诱导的持久癫痫发作与在其他癫痫持续状态模型中观察到的典型神经病理学变化无关。我们建议，11-脱氧皮质醇诱导的癫痫发作可能是一个有利的耐药癫痫的实验模型。最后，更好地了解11-脱氧皮质醇的促癫痫性质是非常重要的，因为这种内源性类固醇前体可能在癫痫的病理生理学中发挥作用。
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 3–10 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-deoxycortisol-induced 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.
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影响因子：
2.5
作者：
Ortinski, PI;Lu, CY;Vicini, S
通讯作者：
Vicini, S
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影响因子：
5.5
作者：
Haage, D;Karlsson, U;Johansson, S
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作者：
MAJEWSKA, MD;HARRISON, NL;PAUL, SM
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影响因子：
2.5
作者：
MURASE, K;RYU, PD;RANDIC, M
通讯作者：
RANDIC, M
影响因子：
3.2
作者：
FIAD, TM;KIRBY, JM;MCKENNA, TJ
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MCKENNA, TJ