Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage
Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage
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DOI：
10.1016/j.tox.2008.11.021
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发表时间：
2009-02-27
期刊：
影响因子：
4.5
通讯作者：
Auta, James
中科院分区：
文献类型：
--
作者：
Kadriu, Bashkim;Guidotti, Alessandro;Auta, James
有机磷（OP）神经毒剂中毒可导致长时间的癫痫样发作活动，从而导致不可逆的神经元脑损伤。及时和有效的控制癫痫发作的药物可以减少继发性和长期的神经病理，可能导致这种损害。安定是目前治疗OP中毒首选的抗惊厥药，但它与镇静、健忘症、心肺抑制、抗惊厥药耐受性和依赖性等不良反应有关。为了寻找一种有效且更安全的抗惊厥药物苯二氮卓类，我们研究了咪唑尼，这是一种有效的抗惊厥药物，没有镇静作用，在α - 1上具有较低的内在功效，但在α - 6-含GABA(a)受体上具有高效的正变构调节剂。我们比较了2 mg/kg阿托品与(a)咪唑尼0.05-0.5 mg/kg i.p.或(b)等效抗双库兰剂量地西泮（0.5- 5mg /kg, i.p.）抗氟磷酸二异丙基（DFP; 1.5 mg/kg, s.c）诱导的癫痫持续状态及其相关神经元损伤的效力。通过连续无线电遥测记录确定癫痫发作活动的严重程度和频率，同时分别使用基于tunel的裂解DNA末端标记技术或神经元特异性核蛋白（NeuN）免疫标记和氟玉B （FJB）染色评估神经元损伤和神经元变性的程度。我们在这里报道，阿托品和咪唑尼联合使用在保护大鼠免受ddp诱导的癫痫发作和相关的神经损伤或前扣带皮层、CA1海马和齿状回的持续变性方面，至少比与地西泮联合使用有效10倍，持续时间更长。虽然0.5 mg/kg咪唑尼能有效减轻dfp诱导的神经元损伤和前扣带皮层、齿状回和CA1海马的持续神经元变性，但5 mg/kg或更高剂量的地西泮才能产生类似的保护作用。这些发现表明咪唑尼是一种非镇静性抗惊厥药BZ配体，在保护大鼠免受ddp诱导的癫痫发作和相关的神经元损伤和/或持续的神经元变性方面，比地西泮更有效、更安全。2008爱思唯尔爱尔兰有限公司版权所有。
Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at alpha 1 - but is a high efficacy positive allosteric modulator at alpha 6-containing GABA(A) receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5 mg/kg or a higher dose of diazepam is required to produce similar protective effects. These finding suggests that imidazenil, a non-sedating anticonvulsant BZ ligand, is a more potent, effective, and safer drug than diazepam in protecting rats from DFP-induced seizures and the associated neuronal damage and/or ongoing neuronal degeneration. (C) 2008 Elsevier Ireland Ltd. All rights reserved.