Allopregnanolone, a positive modulator of GABA_A receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED₅₀, 5.6 mg/kg), picrotoxin (ED₅₀, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a T_max of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (C_max, 16,000 ng/mg) whereas much lower levels (C_max, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

Allopregnanolone 是_一种具有抗癫痫活性的 GABA _A受体的正调节剂，具有治疗癫痫紧急情况的潜力。将 40% 磺基丁基醚-β-环糊精中的别孕酮滴注到小鼠鼻子中，可迅速提高定时静脉注射戊四唑 (ED ₅₀ , 5.6 mg/kg)、苦味毒素 (ED ₅₀ )的癫痫发作阈值, 5.9 mg/kg) 和荷包牡丹碱癫痫试验。效果在 15 分钟达到峰值，在 1 小时内衰减，并且在一些实验中在 6 小时时仍然很明显。在最大 PTZ 测试中，鼻内使用别孕酮也延迟了癫痫发作的发生。在给予与苯二氮卓类咪达唑仑和地西泮（剂量均为 1 毫克/公斤）相当的癫痫阈值效果的别孕烯醇酮剂量（16 毫克/千克）下，在水平筛选试验中，别孕酮引起的镇静或运动毒性最小，而两种苯二氮卓类药物均产生明显的行为障碍。此外，鼻内使用 allopregnanolone 未能在大多数动物中引起翻正反射丧失，但当肌肉注射相同剂量时，所有动物都会受损。鼻内别孕酮 (10 mg/kg) 导致脑内别孕酮迅速增加鼻内给药开始后约 5 分钟的T_最大值。在嗅球中回收到高水平的别孕烯醇酮 ( C _max , 16,000 ng/mg) 而低得多的水平 ( C _{max )}, 670 ng/mg) 存在于大脑的其余部分。我们得出结论，鼻内别孕酮在不引起行为不良影响的情况下防止癫痫发作的独特能力部分是由于直接从鼻子到大脑的传递，优先运输到与癫痫发作相关的大脑区域。苯二氮卓类药物通常通过鼻内给药用于急性癫痫发作治疗，包括用于治疗急性重复性癫痫发作，但不会从鼻子到大脑。鼻内使用别孕酮的作用更快，不良反应的倾向更小，并且能够克服苯二氮卓类药物的难治性。这是第一项证明鼻-脑输送类固醇具有快速功能性中枢神经系统活性的研究。