Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA.
Bioanalysis and Pharmacokinetics Core Facility, UC Davis Medical Center, Sacramento, CA, 95817, USA.
Neurotherapeutics. 2021 Jan;18(1):544-555. doi: 10.1007/s13311-020-00985-5. Epub 2021 Jan 6.
Allopregnanolone, a positive modulator of GABA 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 (ED, 5.6 mg/kg), picrotoxin (ED, 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 of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (C, 16,000 ng/mg) whereas much lower levels (C, 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.
别孕烯醇酮是一种 GABA 受体的正变构调节剂，具有抗癫痫活性，有望用于治疗癫痫急症。在小鼠中，将别孕烯醇酮以 40%磺丁基醚-β-环糊精溶液滴鼻给药，可迅速提高戊四氮（ED，5.6mg/kg）、苦毒蕈碱（ED，5.9mg/kg）和印防己毒素诱发的癫痫发作阈值。作用峰值出现在 15 分钟，1 小时后衰减，在一些实验中 6 小时仍有明显效果。鼻内给予别孕烯醇酮也可延迟最大戊四氮试验中癫痫发作的发生。在一个别孕烯醇酮剂量（16mg/kg）下，其对癫痫发作阈值的影响与苯二氮䓬类药物咪达唑仑和地西泮（均为 1mg/kg）相当，但在水平屏幕测试中，别孕烯醇酮引起的镇静或运动毒性最小，而这两种苯二氮䓬类药物均引起明显的行为障碍。此外，鼻内给予别孕烯醇酮在大多数动物中均未引起翻正反射丧失，但当给予相同剂量的肌肉内注射时，所有动物均出现受损。鼻内给予别孕烯醇酮（10mg/kg）后，可迅速增加脑内别孕烯醇酮水平，在开始鼻内给药后约 5 分钟达到 T。在嗅球（C，16000ng/mg）中回收高浓度的别孕烯醇酮，而在大脑的其余部分（C，670ng/mg）中回收的浓度较低。我们的结论是，鼻内给予别孕烯醇酮具有独特的抗癫痫作用而不引起行为不良反应，部分原因是其具有直接从鼻到脑的传递作用，并且优先向与癫痫相关的脑区传递。苯二氮䓬类药物通常经鼻内给药用于急性癫痫治疗，包括治疗急性反复性癫痫发作，但不能从鼻内递送到脑内。鼻内给予别孕烯醇酮作用更快，不良反应倾向更小，并有克服苯二氮䓬类药物耐药性的能力。这是第一项证明经鼻内给予的类固醇可快速发挥中枢神经系统功能的研究。鼻内给药可绕过别孕烯醇酮口服生物利用度差的问题，提供一种给药途径，使其可作为治疗多种神经精神疾病的候选药物。
