Mareš Pavel, Kozlová Lucie, Mikulecká Anna, Kubová Hana
Department of Developmental Epileptology, Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech Republic.
Department of Rehabilitation and Sport Medicine, 2nd Medical Faculty, Charles University, 15006 Prague, Czech Republic.
Pharmaceutics. 2021 Sep 16;13(9):1482. doi: 10.3390/pharmaceutics13091482.
The GluN2B subunit of NMDA receptors represents a perspective therapeutic target in various CNS pathologies, including epilepsy. Because of its predominant expression in the immature brain, selective GluN2B antagonists are expected to be more effective early in postnatal development. The aim of this study was to identify age-dependent differences in the anticonvulsant activity of the GluN2B-selective antagonist Ro 25-6981 and assess the safety of this drug for the developing brain. Anticonvulsant activity of Ro 25-6981 (1, 3, and 10 mg/kg) was tested in a pentylenetetrazol (PTZ) model in infantile (12-day-old, P12) and juvenile (25-day-old, P25) rats. Ro 25-6981 (1 or 3 mg/kg/day) was administered from P7 till P11 to assess safety for the developing brain. Animals were then tested repeatedly in a battery of behavioral tests focusing on sensorimotor development, cognition, and emotionality till adulthood. Effects of early exposure to Ro 25-6981 on later seizure susceptibility were tested in the PTZ model. Ro 25-6981 was effective against PTZ-induced seizures in infantile rats, specifically suppressing the tonic phase of the generalized tonic-clonic seizures, but it failed in juveniles. Neither sensorimotor development nor cognitive abilities and emotionality were affected by early-life exposure to Ro 25-6981. Treatment cessation did not affect later seizure susceptibility. Our data are in line with the maturational gradient of the GluN2B-subunit of NMDA receptors and demonstrate developmental differences in the anti-seizure activity of the GluN2B-selective antagonist and its safety for the developing brain.
NMDA受体的GluN2B亚基是包括癫痫在内的各种中枢神经系统疾病的一个潜在治疗靶点。由于其在未成熟大脑中占主导地位的表达，选择性GluN2B拮抗剂预计在出生后早期发育阶段会更有效。本研究的目的是确定GluN2B选择性拮抗剂Ro 25-6981抗惊厥活性的年龄依赖性差异，并评估该药物对发育中大脑的安全性。在幼龄（12日龄，P12）和幼年（25日龄，P25）大鼠的戊四氮（PTZ）模型中测试了Ro 25-6981（1、3和10 mg/kg）的抗惊厥活性。从P7至P11给予Ro 25-6981（1或3 mg/kg/天）以评估其对发育中大脑的安全性。然后在一系列侧重于感觉运动发育、认知和情绪的行为测试中对动物进行反复测试直至成年。在PTZ模型中测试了早期接触Ro 25-6981对后期癫痫易感性的影响。Ro 25-6981对幼龄大鼠PTZ诱导的癫痫有效，特别是抑制了全身性强直阵挛性癫痫的强直期，但对幼年大鼠无效。早期接触Ro 25-6981对感觉运动发育、认知能力和情绪均无影响。停药不影响后期癫痫易感性。我们的数据与NMDA受体GluN2B亚基的成熟梯度一致，并证明了GluN2B选择性拮抗剂的抗癫痫活性及其对发育中大脑安全性的发育差异。
