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The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats
Pharmaceutics ( IF 5.4 ) Pub Date : 2021-09-16 , DOI: 10.3390/pharmaceutics13091482
Pavel Mareš 1, 2 , Lucie Kozlová 1, 2 , Anna Mikulecká 1 , Hana Kubová 1
Affiliation  

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.

中文翻译:

GluN2B 选择性拮抗剂 Ro 25-6981 可有效对抗 PTZ 诱发的癫痫发作,并且可安全用于幼鼠的进一步发育

NMDA 受体的 GluN2B 亚基代表了包括癫痫在内的各种中枢神经系统疾病的潜在治疗靶点。由于其在未成熟大脑中的主要表达,预计选择性 GluN2B 拮抗剂在出生后发育早期更有效。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。Ro 25-6981(1、3 和 10 mg/kg)的抗惊厥活性在戊四唑 (PTZ) 模型中对婴儿(12 天大,P12)和幼年(25 天大,P25)大鼠进行测试. Ro 25-6981(1 或 3 mg/kg/天)从 P7 到 P11 给药,以评估发育中大脑的安全性。然后在一系列行为测试中对动物进行反复测试,重点关注感觉运动发育、认知和情绪,直到成年。在 PTZ 模型中测试了早期接触 Ro 25-6981 对后期癫痫发作易感性的影响。Ro 25-6981 对 PTZ 诱发的幼年大鼠癫痫发作有效,特别是抑制全身强直-阵挛癫痫发作的强直阶段,但在幼年大鼠中无效。早期接触 Ro 25-6981 既不影响感觉运动发育,也不影响认知能力和情绪。停止治疗不影响后来的癫痫易感性。
更新日期:2021-09-16
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