The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats
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...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-09-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/13/9/1482 |
| _version_ | 1797517600707575808 |
|---|---|
| author | Pavel Mareš Lucie Kozlová Anna Mikulecká Hana Kubová |
| author_facet | Pavel Mareš Lucie Kozlová Anna Mikulecká Hana Kubová |
| author_sort | Pavel Mareš |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T07:18:47Z |
| format | Article |
| id | doaj.art-e3f59e41c636488aa51e4a0706d95700 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T07:18:47Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-e3f59e41c636488aa51e4a0706d957002023-11-22T14:48:25ZengMDPI AGPharmaceutics1999-49232021-09-01139148210.3390/pharmaceutics13091482The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile RatsPavel Mareš0Lucie Kozlová1Anna Mikulecká2Hana Kubová3Department of Developmental Epileptology, Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech RepublicDepartment of Developmental Epileptology, Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech RepublicDepartment of Developmental Epileptology, Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech RepublicDepartment of Developmental Epileptology, Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech RepublicThe 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.https://www.mdpi.com/1999-4923/13/9/1482developmentGluN2B-selective antagonistRo 25-6981anti-seizure effectsmotor performancememory |
| spellingShingle | Pavel Mareš Lucie Kozlová Anna Mikulecká Hana Kubová The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats Pharmaceutics development GluN2B-selective antagonist Ro 25-6981 anti-seizure effects motor performance memory |
| title | The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats |
| title_full | The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats |
| title_fullStr | The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats |
| title_full_unstemmed | The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats |
| title_short | The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats |
| title_sort | glun2b selective antagonist ro 25 6981 is effective against ptz induced seizures and safe for further development in infantile rats |
| topic | development GluN2B-selective antagonist Ro 25-6981 anti-seizure effects motor performance memory |
| url | https://www.mdpi.com/1999-4923/13/9/1482 |
| work_keys_str_mv | AT pavelmares theglun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats AT luciekozlova theglun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats AT annamikulecka theglun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats AT hanakubova theglun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats AT pavelmares glun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats AT luciekozlova glun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats AT annamikulecka glun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats AT hanakubova glun2bselectiveantagonistro256981iseffectiveagainstptzinducedseizuresandsafeforfurtherdevelopmentininfantilerats |