The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats

Abstract

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.

Targeting NMDA Receptor Complex in Management of Epilepsy

“…Recently, the use of GNE-0723 (a positive allosteric modulator of GluN2A-subunit-containing NMDARs) reduced low-frequency oscillatory and epileptiform activities in J20 mice [ 204 ]. The GluN2B-selective antagonist Ro 25-6981 suppressed the tonic phase of generalized tonic–clonic seizures in a PTZ model of infantile rats [ 205 ].…”

The outcome of early life status epilepticus—lessons from laboratory animals

“…The context of learning and retention is present at age 21–24 days. 45 , 112 , 131 The light/dark box (anxiety in a highly illuminated situation) is a conflict test similar to the EPM and is based on the tendency of animals to explore a novel environment versus the aversive properties of a brightly illuminated area. The percentage of the time spent in the illuminated area is used as an anxiety index.…”

“…The rotarod test is used to assess somatosensory, proprioceptive, and vestibular abilities, motor coordination, equilibrium function, and fatigue resistance. The ladder rung walking test is used to test sensorimotor function as proprioception (number of slips in one trial with regular gaps and another with irregular gaps), motor coordination, and balance 112,113 The measurement of cognitive performance in rats incorporates modulatory functions, such as sensory, attentional, motivational, emotional, and motor processes 114 . Immature animals generally show an excellent learning capacity in conventional or modified tests that consider the ethological characteristics of the animals and their sensorimotor abilities at a particular developmental stage 85,115 .…”

“…Rat pups aged 17–18 days can acquire and express context–shock association after short but not long retention intervals. The context of learning and retention is present at age 21–24 days 45,112,131 . The light/dark box (anxiety in a highly illuminated situation) is a conflict test similar to the EPM and is based on the tendency of animals to explore a novel environment versus the aversive properties of a brightly illuminated area.…”

NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease

“…In the hippocampus both a decrease in GluN2A expression [ 58 ] and upregulation of GluN2B [ 59 ] have been implicated in contributing to seizure pathogenesis. In addition, selective blockade of GluN2B has been shown to reduce seizure susceptibility [ 60 , 61 ] and dextromethorphan induced convulsive behaviours [ 62 ]. However, it remains unclear whether the beneficial effect of modifying the relative activity of GluN2A/2B is solely the result of restoring homeostatic balance or whether subunit specific signalling pathways are also involved.…”