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 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.

Download Full-text

Targeted Blockade of TARP-γ8-Associated AMPA Receptors: Anticonvulsant Activity with the Selective Antagonist LY3130481 (CERC-611)

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527316666171101132047 ◽

2018 ◽

Vol 16 (10) ◽

pp. 1099-1110 ◽

Cited By ~ 4

Author(s):

Jeffrey M. Witkin ◽

Douglas A. Schober ◽

Scott D. Gleason ◽

John T. Catlow ◽

Warren J. Porter ◽

...

Keyword(s):

Ampa Receptors ◽

Anticonvulsant Activity ◽

Selective Antagonist

Download Full-text

Functional change of NMDA receptors related to enhancement of susceptibility in developing brain

Neuroscience Research ◽

10.1016/s0168-0102(98)82507-8 ◽

1998 ◽

Vol 31 ◽

pp. S342

Author(s):

Akira Mitani ◽

Masahiko Watanabe ◽

Kiyoshi Kataoka

Keyword(s):

Nmda Receptors ◽

Functional Change ◽

Developing Brain

Download Full-text

Developmental Differences in Seizure Susceptibility and Hippocampal Vulnerability: Molecular Correlates

Status Epilepticus ◽

10.7551/mitpress/6456.003.0031 ◽

2006 ◽

Keyword(s):

Developmental Differences ◽

Seizure Susceptibility

Download Full-text

Seizure susceptibility and anticonvulsant activity of carbamazepine, diphenylhydantoin and phenobarbital in rats with selective depletions of brain monoamines

Neuropharmacology ◽

10.1016/0028-3908(78)90161-2 ◽

1978 ◽

Vol 17 (8) ◽

pp. 643-647 ◽

Cited By ~ 49

Author(s):

A. Quattrone ◽

V. Crunelli ◽

R. Samanin

Keyword(s):

Anticonvulsant Activity ◽

Seizure Susceptibility ◽

Brain Monoamines

Download Full-text

Music and brain plasticity

European Review ◽

10.1017/s1062798706000056 ◽

2006 ◽

Vol 14 (1) ◽

pp. 49-64 ◽

Cited By ~ 11

Author(s):

BARBRO B. JOHANSSON

Keyword(s):

Cognitive Abilities ◽

Brain Plasticity ◽

Musical Training ◽

Musical Instrument ◽

Developing Brain ◽

Previous Exposure ◽

Emotional Involvement ◽

Brain Areas ◽

And Training ◽

Little Finger

Complex and widespread activation in many brain areas is seen while performing, listening or mentally imaging music, activity that varies with training, previous exposure, personal preference, emotional involvement and many other factors. Playing a musical instrument demands extensive motor and cognitive abilities, and early musical learning results in plastic reorganization of the developing brain – one example being the increased cortical representation area for the left little finger in (right-handed) string-players, which correlates with age at the start of training. Even though the developing brain has the most pronounced changes, the adult healthy brain has a considerable plasticity. Conductors have superior spatial tuning compared with non-musicians and pianists. Attentive listening to music for as little as three hours can temporarily alter the auditory cortex. Interactions between genetic predisposition, environment and training play a role in music as in other areas. It has been proposed that musical training may improve other cognitive functions. There is some evidence that this may be the case but it is an area that needs further exploration.

Download Full-text

Epileptiform seizures in domestic fowl. IX. Implications of the absence of anticonvulsant activity of ethosuximide in a pharmacological model of epilepsy

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y78-141 ◽

1978 ◽

Vol 56 (5) ◽

pp. 893-896 ◽

Cited By ~ 2

Author(s):

H. L. Davis ◽

D. D. Johnson ◽

R. D. Crawford

Keyword(s):

Dose Response ◽

Domestic Fowl ◽

Anticonvulsant Activity ◽

Plasma Concentrations ◽

High Specificity ◽

Seizure Susceptibility ◽

Epileptiform Seizures ◽

Pharmacological Model ◽

Anticonvulsant Effects ◽

Stimulation Of

Acute dose–response studies were conducted to determine if ethosuximide had anticonvulsant activity against seizures evoked by stroboscopic stimulation of epileptic fowl and to correlate the observed effects with the concentration of the drug in the plasma. Ethosuximide, in doses that produced mean plasma concentrations of 366 μg/ml and signs of sedation, did not reduce seizure susceptibility. Twice daily administration of ethosuximide produced mean plasma concentrations of 430 μg/ml after 36 h without affecting seizure susceptibility even in the presence of marked sedation. Previous studies have shown that epileptic fowl are sensitive to the anticonvulsant effects of phenobarbital, phenytoin, and primidone at plasma concentrations similar to those required in humans. Since ethosuximide has a high specificity against petit mal seizures in humans, the failure of ethosuximide to provide protection indicates that epileptic fowl represent a relatively specific pharmacological model for drugs effective against generalized tonic–clonic and focal cortical epilepsies in humans.

Download Full-text