Effects of antisense oligodeoxynucleotides to NR1 on suppression of seizures and protection of cortical neurons from excitotoxicity in vivo and in vitro.
OBJECTIVE
To investigate the effects of NR1 subunit on the initiation and development of seizures and protection of cortical neurons from excitotoxicity by using antisense oligodeoxynucleotides (ODN) to NR1 in vivo and in vitro.


METHODS
Intracerebroventricular injection, temporal cortex slices discharge, cerebral cortical neuronal culture, induction of neurotoxicity and [3H]MK-801 binding were used in this study.


RESULTS
After an antisense ODN for NR1 was administered intracerebroventricularly (i.c.v. 100 micrograms in 10 microliters) once daily, for three days in genetically epilepsy-prone rats (GEPR, P77PMC), the animals did not develop any clonic and tonic convulsions and their seizure scores were significantly lower compared to the control groups. The frequency and amplitude of early seizure-like events (SLEs) and late recurrent discharges (LRD), induced by lowering Mg2+, were reduced in entorhinal cortex (EC) of the temporal slice treated by antisense ODNs. Pretreatment with antisense ODN (2 microM) protected more than 52% of glutamate-sensitive neurons and reduced the [3H]MK-801 binding to 50% in cultured cerebral cortical neurons.


CONCLUSIONS
N-methy-D-aspartate-receptors (NMDAR), specifically the NR1 subunit, may participate and play important roles in the initiation and propagation of epilepsy in the P77PMC rat.
Shan
W
W
Department of Pediatrics, First Teaching Hospital, Beijing Medical University, China.
Wu
X
X
Zhang
G
G
Zhang
Y
Y
Liang
Y
Y
Wang
Z
Z
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015536:Down-Regulation; D004827:Epilepsy / Q000473:pathology / Q000517:prevention & control*; D018846:Excitatory Amino Acids / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D013702:Temporal Lobe / Q000503:physiopathology
D018846:Excitatory Amino Acids; D016376:Oligonucleotides, Antisense; D016194:Receptors, N-Methyl-D-Aspartate