Acute effects of MK801 on kainic acid-induced seizures in neonatal rats.
Kainic acid (KA) causes behavioral and electrographic status epilepticus (SE) in rats of all ages. In adult rats, the noncompetitive N-methyl-D-aspartate (NMDA) channel blocker MK801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ) is anticonvulsant against KA-induced seizures: it reduces their severity and protects against neuronal damage, although it may worsen electrographic seizures. Here we examined the effects of MK801 on KA seizures in the immature brain. Neonatal rats (P11-P12) were pretreated with MK801 (0.01, 0.1, 0.5 or 1.0 mg/kg, i.p.) or saline twenty minutes prior to KA (2 mg/kg, i.p.). Clinical seizure behavior was monitored for > 6 hrs, and in some rats the EEG was monitored with an intrahippocampal or intracortical electrode. MK801 caused immobility alternating with hyperactivity, ataxia, scratching and sometimes alternate limb cycling, which correlated with the appearance of spikes on the EEG. Compared to KA alone or KA preceded by 0.01 mg/kg MK801, the higher doses of MK801 (0.1, 0.5 and 1.0 mg/kg) significantly lowered the latency to electrographic seizures (P < 0.001), ictal scratching (P < 0.0001), and status epilepticus (P < 0.0001). MK801 pretreatment did not lower significantly the death rate due to KA seizures. No histologic damage was seen after MK801, KA or both agents together. These results suggest that MK801 exacerbates KA-induced seizures in the neonatal brain, and may even cause ictal behavioral and electrographic manifestations by itself. The findings point to an age-dependency of NMDA antagonist action, and suggest caution in considering the use of NMDA antagonists in neonates.
Stafstrom
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CE
Division of Pediatric Neurology, New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
Tandon
P
P
Hori
A
A
Liu
Z
Z
Mikati
M A
MA
Holmes
G L
GL
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013997:Time Factors
D016291:Dizocilpine Maleate; D007608:Kainic Acid