Acute effects of MK801 on kainic acid-induced seizures in neonatal rats

Stafstrom, Carl E; Tandon, Pushpa; Hori, Ariyuki; Liu, Zhao; Mikati, Mohamad A; Holmes, Gregory L

doi:10.1016/S0920-1211(96)00904-7

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Volume 26, Issue 2 , Pages 335-344, January 1997

Acute effects of MK801 on kainic acid-induced seizures in neonatal rats

Carl E Stafstrom
- Division of Pediatric Neurology, New England Medical Center, Tufts University School of Medicine, 750 Washington Stree, Boston, MA 02111, USA
- Department of Neurology, Children's Hospital and Medical Center, Harvard Medical School, Boston, MA 02111, USA
- Corresponding author.
- M.D., Ph.D.
Pushpa Tandon
- Department of Neurology, Children's Hospital and Medical Center, Harvard Medical School, Boston, MA 02111, USA
- Ph.D.
Ariyuki Hori
- M.D., Ph.D.
- Department of Neurology, Children's Hospital and Medical Center, Harvard Medical School, Boston, MA 02111, USA
Zhao Liu
- M.D., Ph.D.
- Department of Neurology, Children's Hospital and Medical Center, Harvard Medical School, Boston, MA 02111, USA
Mohamad A Mikati
- Department of Neurology, Children's Hospital and Medical Center, Harvard Medical School, Boston, MA 02111, USA
- M.D.
Gregory L Holmes
- M.D.
- Department of Neurology, Children's Hospital and Medical Center, Harvard Medical School, Boston, MA 02111, USA

Received 12 June 1996; received in revised form 24 July 1996; accepted 24 July 1996.

Abstract

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.

Keywords: Kainic acid, MK801, Seizure immature rat, NMDA receptor