Neuroprotective Effect of Ketamine Administered After Status Epilepticus Onset

Abstract

We investigated the neuroprotective effect of the noncompetitive N-methyl-D-asparatate (NMDA) antagonist ketamine when administered after onset of lithium-pilocarpine-induced status epilepticus (SE). Seizures were induced in Wistar rats with lithium chloride (3 mEq/kg) and pilocarpine (PC) (30-60 mg/kg intraperitoneally, i.p.). Fifteen minutes after SE onset, either ketamine 100 mg/kg or normal saline was injected i.p., and 3 h after SE onset atropine, diazepam (DZP), and phenobarbital (PB) were administered i.p. to terminate the seizures. Twenty-four hours later, rats underwent brain perfusion-fixation, with subsequent brain processing for light-microscopic examination. Rats adminstered saline (n = 5) had neuronal damage in 24 of 25 brain regions examined. Rats administered ketamine (n = 7) had significant neuroprotection in 22 of 24 damaged regions. Ketamine reduced the amplitude of seizure discharges, and in 3 rats EEG seizure activity ceased in 30 min; none of these rats had neuronal damage. In the other 4 rats, EEG seizure discharges persisted > 90 min; in these animals, 21 of 24 damaged regions were protected. In contrast, rats with 1-h high-dose PC-induced SE (400 mg/kg i.p. without lithium chloride preadministration) had 14 damaged regions, of which 7 were significantly different from the undamaged regions of the ketamine subgroup with persistent electrographic seizures. Thus, ketamine is remarkably neuroprotective when administered after onset of SE, whether or not seizure discharges are eliminated.

Convulsive status epilepticus duration as determinant for epileptogenesis and interictal discharge generation in the rat limbic system

“…Indeed, diazepam is per se able to limit damage by acting on seizure activity, both by neuroprotection (Pitkänen et al, 2005;Qashu et al, 2010) and by shifting SE from motor to non-convulsive seizures (Goffin et al, 2007). Ketamine is also neuroprotective when administered after the SE onset (Fujikawa, 1995). Thus, the significantly prolonged ictal discharges found in rats exposed to 30 min SE could be explained by the better preserved neuronal networks, which are required for seizures to generalize.…”

Status Epilepticus: Risk Factors and Complications

“…They are as effective as conventional therapies in experimental status epilepticus, but studies have not been performed in humans (72). Ketamine is a commonly available NMDA antagonist used for short-term anesthesia that reduces neuronal injury in experimental GCSE even when EEG seizure activity continues (73). Specific non-NMDA antagonists may also be useful, but none are nearing human use.…”

Seizure‐Induced Neuronal Necrosis: Implications for Programmed Cell Death Mechanisms

“…As described by Fujikawa et al (23,24) and in previous reports (3,4,25), percentages of acidophilic neurons by hematoxylin and eosin (H & E) and TUNEL-positive neurons by TUNEL were estimated in 23 brain regions on a four-point scale (0 to 3). The data were analyzed with three-factor, repeated-measures analysis of variance and post hoc t tests using pooled standard deviations and p = 0.05.…”