It remains under dispute whether status epilepticus (SE) in the perinatal period or early childhood or the underlying neuropathology is the cause of functional impairment later in life. The present study examined whether SE induced by LiCl-pilocarpine in normal immature brain (at the age of 12 or 25 days; P12 or P25) causes cognitive decline and epileptogenesis, and the data were compared to those of rats undergoing SE as adults. Rats in the P12 group had impaired memory (repeated exposure to open-field paradigm) and emotional behaviour (lower proportion of open-arm entries and higher incidence of risk assessment period in elevated plus-maze) when assessed 3 months after SE, although not as severe as in the older age groups. Importantly, video-electroencephalography monitoring 3 months after SE demonstrated that 25% of rats in the P12 and 50% in P25 group developed spontaneous seizures. Only nonconvulsive seizures (ictal activity in hippocampus accompanied by automatisms) were recorded in the P12 group whereas rats in the P25 group exhibited clonic convulsions. The present findings indicate that SE is harmful to the immature brain as early as P12, which might be compared with early infancy in humans.
Status epilepticus (StE) in immature rats causes long-term functional impairment. Whether this is associated with structural alterations remains controversial. The present study was designed to test the hypothesis that StE at an early age results in neuronal loss. StE was induced with lithium-pilocarpine in 12-d-old rats, and the presence of neuronal damage was investigated in the brain from 12 hr up to 1 week later using silver and Fluoro-Jade B staining techniques. Analysis of the sections indicated consistent neuronal damage in the central and lateral segments of the mediodorsal nucleus of the thalamus, which was confirmed using adjacent cresyl violet-stained preparations. The mechanism of thalamic damage (necrosis vs apoptosis) was investigated further using TUNEL, immunohistochemistry for caspase-3 and cytochrome c, and electron microscopy. Activated microglia were detected using OX-42 immunohistochemistry. The presence of silver and Fluoro-Jade B-positive degenerating neurons in the mediodorsal thalamic nucleus was associated with the appearance of OX-42-immunopositive activated microglia but not with the expression of markers of programmed cell death, caspase-3, or cytochrome c. Electron microscopy revealed necrosis of the ultrastructure of damaged neurons, providing further evidence that the mechanism of StE-induced damage in the mediodorsal thalamic nucleus at postnatal day 12 is necrosis rather than apoptosis. Finally, these data together with previously described functions of the medial and lateral segments of the mediodorsal thalamic nucleus suggest that some functions, such as adaptation to novelty, might become compromised after StE early in development.
SUMMARY Objective Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic GABAA receptors and externalization of NMDA receptors that may explain the loss of potency of standard anti-epileptic drugs (AED). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. Methods A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. Results Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis and MWM deficits. Significance This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early Midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.
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