Ketamine Prevents Learning Impairment When Administered Immediately after Status Epilepticus Onset

doi:10.1006/ebeh.2001.0272

Epilepsy & Behavior

Volume 2, Issue 6, December 2001, Pages 585-591

https://doi.org/10.1006/ebeh.2001.0272 Get rights and content

Abstract

Permanent cognitive impairment is common following status epilepticus (SE) in both humans and animals. We examined the effect of the NMDA antagonist ketamine administered after SE onset on two forms of associative learning in the rat: conditioned taste aversion and fear-conditioned analgesia. Following the onset of lithium/pilocarpine-induced SE, rats were administered either ketamine (100 mg/kg) or acepromazine (25 mg/kg). Acepromazine-treated animals show marked deficits in both learning measures at 1 month after SE. In contrast, ketamine-treated and nonepileptic control animals did not differ in performance for either task. Although studies have shown that ketamine is ineffective at controlling electrographic seizures early in SE, these results are consistent with previous studies showing that ketamine can preserve learning proficiency if administered shortly after seizure onset. As a clinically available drug, ketamine may prove useful in the treatment of SE when combined with conventional antiepileptic strategies.

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Cited by (29)

Pentylenetetrazol kindling induces cortical astrocytosis and increased expression of extracellular matrix molecules in mice
2020, Brain Research Bulletin
Citation Excerpt :
Status epilepticus (SE) is an emergency medical procedure associated with significant mortality (Shorvon, 1994). It is defined as continuous seizure activity, which causes neuronal cell death (Fujikawa, 1995; Rice and DeLorenzo, 1998), epileptogenesis (Rice and DeLorenzo, 1998), and learning disabilities (Stewart and Persinger, 2001). However, the pathophysiological processes leading to epilepsy remain poorly understood.
Although epilepsy is one of the most common chronic neurological disorders with a prevalence of approximately 1.0 %, the underlying pathophysiology remains to be elucidated. Understanding the molecular and cellular mechanisms involved in the development of epilepsy is important for the development of appropriate therapeutic strategy. In this study, we investigated the effects of status epilepticus on astrocytes, microglia, and extracellular matrix (ECM) molecules in the somatosensory cortex and piriform cortex of mice. Activation of astrocytes was observed in many cortices except the retrosplenial granular cortex after pentylenetetrazol (PTZ)-induced kindling in mice. Activated astrocytes in the cortex were found in layers 1–3 but not in layers 4–6. In the somatosensory and piriform cortices, no change was observed in the number of parvalbumin (PV)-positive neurons and PV-positive neurons covered with perineuronal nets. However, the amount of ECM in the extracellular space increased. The expression of VGLUT1- and GAD67-positive synapses also increased. Thus, in the PTZ-kindling epilepsy mice model, an increase in the number of ECM molecules and activation of astrocytes were observed in the somatosensory cortex and piriform cortex. These results indicate that PTZ-induced seizures affect not only the hippocampus but also other cortical areas. Our study findings may help to develop new therapeutic approaches to prevent seizures or their sequelae.
Acute Seizures and Status Epilepticus
2017, Handbook of Neuroemergency Clinical Trials
Acute repetitive seizures and status epilepticus (SE) are common neurologic emergencies with high morbidity and mortality (Zaccara et al., 2017). Most epileptic seizures are stopped within seconds to minutes by intrinsic seizure terminating mechanisms (Theodore et al., 1994). Individual seizures are usually followed by a refractory period, during which additional seizures do not occur. Failure of the normal seizure terminating mechanisms or the postictal refractory period leads to seizure emergencies. Prolonged or repetitive seizures can lead to neuronal damage and clinical sequelae such as focal neurological deficits, cognitive and motor impairments, and epilepsy. Acute seizure emergencies fall into several subgroups based on the seizure type, duration of seizures, etiology, electroencephalographic patterns, and age.
Clinical trials to address acute seizures can have one of several purposes: (1) rapid termination of prolonged or repetitive seizures before SE occurs; (2) termination of established SE; (3) termination of refractory SE (RSE); or (4) amelioration of neuronal damage induced by prolonged seizures (neuroprotection), to prevent long-term sequelae such as cognitive dysfunction and epilepsy (antiepileptogenesis). Recently completed randomized clinical trials (Alldredge et al., 2001; Treiman et al., 1998; Silbergleit et al., 2012) provide some guidelines for aims (1) and (2), but available treatments for seizure emergencies and SE are effective in terminating seizures in only about 60% of patients. Treatment options for patients not responding to initial therapy are controversial. No clinical trials have yet addressed neuroprotection or antiepileptogenesis after acute seizures and SE in humans. This chapter will review the epidemiology, pathophysiology, current management, and trial design methodology for acute prolonged or repetitive seizures and SE.
Post-seizure drug treatment in young rats determines clear incremental losses of frontal cortical and hippocampal neurons: The resultant damage is similar to very old brains
2013, Epilepsy and Behavior
Citation Excerpt :
Ketamine injected immediately and even 1 h after seizure onset minimized neuronal loss. Several behavioral studies have shown that seized rats injected with ketamine behave remarkably similar to non-seized controls [3–5]. Other NMDA receptor antagonists such as CGP 40116 also produce qualitatively conspicuous reduction in neuronal damage [15].
Loss of neurons occurs with aging and following lithium/pilocarpine-induced epileptic seizures. In the present study, the numbers of neurons within the layers from sample areas of the four lobes of the neocortices and the hippocampus were counted by light microscopy in brains of rats that had been administered lithium or pilocarpine and then injected immediately or shortly after seizure onset with either acepromazine, ketamine, or prazosin. The mean numbers of neocortical and hippocampal neurons were lowest in rats treated with acepromazine or prazosin 1 h after seizure onset, while those of rats immediately treated with ketamine displayed the least decrements and were most similar to normal rats. The largest loss of neurons occurred within the CA1 field and layers 5 and 6 of the frontal cortices. The mean numbers of neurons within the cortices in rats whose treatments had been delayed for 1 h were similar to those of normal rats over 700 days of age. These results support the hypothesis that neuronal loss from cumulative effects of seizure-induced brain damage simulates aging.
Large differences in blood measures, tissue weights, and focal areas of damage 1 year after postseizure treatment with acepromazine or ketamine
2009, Epilepsy and Behavior
Citation Excerpt :
The concept of the neuromatrix [18] predicts that different patterns of partial damage and the subsequent differential reorganization of synaptic networks should produce different effects on behavior. A single postseizure injection of 100 mg/kg ketamine normalizes rats’ learning within a variety of contexts [19–21] compared with that of rats seized but given acepromazine to facilitate survival. Whereas spontaneous seizures emerge [22] after a “silent period” corresponding to the latency of neurogenesis within the dentate gyrus [23] in seized rats treated with acepromazine, such seizures are not observed in ketamine-treated rats [24,25].
Approximately 1 year after rats were seized as young adults with lithium (3 mEq/kg) and pilocarpine (30 mg/kg) and given acepromazine or ketamine, 18 blood measures, wet tissue weights, and detailed damage scores for 107 brain structures were completed. Compared with normal and ketamine-treated rats, acepromazine-treated seized rats (total n = 54) had lighter pancreata and spleens and elevated aspartate aminotransferase and alanine aminotransferase blood levels. Even though average damage did not differ, the mosaic of brain damage completely discriminated the two seized groups. Differential effects of postseizure treatment on functions of the thyroid, pancreas, and spleen were indicated. Ketamine-treated seized rats were healthier than acepromazine-treated seized rats or normal rats. This experiment demonstrates the importance of whole-organism assessment and that the single administration of a specific drug after onset of status epilepticus can produce marked differences in the evolution of brain damage and its influence on specific organs for the rest of the animal’s life.
Amelioration of water maze performance deficits by topiramate applied during pilocarpine-induced status epilepticus is negatively dose-dependent
2007, Epilepsy Research
Citation Excerpt :
After SE, rats exhibit a “silent” seizure-free phase characterized by development of extensive damage in hippocampal structures crucially involved in spatial memory (see Silva et al., 1998; Pothuizen et al., 2004), followed by occurrence of spontaneous seizures over the entire life span. Persisting cognitive deficits, observable several days after induction of SE (Rice et al., 1998; Detour et al., 2005; Niessen et al., 2005), are sensitive to pharmacological and environmental interventions during and after SE (Stewart and Persinger, 2001; Faverjon et al., 2002; Pitkanen and Kubova, 2004). TPM was effective in SE suppression in patients (Blumkin et al., 2005) and in animal models (Fisher et al., 2004).
Temporal lobe epilepsy is characterized by a progressive loss of memory capacities, due to sclerosis and functional impairment of mesiotemporal brain areas. We have shown recently that topiramate (TPM) dose-dependently protects hippocampal CA1 and CA3 neurons during initial status epilepticus in the rat pilocarpine model of temporal lobe epilepsy by inhibition of mitochondrial transition pore opening. In the present study, in order to evaluate possible positive effects of the treatment on learning and memory, we investigated water maze performance of rats receiving different dosages of TPM (20 and 100 mg/kg) after 40 min and 4 mg/kg diazepam after 160 min of pilocarpine-induced status epilepticus in relation to performance of animals receiving 4 mg/kg diazepam after 40 min of SE, and to performance of sham-treated control animals. Unexpectedly, 20 but not 100 mg/kg TPM significantly extenuated short-term memory deficits. While neuroprotective effects of TPM were observed in hippocampal CA subfields of animals treated with 100 mg/kg TPM, cell loss in rats treated with 20 mg/kg TPM was indistinguishable from animals receiving diazepam only. The present results indicate a negative dose-dependency of memory-saving effects of TPM applied during status epilepticus apparently dissociated from hippocampal neuroprotection.
Weak, physiologically patterned magnetic fields do not affect maze performance in normal rats, but disrupt seized rats normalized with ketamine: Possible support for a neuromatrix concept?
2006, Epilepsy and Behavior
The concept of a neuromatrix as a determinant of behavior proposes that complex neuroelectromagnetic patterns supported by specific spatial configurations of neurons underlie the generation of behaviors. When the pattern of neuronal connectivity is changed, as occurs during limbic epilepsy, neuroelectromagnetic patterns change in parallel to sustain behavioral output. Thus, a testable prediction of the neuromatrix concept is that the “normal” behaviors of animals with markedly reorganized neuroelectromagnetic patterns are vulnerable to specific stimuli that are ineffective when applied to a normal population. Because rats treated with ketamine after being induced to seize with pilocarpine exhibit behaviors indistinguishable from those of control populations despite marked changes in brain structure, they represent an ideal population in which to examine this hypothesis. Ketamine-treated pilocarpine-seized rats and normal rats were exposed continuously either to a complex sequence magnetic field or to control conditions during the acquisition of a radial arm maze task for 8 consecutive days. After 14 days of subsequent exposure to a frequency-modulated field (7–500 nT), during which time there was no training, the rats that had been induced to seize and had been exposed continuously to this magnetic configuration exhibited conspicuously slower response durations per arm than rats that had been induced to seize and exposed to control conditions or normal rats that had been exposed to either magnetic fields or control conditions. Thus, the behaviors of rats who have sustained multiple, discrete injuries throughout the brain may be seriously disrupted by the appropriate pattern of exogenous weak magnetic fields. Our results represent the first empirical support for the concept of the neuromatrix.

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¹: Current address: Department of Physiology, Medical Sciences Building, University of Western Ontario, London, Ontario N6A 3C1, Canada. E-mail: [email protected]. To whom correspondence should be addressed.

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Original ReportsKetamine Prevents Learning Impairment When Administered Immediately after Status Epilepticus Onset

Abstract

Brain Dev

Neurosci Biobehav Rev

Physiol Behav

Epilepsy Res

Epilepsy Res

Physiol Behav

Physiol Behav

Epilepsy Res

Trends, Cogn Sci

Neurosci Lett

Neurosci Res

Brain Res

Brain Res.

Neuron

Neurosci Lett

Original Reports
Ketamine Prevents Learning Impairment When Administered Immediately after Status Epilepticus Onset