Are seizures harmful: what can we learn from animal models?

Cole, Andrew J.; Koh, Sookyong; Zheng, Yi

doi:10.1016/s0079-6123(02)35004-0

Cited by 25 publications

(8 citation statements)

References 47 publications

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“…It is unclear whether seizures per se cause new brain injury, or are a manifestation of evolving injury (Cole et al, 2002; Ferriero, 2004). In preterm neonates with hypoxic-ischemic encephalopathy 65% of infants with seizures had severe outcome or died, whereas absence of seizures was associated with good outcome (Logitharajah et al, 2009; Shah et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep

et al. 2014

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Basal ganglia injury after hypoxia-ischemia remains common in preterm infants, and is closely associated with later cerebral palsy. In the present study we tested the hypothesis that a highly selective neuronal nitric oxide synthase (nNOS) inhibitor, JI-10, would improve survival of striatal phenotypic neurons after profound asphyxia, and that the subsequent seizure burden and recovery of EEG are associated with neural outcome. 24 chronically instrumented preterm fetal sheep were randomized to either JI-10 (3 ml of 0.022 mg/ml, n=8) or saline (n=8) infusion 15 min before 25 min complete umbilical cord occlusion, or saline plus sham-occlusion (n=8). Umbilical cord occlusion was associated with reduced numbers of calbindin-28k-, GAD-, NPY-, PV-, Calretinin- and nNOS-positive striatal neurons (p < 0.05 vs. sham occlusion) but not ChAT-positive neurons. JI-10 was associated with increased numbers of calbindin-28k-, GAD-, nNOS-, NPY-, PV-, Calretinin- and ChAT-positive striatal neurons (p < 0.05 vs. saline+occlusion). Seizure burden was strongly associated with loss of calbindin-positive cells (p < 0.05), greater seizure amplitude was associated with loss of GAD-positive cells (p < 0.05), and with more activated microglia in the white matter tracts (p < 0.05). There was no relationship between EEG power after 7 days recovery and total striatal cell loss, but better survival of NPY-positive neurons was associated with lower EEG power. In summary, these findings suggest that selective nNOS inhibition during asphyxia is associated with protection of phenotypic striatal projection neurons and has potential to help reduce basal ganglia injury in some premature babies.

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Section: Discussionmentioning

confidence: 99%

nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep

et al. 2014

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“…The choice of model and assessment tool is critical, because different results have been obtained with different methods. The limitations of rodents as an experimental model for epilepsy were discussed recently (47,48). Furthermore, detailed knowledge of the chosen behavioral test is crucial before attributing a cognitive deficit to an experimental paradigm (25,42,43,49).…”

Section: Discussionmentioning

confidence: 99%

Seizures in the Developing Brain Cause Adverse Long‐term Effects on Spatial Learning and Anxiety

Sayın¹,

Sutula²,

Stafstrom³

2004

Epilepsia

146

106

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Summary:Purpose: Seizures in the developing brain cause less macroscopic structural damage than do seizures in adulthood, but accumulating evidence shows that seizures early in life can be associated with persistent behavioral and cognitive impairments. We previously showed that long-term spatial memory in the eight-arm radial-arm maze was impaired in rats that experienced a single episode of kainic acid (KA)-induced status epilepticus during early development (postnatal days (P) 1-14). Here we extend those findings by using a set of behavioral paradigms that are sensitive to additional aspects of learning and behavior.Methods: On P1, P7, P14, or P24, rats underwent status epilepticus induced by intraperitoneal injections of age-specific doses of KA. In adulthood (P90-P100), the behavioral performance of these rats was compared with that of control rats that did not receive KA. A modified version of the radial-arm maze was used to assess short-term spatial memory; the Morris water maze was used to evaluate long-term spatial memory and retrieval; and the elevated plus maze was used to determine anxiety.Results: Compared with controls, rats with KA seizures at each tested age had impaired short-term spatial memory in the radial-arm maze (longer latency to criterion and more reference errors), deficient long-term spatial learning and retrieval in the water maze (longer escape latencies and memory for platform location), and a greater degree of anxiety in the elevated plus maze (greater time spent in open arms).Conclusions: These findings provide additional support for the concept that seizures early in life may be followed by life-long impairment of certain cognitive and behavioral functions. These results may have clinical implications, favoring early and aggressive control of seizures during development.

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“…PTZ seizures are believed to alter brain neurotransmitter homeostasis (Szyndler et al ., 2002; Eloqayli et al ., 2003) and to rapidly induce the transient expression of immediate‐early genes encoding transcription factors (Yount et al ., 1994; Cole et al ., 2002). While the chronic administration of subconvulsive doses of PTZ (or kindling) is associated with various neurochemical, neurophysiological and behavioral modifications (Schroder et al ., 1993), the long‐term effects of its acute administration are less well documented.…”

Section: Discussionmentioning

confidence: 99%

A pentylenetetrazole‐induced generalized seizure in early life enhances the efficacy of muscarinic receptor coupling to G‐protein in hippocampus and neocortex of adult rat

Potier

Sénécal

Chabot

et al. 2005

Eur J of Neuroscience

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We have previously shown that exposure to the anti-cholinesterase eserine provokes interictal-like discharges in the CA3 area of hippocampal slices from adult rats in which a generalized seizure has been induced by pentylenetetrazole (PTZ) when immature (at 20 days). Such increased responsiveness to acetylcholine (ACh) was not associated with any change in hippocampal acetylcholine or gamma-aminobutyric acid (GABA) content, GABAergic inhibition or density of ACh innervation, but was blocked by the muscarinic receptor antagonist atropine. We therefore turned to quantitative radioligand binding autoradiography, in situ hybridization and the [35S]GTPgammaS method to assess the properties of hippocampal and neocortical muscarinic receptors in adult rats having experienced a PTZ seizure at P20. The densities of M1 and M2 receptor binding sites, respectively labeled with [3H]pirenzepine and [3H]AFDX-384, as well as the amount of m1, m2 and m3 receptor mRNAs, did not differ from control in the hippocampus and neocortex of these rats. In contrast, in PTZ rats, both brain regions displayed a marked increase in [35S]GTPgammaS incorporation stimulated by ACh, bethanechol and particularly oxotremorine. This finding indicates that a generalized seizure in immature rat can entail a long-term and presumably permanent increase in the efficacy of G-protein coupling to muscarinic receptors in the hippocampus and neocortex of the adult. By analogy, such a mechanism could account for the susceptibility to epilepsy of human adults having suffered from prolonged convulsions in early life.

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Are seizures harmful: what can we learn from animal models?

Cited by 25 publications

References 47 publications

nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep

nNOS inhibition during profound asphyxia reduces seizure burden and improves survival of striatal phenotypic neurons in preterm fetal sheep

Seizures in the Developing Brain Cause Adverse Long‐term Effects on Spatial Learning and Anxiety

A pentylenetetrazole‐induced generalized seizure in early life enhances the efficacy of muscarinic receptor coupling to G‐protein in hippocampus and neocortex of adult rat

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