Long-term behavioral deficits following pilocarpine seizures in immature rats

Zhao, Lina; Gatt, Arkadi; Werner, Suzanne; Mikati, Mohamad A.; Holmes, Gregory L.

doi:10.1016/0920-1211(94)90062-0

Cited by 122 publications

(63 citation statements)

References 63 publications

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“…Impaired cognitive functions were previously reported to occur before epilepsy onset during both post-natal development (Cilio et al, 2003;Kubova et al, 2004;Liu et al, 1994;Sayin et al, 2004) and in adulthood (Chauviere et al, 2009;Hort et al, 2000;Jones et al, 2010) but it was unknown whether these deficits correlated with epilepsy development. We describe for the first time that a reduced rate of learning and an accelerated forgetting are two specific features of rats prone to develop epilepsy, and these deficits anticipate the onset of spontaneous seizures.…”

Section: Discussionmentioning

confidence: 99%

Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

Pascente

Frigerio

Rizzi

et al. 2016

Neurobiology of Disease

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Cognitive deficits and brain myoInositol are early biomarkers of epileptogenesis in a rat model of epilepsy, Neurobiology of Disease (2016Disease ( ), doi: 10.1016Disease ( /j.nbd.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E DM A N U S C R I P T ACCEPTED MANUSCRIPT AbstractOne major unmet clinical need in epilepsy is the identification of therapies to prevent or arrest epilepsy development in patients exposed to a potential epileptogenic insult. The development of such treatments has been hampered by the lack of non-invasive biomarkers that could be used to identify the patients at-risk, thereby allowing to design affordable clinical studies. Our goal was to test the predictive value of cognitive deficits and brain astrocyte activation for the development of epilepsy following a potential epileptogenic injury. We used a model of epilepsy induced by pilocarpine-evoked status epilepticus (SE) in 21-day old rats where 60-70% of animals develop spontaneous seizures after around 70 days, although SE is similar in all rats. Learning was evaluated in the Morris water-maze at days 15 and 65 post-SE, each time followed by proton magnetic resonance spectroscopy for measuring hippocampal myo-Inositol levels, a marker of astrocyte activation. Rats were video-EEG monitored for two weeks at seven months post-SE to detect spontaneous seizures, then brain histology was done. Behavioral and imaging data were retrospectively analysed in epileptic rats and compared with non epileptic and control animals. Rats displayed spatial learning deficits within three weeks from SE. However, only epilepsy-prone rats showed accelerated forgetting and reduced learning rate compared to both rats not developing epilepsy and controls. These deficits were associated with reduced hippocampal neurogenesis. myoInositol levels increased transiently in the hippocampus of SE-rats not developing epilepsy while this increase persisted until spontaneous seizures onset in epilepsy-prone rats, being associated with a local increase in S100-positive astrocytes. Neuronal cell loss was similar in all SE-rats. Our data show that behavioral deficits, together with a non-invasive marker of astrocyte activation, predict which rats develop epilepsy after an acute injury. These measures have potential clinical relevance for identifying individuals at-risk for developing epilepsy following exposure to epileptogenic insults, and consequently, for designing adequately powered antiepileptogenesis trials.

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Section: Discussionmentioning

confidence: 99%

Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

Pascente

Frigerio

Rizzi

et al. 2016

Neurobiology of Disease

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“…Behavioral consequences following status epilepticus are also related to age of the animal at the time of the status; adult animals surviving status epilepticus have significant deficits in learning, memory, and behavior (27) whereas young rats following status epilepticus have fewer deficits in learning, memory, and behavior (27,34). Likewise, spontaneous seizures following status epilepticus are more likely to occur in older 322 animals experiencing status epilepticus than in younger animals (35)(36)(37).…”

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confidence: 99%

The Neurobiology and Consequences of Epilepsy in the Developing Brain

2001

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The following article is the second in our series on the developmental biology of the nervous system and its relation to diseases and disorders that are found in newborn infants and children. This article, by Gregory Holmes and Yehezkiel Ben-Ari, Epilepsy is a disorder in which the balance between cerebral excitability and inhibition is tipped toward uncontrolled excitability. There is now clear evidence that there are distinct differences between the immature and mature brain in the pathophysiology and consequences of seizures. Both the enhanced excitability of the immature brain compared with the mature brain and the unique pathologic consequences of seizures are related to the sequential development and expression of essential signaling pathways. Although the immature brain is less vulnerable than the mature brain to seizure-induced cell death, seizures in the developing brain can result in irreversible alterations in neuronal connectivity. Developing novel strategies to treat and avert the consequences of seizures in children will require further understanding of the unique mechanisms of seizure initiation and propagation in the immature brain. As originally described by J. Hughlings Jackson in 1870, a seizure is an "excessive discharge of nerve tissue on muscle" (1). Jackson went on to say that "this discharge occurs in all degrees, it occurs with all sorts of conditions of ill health, at all ages, and under innumerable circumstances." These comments by Jackson are as true now as they were 130 years ago. Epileptic seizures are one of the most common, and frightening, neurologic conditions that occur in children. The incidence of seizures in children is significantly higher than in adults, with the highest incidence during the first year of life (2). Although there are many common features of the disorder across age groups, it has become clear that there are also significant differences between young children and adults in both the pathogenesis and consequences of epilepsy.

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“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. accompanied by deficits in hippocampal-dependent learning and memory (Stafstrom et al, 1993;Liu et al, 1994;Sarkisian et al, 1997;Hort et al, 1999;Mikati et al, 2001). Understanding the relationship between the hippocampal response to SE and its cognitive consequences may lead to new insights into the treatment of SE and epilepsy.…”

Section: Introductionmentioning

confidence: 99%

“…SE results in substantial neuronal loss (Cavazos et al, 1994;Haas et al, 2001;Gorter et al, 2003), γ-aminobutyric acid (GABA) system alterations (e.g., Houser & Esclapez, 1996), reactive gliosis (Jorgensen et al 1993;Niquet et al, 1994a;Kang et al, 2006), mossy fiber innervation of the dentate gyrus (Sutula et al, 1988;Ben-Ari & Represa, 1990), changes in levels of growth factors (Khrestchatisky et al, 1995;Mudo et al, 1996;Schmidt-Kastner et al, 1996;Shetty et al, 2004), and a transient increase in cell proliferation and neurogenesis (Bengzon et al, 1997;Parent et al, 1997;Scharfman et al, 2000;Hattiangady et al, 2004). These SE-induced degenerative and regenerative changes in the hippocampus are also accompanied by deficits in hippocampal-dependent learning and memory (Stafstrom et al, 1993;Liu et al, 1994;Sarkisian et al, 1997;Hort et al, 1999;Mikati et al, 2001). Understanding the relationship between the hippocampal response to SE and its cognitive consequences may lead to new insights into the treatment of SE and epilepsy.…”

mentioning

confidence: 99%

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus

Wong-Goodrich¹,

Mellott²,

Glenn³

et al. 2008

Neurobiology of Disease

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Prenatal choline supplementation (SUP) protects adult rats against spatial memory deficits observed after excitotoxin-induced status epilepticus (SE). To examine the mechanism underlying this neuroprotection, we determined the effects of SUP on a variety of hippocampal markers known to change in response to SE and thought to underlie ensuing cognitive deficits. Adult offspring from rat dams that received either a Control or SUP diet on embryonic days 12-17 were administered saline or kainic acid (i.p.) to induce SE and were euthanized 16 days later. SUP markedly attenuated seizure-induced hippocampal neurodegeneration, dentate cell proliferation, hippocampal GFAP mRNA expression levels, prevented the loss of hippocampal GAD65 protein and mRNA expression, and altered growth factor expression patterns. SUP also enhanced pre-seizure hippocampal levels of BDNF, NGF, and IGF-1, which may confer a neuroprotective hippocampal microenvironment that dampens the neuropathological response to and/or helps facilitate recovery from SE to protect cognitive function. Keywords choline; kainic acid; hippocampus; seizures; bromodeoxyuridine; growth factor; glutamic acid decarboxylase; glial fibrillary acidic protein; neuroprotection Status epilepticus (SE), a period of prolonged seizures, produces a host of plastic changes in the hippocampus that are thought to contribute to the development of temporal lobe epilepsy. SE results in substantial neuronal loss (Cavazos et al., 1994;Haas et al., 2001;Gorter et al., 2003), γ-aminobutyric acid (GABA) system alterations (e.g., Houser & Esclapez, 1996), reactive gliosis (Jorgensen et al. 1993; Niquet et al., 1994a;Kang et al., 2006), mossy fiber innervation of the dentate gyrus (Sutula et al., 1988;Ben-Ari & Represa, 1990), changes in levels of growth factors (Khrestchatisky et al., 1995;Mudo et al., 1996;Schmidt-Kastner et al., 1996;Shetty et al., 2004), and a transient increase in cell proliferation and neurogenesis (Bengzon et al., 1997;Parent et al., 1997;Scharfman et al., 2000;Hattiangady et al., 2004). These SE-induced degenerative and regenerative changes in the hippocampus are also Corresponding author: Dr. Christina L. Williams, Department of Psychology and Neuroscience, 572 Research Drive, Box 91050, GSRB-II, Room 3022, Duke University, Durham, NC 27708, USA, Phone: 919-660-5638, Fax: 919-660-5798, Email: williams@psych.duke.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. accompanied by deficits in hippocampal-dependent learning and memory (Stafstrom et al., 1993;Liu et al., 1994;Sarkisian et al., 1997;Hort et al., 1999;Mik...

show abstract

Long-term behavioral deficits following pilocarpine seizures in immature rats

Cited by 122 publications

References 63 publications

Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

The Neurobiology and Consequences of Epilepsy in the Developing Brain

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus

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