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Epilepsy
Seizure Semiology, Neurotransmitter Receptors and Cellular-stress Responses
in Pentylenetetrazole Models of Epilepsy
Hans-J Bidmon,
1
Erwin-J Speckmann
2
and Karl J Zilles
1,3,4
1. C & O Vogt Institute for Brain Research, Heinrich Heine University, Düsseldorf; 2. Institute of Physiology I, Westfälische Wilhelms University, Münster;
3. Institute for Neuroscience and Medicine INM2, Research Centre, Jülich; 4. Jülich Aachen Research Alliance, Research Centre
Abstract
Ongoing research has elucidated a large variety of genes, proteins and enzyme products that are affected in epilepsy. Despite the
pharmacological advances achieved by the development of antiepileptic drugs, numerous patients become pharmacoresistant.
Therefore, animal models addressing these complex interactions among compensatory gene-expression cascades and consecutive
molecular mechanisms are still a necessity for research-based gene and pharmacotherapy. In this article, we focus on pentylenetetrazole
models to study the consequences of tonic–clonic seizures. We address two complex and closely linked aspects: alterations in
neurotransmission and oxidative-stress responses. Reviewing just these two aspects highlights the need for a more standardised use of
animal models and methods to allow a better integration of data from different lines of research. The latter will be most applicable for
the understanding of complex disease-related interactions of gene networks, proteins and enzyme products and timely, research-based
development of future therapeutic options.
Keywords
Epilepsy, gene networks, neurotransmission, cyclo-oxygenase, oxidative stress, neuron–glia interaction
Disclosure: The authors have no conflicts of interest to declare.
Received: 14 April 2009 Accepted: 15 July 2009
Correspondence: Hans-J Bidmon, C & O Vogt Institute for Brain Research, Heinrich-Heine-University, Düsseldorf, Bldg 22.03.05, University St 1, D-40225 Düsseldorf, Germany.
E:
hjb@hirn.uni-duesseldorf.de
Epilepsy affects about 1% of the human population at some point stress-response genes). These primary CGECs (pCGECs) are
during their life. The causes of human epilepsies are diverse, ranging followed by additional secondary endogenous responses (e.g. an
from defects during brain development resulting in dysplasias or upregulation of multidrug transporters at the blood–brain barrier or
ectopic cortical neurons to inherited forms involving certain certain neurons
10
) and tertiary responses induced by the short- and
mutations, e.g. ion channel defects or metabolic impairments; long-term effects of specific pharmacological interventions. This
however, most causes are still unknown.
1,2
Furthermore, post- tertiary response may also be described as an exogenously or
traumatic epilepsies are also known;
3
therefore, epilepsies are not a pharmacologically induced phCGEC.
homogeneous pathogenetical entity, but rather are defined as the
“occurrence of repeated seizures”,
4
which will be grouped into various According to these multifactorial and interdependent mechanisms,
epileptic syndromes according to the individual semiology of patients.
5
in vivo animal models continue to play a major role in the elucidation
and understanding of the ongoing pathomechanisms, as well as the
The causes of the initial mechanisms in the development response mechanisms to pharmacological intervention and therapy.
of epileptic seizures are still elusive and only partial aspects of Furthermore, due to ethical reasons, animal models are essential for
specific epileptic phenomena may be attributable to mutations at studies addressing the onset mechanisms of epileptic symptoms or
certain gene loci.
6–8
Furthermore, during onset and progression of questions such as: what are the progressing pathophysiological
the disease, multiple changes in the expression patterns of many consequences and therapeutic options after a pathological status is
genes and gene products have been reported.
2,9
This indicates that reached from a sample resected tissue of patients with pharmaco-
there are no single and specific gene mutations associated with a resistant forms of epilepsy?
certain type of epilepsy, as has been established for Huntington’s
disease, for example. These multiple molecular responses (at the In order to address these questions, a wide variety of animal
level of genes, RNA splicing and proteins) provide strong evidence models have been developed including genetic models, certain
for the induction of pathology-associated responses. naturally occurring wild-type mutations, ‘electrical’ models (e.g.
electroconvulsive kindling) and several pharmacological models for
In our view, these changes are best explained as an initiation of in vivo and/or in vitro use such as the kainate, pilocarpin, penicillin,
compensatory gene-expression cascades (CGECs), i.e. a response to 4-aminopyridine, cholera toxin, bicuculline, picrotoxin and
cope with the primary functional alterations caused by the disease pentylenetetrazole models, etc.
11,12
All of these models address
(e.g. changes in the expression of neurotransmitter receptors or single aspects of epilepsy and have their specific limitations.
76 © TOUCH BRIEFINGS 2009
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