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Seizure Semiology, Neurotransmitter Receptors and Cellular-stress Responses in Pentylenetetrazole Models of Epilepsy

European Neurological Review, 2009;4(1):76-80 DOI: http://doi.org/10.17925/ENR.2009.04.01.76

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: April 14, 2009 Accepted: July 15, 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 during their life. The causes of human epilepsies are diverse, ranging from defects during brain development resulting in dysplasias or ectopic cortical neurons to inherited forms involving certain mutations, e.g. ion channel defects or metabolic impairments; however, most causes are still unknown.1,2 Furthermore, post-traumatic epilepsies are also known;3 therefore, epilepsies are not a homogeneous pathogenetical entity, but rather are defined as the “occurrence of repeated seizures”,4 which will be grouped into various epileptic syndromes according to the individual semiology of patients.5

The causes of the initial mechanisms in the development of epileptic seizures are still elusive and only partial aspects of specific epileptic phenomena may be attributable to mutations at certain gene loci.6–8 Furthermore, during onset and progression of the disease, multiple changes in the expression patterns of many genes and gene products have been reported.2,9 This indicates that there are no single and specific gene mutations associated with a certain type of epilepsy, as has been established for Huntington’s disease, for example. These multiple molecular responses (at the level of genes, RNA splicing and proteins) provide strong evidence for the induction of pathology-associated responses.

In our view, these changes are best explained as an initiation of compensatory gene-expression cascades (CGECs), i.e. a response to cope with the primary functional alterations caused by the disease (e.g. changes in the expression of neurotransmitter receptors or stress-response genes). These primary CGECs (pCGECs) are followed by additional secondary endogenous responses (e.g. an upregulation of multidrug transporters at the blood–brain barrier or certain neurons10) and tertiary responses induced by the short- and long-term effects of specific pharmacological interventions. This tertiary response may also be described as an exogenously or pharmacologically induced phCGEC.

According to these multifactorial and interdependent mechanisms, in vivo animal models continue to play a major role in the elucidation and understanding of the ongoing pathomechanisms, as well as the response mechanisms to pharmacological intervention and therapy. Furthermore, due to ethical reasons, animal models are essential for studies addressing the onset mechanisms of epileptic symptoms or questions such as: what are the progressing pathophysiological consequences and therapeutic options after a pathological status is reached from a sample resected tissue of patients with pharmaco-resistant forms of epilepsy?

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Keywords: Epilepsy, gene networks, neurotransmission, cyclo-oxygenase, oxidative stress, neuron–glia interaction