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      Experimental Models of Status Epilepticus and Neuronal Injury for Evaluation of Therapeutic Interventions

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          Abstract

          This article describes current experimental models of status epilepticus (SE) and neuronal injury for use in the screening of new therapeutic agents. Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SE is an emergency condition associated with continuous seizures lasting more than 30 min. It causes significant mortality and morbidity. SE can cause devastating damage to the brain leading to cognitive impairment and increased risk of epilepsy. Benzodiazepines are the first-line drugs for the treatment of SE, however, many people exhibit partial or complete resistance due to a breakdown of GABA inhibition. Therefore, new drugs with neuroprotective effects against the SE-induced neuronal injury and degeneration are desirable. Animal models are used to study the pathophysiology of SE and for the discovery of newer anticonvulsants. In SE paradigms, seizures are induced in rodents by chemical agents or by electrical stimulation of brain structures. Electrical stimulation includes perforant path and self-sustaining stimulation models. Pharmacological models include kainic acid, pilocarpine, flurothyl, organophosphates and other convulsants that induce SE in rodents. Neuronal injury occurs within the initial SE episode, and animals exhibit cognitive dysfunction and spontaneous seizures several weeks after this precipitating event. Current SE models have potential applications but have some limitations. In general, the experimental SE model should be analogous to the human seizure state and it should share very similar neuropathological mechanisms. The pilocarpine and diisopropylfluorophosphate models are associated with prolonged, diazepam-insensitive seizures and neurodegeneration and therefore represent paradigms of refractory SE. Novel mechanism-based or clinically relevant models are essential to identify new therapies for SE and neuroprotective interventions.

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          Most cited references168

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          A simple method for organotypic cultures of nervous tissue.

          Hippocampal slices prepared from 2-23-day-old neonates were maintained in culture at the interface between air and a culture medium. They were placed on a sterile, transparent and porous membrane and kept in petri dishes in an incubator. No plasma clot or roller drum were used. This method yields thin slices which remain 1-4 cell layers thick and are characterized by a well preserved organotypic organization. Pyramidal neurons labelled by extra- and intracellular application of horse radish peroxidase resemble by the organization and complexity of their dendritic processes those observed in situ at a comparable developmental stage. Excitatory and inhibitory synaptic potentials can easily be analysed using extra- or intracellular recording techniques. After a few days in culture, long-term potentiation of synaptic responses can reproducibly be induced. Evidence for a sprouting response during the first days in culture or following sections is illustrated. This technique may represent an interesting alternative to roller tube cultures for studies of the developmental changes occurring during the first days or weeks in culture.
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            Mechanisms of epileptogenesis and potential treatment targets.

            Prevention of epileptogenesis after brain trauma is an unmet medical challenge. Recent molecular profiling studies have provided an insight into molecular changes that contribute to formation of ictogenic neuronal networks, including genes regulating synaptic or neuronal plasticity, cell death, proliferation, and inflammatory or immune responses. These mechanisms have been targeted to prevent epileptogenesis in animal models. Favourable effects have been obtained using immunosuppressants, antibodies blocking adhesion of leucocytes to endothelial cells, gene therapy driving expression of neurotrophic factors, pharmacological neurostimulation, or even with conventional antiepileptic drugs by administering them before the appearance of genetic epilepsy. Further studies are needed to clarify the optimum time window and aetiological specificity of treatments. Questions related to adverse events also need further consideration. Encouragingly, the recent experimental studies emphasise that the complicated process of epileptogenesis can be favourably modified, and that antiepileptogenesis as a treatment indication might not be an impossible mission. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              Organotypic slice cultures: a technique has come of age.

              B Gahwiler (1997)
              Slices of CNS tissue prepared from young rodents can be maintained in culture for many weeks to months. The basic requirements are simple: a stable substratum, culture medium, sufficient oxygenation and incubation at a temperature of about 36 degrees C. Under these conditions, nerve cells continue to differentiate and to develop a tissue organization that closely resembles that observed in situ. Several alternative culturing methods have been developed recently. Slices maintained in stationary culture with the interface method are ideally suited for questions requiring a three-dimensional structure, whereas slices cultured in roller-tubes remain the method of choice for experiments that require optimal optical conditions. In this report, three typical experiments are discussed that illustrate the potential of the slice-culture technique. The first example indicates that, due to their high neuronal connectivity, slice cultures provide a very useful tool for studying the properties of synaptic transmission between monosynaptically coupled cell pairs. The other two studies show how long-term application of substances to slice cultures can be used to examine the consequences of epileptic discharges in vitro, as well as the effects of slowly acting clostridial neurotoxins on synaptic transmission.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                Molecular Diversity Preservation International (MDPI)
                1422-0067
                September 2013
                05 September 2013
                : 14
                : 9
                : 18284-18318
                Affiliations
                Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, 8447 State Highway 47, MREB Building, Bryan, TX 77807, USA
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: reddy@ 123456medicine.tamhsc.edu ; Tel.: +1-979-436-0324; Fax: +1-979-436-0086.
                Article
                ijms-14-18284
                10.3390/ijms140918284
                3794781
                24013377
                890504e7-7607-4399-a434-005d490c15e3
                © 2013 by the authors; licensee MDPI, Basel, Switzerland

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 03 July 2013
                : 31 July 2013
                : 09 August 2013
                Categories
                Review

                Molecular biology
                perforant stimulation,pilocarpine,kainic acid,epilepsy,seizure,dfp,neurodegeneration
                Molecular biology
                perforant stimulation, pilocarpine, kainic acid, epilepsy, seizure, dfp, neurodegeneration

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