Abstract
Studies of short and long-term changes in regional metabolism, blood flow, gene expression (including immediate early genes and genes for neurotrophic factors), sprouting and cell death following seizures are pivotal to an under-standing of the neural networks responsible for the generation of seizures. At the same time, this information forms a basis for understanding the pathophysiology associated with chronic, recurrent seizures. Systemic chemoconvulsant seizure models, produced by systemically administered chemoconvulsant agents, although convenient, are plagued with difficulties which confound the interpretation of their effects on the nervous system. These difficulties include widespread direct cellular and physiological effects of the chemoconvulsant drugs, most of which are independent of seizures. In addition, numerous physiological changes occur as a secondary consequence of, or ancillary to, seizures, and it can be especially difficult to separate these effects from the direct effects of the propagated seizure discharge itself. Some of these difficulties can be overcome by the use of focally-evoked seizure models. Such models avoid the diffuse presence of drug throughout the CNS and thereby eliminate most of the direct cellular and physiologic actions of the drug apart from seizure-induction. Large regions of the brain distant from the focal site of drug application then can be examined for molecular, structural and physiologic changes uncomplicated by the presence of drug. Moreover, different focal sites of drug application can be compared to evaluate the specificity of the molecular changes to the neural network engaged in the seizure discharge. For example, limbic seizures, evoked by chemoconvulsant application into area tempestas, can be compared with brainstem convulsions evoked by chemoconvulsant application into inferior colliculus. Studies using focal drug application have also been successful in producing distant damage following status epilepticus and in demonstrating “distant neuroprotection”. The importance of identifying seizure-specific pathophysiological alterations is discussed in the context of focal vs. systemic chemoconvulsant seizure models.
Sommario
Studi su modificazioni a breve e lungo termine del metabolismo regionale, del flusso, della espressione genica, dei fenomeni degenerativi e rigenerativi conseguenti alle crisi forniscono informazioni cruciali per la comprensione dei meccanismi neuronali responsabili della generazione delle crisi. Modelli sperimentali prodotti dalla somministrazione sistemica di agenti chimici convulsivanti, benché utili danno risultati di difficile interpretazione. Le difficoltà interpretative derivano dai molti effetti cellulari e fisiologici dei farmaci convulsivanti che sono indipendenti dalle crisi. Inoltre numerosi effetti fisiologici secondari o collaterali alle crisi sono difficilmente discriminabili da quelli direttamente dipendenti dalla scarica critica. Alcune di queste difficoltà possono essere superate dall'uso di modelli di crisi focali, nei quali l'effetto epilettogeno diretto delle sostanze impiegate non è contaminato dagli effetti generali. In questo modo le modificazioni molecolari, strutturali e fisiologiche che si verificano in regioni lontane dalla zona di applicazione del farmaco possono essere studiate senza l'interferenza dei suoi effetti diretti. Per di più in questi modelli lo studio comparativo delle diverse zone di applicazione dell'agente epilettogeno permette di valutare la specificità delle modificazioni molecolari in rapporto all'aggregato neuronale generatore della scarica critica. Ad esempio crisi limbiche evocate da applicazione di chemoconvulsivanti nell'area tempestas possono essere studiate comparativamente con convulsioni troncoencefaliche da somministrazione di chemoconvulsivanti nel collicolo inferiore. L'applicazione locale di farmaci si è dimostrata in grado di indurre danni a distanza conseguenti a stato epilettico e ha rivelato l'esistenza di neuroprotezione a distanza. L'importanza dell'identificazione di alterazioni epilettogene specifiche per tipo di crisi viene discussa nel contesto di modelli di crisi epilettiche indotte da somministrazione focale o generalizzata di chemoconvulsivanti.
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Gale, K. Chemoconvulsant seizures: Advantages of focally-evoked seizure models. Ital J Neuro Sci 16, 17–25 (1995). https://doi.org/10.1007/BF02229070
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DOI: https://doi.org/10.1007/BF02229070