This application is in response to the NINDS Translational Research Program request for proposals regarding the preclinical development of therapeutics for neurological disorders. Infantile spasms are an age-specific epileptic disorder characterized by repetitive seizures (spasms), specific EEG abnormalities and developmental delay or regression. The long-term outcome is usually catastrophic with a high proportion of children developing mental retardation and chronic epilepsy. The currently available treatments [adrenocorticotropic hormone (ACTH) and vigabatrin] are partly effective but often toxic. Because infantile spasms have such debilitating effects on cognitive development, it is important to develop innovative treatments to stop the seizures and the regression. This will require the identification of a model system to be used to identify candidate therapeutics and to screen for efficacy in preclinical studies. Up to now, there is no such model. Preliminary data suggest that we may have developed a new model of symptomatic infantile spasms. Following injections of three toxins (doxorubicin, lipopolysaccharide, and p- chlorophenylalanine) in the neonatal period, the infant rats experience recurrent spasms over several days associated with ictal seizure discharges resembling in part the EEG features seen in humans including electrodecremental-like responses. Several of the pups will go on to develop partial (limbic) seizures. The pups also show marked deficits in behavioral tests. In this application, we have designed experiments to establish and validate this model.
The specific aims are 1) To characterize: A. the behavioral phenotype of the spasms, including age of onset, frequency, clustering and transition from spasms to other seizure types, B. the EEG correlates of the spasms and C. the neurodevelopmental profile of the rats with spasms in terms of acquisition of developmental milestones; and 2. To determine the effectiveness of ACTH and vigabatrin treatment in controlling the spasms both behavioral y and electrogaphically. If successful, our model will satisfy the criteria considered important for the acceptance of a model of infantile spasms by the panelists invited to participate in a NINDS sponsored workshop held in Bethesda, MD on May 13-14, 2004. We have already begun to establish the necessary collaborations to satisfactory complete in the future the drug development process. The establishment and validation of the model may lead to the development of new, effective, therapeutic regimens that can be screened preclinical y and then introduced in the clinic to improve the outcome of infants with this catastrophic condition. ? ? ?
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