Infantile spasms belong to catastrophic epilepsy syndromes of childhood. These epilepsies are intractable to treatment and are associated with progressive cognitive decline. Infantile spasms are classified as symptomatic (associated with a diagnosed brain lesion) or idiopathic/cryptogenic (no lesion can be revealed). Therapy is hormonal, adrenocorticotropic hormone (ACTH) is a drug of choice followed by corticosteroids and vigabatrin. All these drugs have serious side effects. There is no appropriate animal model of idiopathic/cryptogenic infantile spasms suitable for testing new putative treatments with better efficacy on seizures and associated cognitive decline, and with limited side effects. Because ACTH and corticosteroid have positive effects on infantile spasms, we hypothesized that impairment of the brain hypothalamus-pituitary-adrenal axis control systems could be involved in building the appropriate model of the idiopathic/cryptogenic infantile spasms. We propose a new animal model of infantile spasms created in rats prenatally exposed to betamethasone. Age-specific spastic seizures are then triggered postnatally by systemic N-methyl-D-aspartate (NMDA) injection. The spasms are similar to infantile spasms. Additionally, there is EEG suppression during the spasms similar to electrodecremental response in humans, and the spasms are sensitive to ACTH therapy. In this proposal we will characterize this new model of idiopathic/cryptogenic infantile spasms based on prenatal exposure to betamethasone and triggered during infancy with NMDA using behavioral and electrographic seizures, behavioral/cognitive outcome (horizontal bar, elevated plus maze, open field and Morris Water Maze tests) and screening for the development of spontaneous seizures using long-term EEG/videomonitoring. Further, we will validate the model by using drugs effective against infantile spasms in humans (ACTH, vigabatrin, prednisone) and their effects on behavioral and electrographic seizures, behavioral/cognitive outcome and seizure susceptibility later in the development. The goal of this proposal is to develop sufficiently reliable yet relatively simple model of infantile spasms, which could be used for routine testing of new anticonvulsant drugs and treatment procedures. Based on the results we collect, we will continue in preclinical development of new treatments in the sense of the NIH announcement (PAR-06-189).Infantile spasms are devastating epilepsy of childhood, which is associated with severe developmental decline despite the treatments. Development of new effective drugs and treatment strategies that would improve the outcome depends on availability of an animal model of infantile spasms. Here we propose a new model for infantile spasms triggered in young animals after prenatal brain impairment. Purpose of this proposal is to further characterize the model including behavioral and cognitive outcome and verify the model by using therapies effective in human infantile spasms. The goal is to develop sufficiently reliable yet relatively simple model of infantile spasms, which could be used for routine testing of new safer and more effective treatments. ? ? ? ?
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