The long-term neurological sequelae of intractable epilepsy that begins in childhood are truly devastating. Conventional antiepileptic drugs are not only inadequate to control seizures, but can cause detrimental side effects to further burden the development of children with epilepsy. Alternative therapies that prevent the progression of epilepsy and limit cellular injury associated with seizures are critically needed. A dysregulated innate immune response, peripheral inflammatory cell infiltration and breakdown of the blood- brain barrier have been implicated in the initiation, progression and perpetuation of seizures. A recent genome-wide search to identify novel drug targets in our laboratory has revealed that proinflammatory molecules may be therapeutic targets in the epileptogenic process. We have developed a new clinically relevant murine model of prolonged febrile convulsions (FCs) followed by """"""""second hit"""""""" kainic acid-induced seizures later in life. Our preliminary results using an unbiased flow cytometric analyses of inflammatory cells detected significant increases in both CNS-infiltrating and CNS- resident immune cells after a """"""""second hit"""""""" in animals with prior experience of early-life seizures. Using our """"""""two hit"""""""" model, we propose to test the hypothesis that innate and adaptive immune responses play a causal role in mediating the long-term epileptogenic effects of early life seizures.
The Specific Aims are: (1) To test the hypothesis that immunologic responses to FCs cause heightened susceptibility to subsequent seizures, we will determine whether the acute pro-inflammatory cytokine production and long-term epileptogenic effect of early-life FCs is prevented by post-treatment with an anti- inflammatory drug minozac or ACTH;(2) To distinguish the involvement of innate and adaptive immunity in the sensitizing effects of early-life febrile convulsions, we will utilize Cx3cr1EGFP/+ transgenic mice, dual-color MCP-1::mRFP1;CCR2::CCR2-EGFP reporter mice, and multi-color flow cytometric analysis to detect and quantify innate and adaptive immune cells. 3. To directly address the role of CNS-resident and peripheral inflammatory cells in the epileptogenic process, we will test our epilepsy model in mice genetically incapable of mounting innate (MyD88-/-) or adaptive (Rag1-/-) immunity. Results of these studies will reveal the relative contributions of adaptive and innate immunity to the epileptogenic process that starts in early life. The results should also determine the potential beneficial impact of anti-inflammatory drugs for early anti- epileptic therapy.
Febrile convulsion is the most common cause of prolonged seizures during first 2 years of life, affecting 5,000 to 10,000 children annually in the U.S. While early childhood prolonged febrile convulsions have both acute and long-lasting effects on the developing brain, there is currently no effective therapy. Using a clinically relevant animal model of prolonged febrile convulsions, we propose to study the role of inflammation and immunity in the development of epilepsy and to test the efficacy of anti-inflammatory drug as a potential anti-epileptic therapy.
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