This renewal proposal has 2 broad objectives: 1) to develop means to identify and characterize drugs effective for the treatment of epilepsy; 2) to explore mechanisms of epileptogenesis. A host of molecular, cellular, and synaptic processes have been implicated in the initiation and elaboration of seizures. Different categories of seizures exist, depending on which of these processes are involved, where paroxysms begin, and how they spread through the brain. Moreover, epilepsy is distinguished by multiple seizures over an extended period. With in vitro models it is difficult or impossible to examine certain key features of epilepsy, such as its functional anatomy or its extended chronobiology. In more than 25% of patients with epilepsy, seizures remain refractory to available antiepileptic drugs (AED); the majority of such individuals have complex partial seizures (CPS), often associated with generalized tonic clonic (GTCS) seizures. Accordingly, our laboratory has devised, characterized, and validated in vivo test systems to screen new compounds as AED, using a model of CPS with GTCS elicited with focal hippocampal stimuli. Our prior studies have focused on a condition of augmented, triggered seizures (a kindled state) to reliably, readily and quickly screen drugs for their AED efficacy, their pharmacokinetic properties, and their network mechanisms of action. Interestingly, several differences were demonstrated among AED that cannot be explained solely on the basis of their cellular mechanisms of action. In the course of prior work we have developed two stimulus protocols (Recurrent Hippocampal Seizures [RHS] and Continuous Hippocampal Stimulation [CHS]) that establish various acute and chronic epileptic states with spontaneous or triggered seizures. The work proposed will use these two protocols to test 4 hypotheses: Hypothesis 1. The time between seizures (ictal density) is a critical factor in determining what type of epileptic responses are engendered. Different responses depend on unique pathophysiological mechanisms. Hypothesis 2. Drugs can exert an antiepileptogenic (as distinguished from antiepileptic and anticonvulsant) effect. Hypothesis 3. With RHS protocols, drugs useful for treating epilepsy can be readily identified and thoroughly characterized for their ability to block: 1) seizure initiation; 2) seizure propagation in the hippocampus and adjacent limbic circuits; 3) seizure generalization; and 4) epileptogenesis. Hypothesis 4. Status epilepticus evolves through various stages with different pathophysiological bases. These stages predict responsiveness to AED and allow tailoring of treatment to particular stages. As a result of the proposed work, we will better understand mechanisms of epileptogenesis as processes which establish and intensify seizures and we will identify better means to treat epilepsy.
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