Functional role of HSP70 expression regulation in the pathogenesis of epilepsy and associated inflammatory processes

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Excessive inflammatory signaling has been confirmed as one key mechanism contributing to epilepsy development (=epileptogenesis) and to hyperexcitability in the epileptic brain. Considering the fact that available antiepileptic drugs fail to control epileptic seizures in a large subgroup of canine patients, it is of particular interest to develop preventive or disease-modifying strategies targeting the pathophysiological mechanisms of epileptogenesis or of intrinsic disease severity.The heat-shock protein superfamily HSP70 comprises a stress-inducible HSP70i, which at least partly mediated by an interaction with Toll-like receptor 4 (TLR4) acts as modulator of inflammatory responses. Despite a dichotomous role described for HSP70i, the current state-of-knowledge indicates that HSP70i up-regulation associated with neurological insults appears to be predominantly anti-inflammatory. In line with this concept, we will address the hypothesis that genetic or pharmacological strategies increasing HSP70i expression exert beneficial preventive effects in a chronic epilepsy model. Immunhistochemical analysis in tissue from rodent models of epileptogenesis and epilepsy, and in post mortem tissue from canine patients will provide comprehensive information about disease-associated regulation patterns of HSP70i and further members of the HSP70 superfamily. The information is crucial for the development of targeting strategies. Using transgenic HSP70i overexpressing mice we will assess the impact of the protein on seizure susceptibility, seizure progression, microglia activation, and production of pro-inflammatory cytokines in the kindling model of temporal lobe epilepsy. In subsequent experiments, the efficacy of pharmacological induction of HSP70i will be determined in the kindling model. Thereby, the HSP70i- and TLR4-dependency of the pharmacological effect will be controlled by parallel experiments in HSP70i and TLR4 knockout mice. We expect that the HSP70i targeting experiments provide a basis for future translational development of novel disease-modifying or preventive approaches.