Kovac, S; (2013) Mechanisms and modulation of seizure induced cell death. Doctoral thesis , UCL (University College London).

Abstract

Epilepsy, one of the most prevalent neurological diseases, is characterized by recurrent seizures, which are often poorly controlled by present treatments. Neuronal cell death, one of the complications of uncontrolled seizures, contributes substantially to the disease-burden through cognitive decline. This thesis explores mechanisms underlying neuronal death following seizure activity with a focus on mitochondria and ROS as major culprits of seizure induced neuronal cell death. By applying fluorescent dye imaging to glio-neuronal cell cultures, the first study examines mitochondrial mechanisms of seizure induced cell death and how such cell death can be reversed. The second study, using both in vitro and in vivo epilepsy models, explores sources of ROS production during seizures and in chronic epilepsy and how these can be reversed by blocking ROS producing enzymes. Experiments performed in the first part demonstrate that seizure activity leads to a sustained cyclosporine-A-sensitive depolarization of the mitochondrial membrane potential indicating mitochondrial permeability transition pore opening. This work proposes that neuronal ATP levels decrease, and correlate with the frequency of the oscillatory Ca2+ signal, indicative of activity-dependent ATP consumption. Cellular ATP levels during seizure like activity are dependent on the functioning of the mitochondrial complexes and seizure induced neuronal death is reduced when mitochondrial complex I substrate pyruvate is supplemented. In the second part I show that seizure activity induced increases in ROS production were seen both in vitro and in vivo. ROS production in vivo is elevated during periods of spontaneous brief seizures leading to a brain-region specific decrease in the major antioxidant system glutathione. Seizure-induced ROS were not dependent upon mitochondrial dysfunction but were generated in a Ca2+ -independent fashion through initially NADPH oxidase and later xanthine oxidase activity. Inhibition of either enzyme, consequently, reduced seizure-induced neuronal cell death. This works outlines strategies to treat seizure induced cell death.

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