Effect of Dual Leucine Zipper Kinase Inhibitor GNE-3511 on Epileptogenesis and Cognitive and Behavioral Changes in a Temporal Lobe Epilepsy Model in Mice

Inflammation and neuronal loss are key factors in the pathophysiology of epilepsy. It is known that activation of Dual Leucine Zipper Kinase (DLK) in chronic neurodegenerative diseases causes neuron death and axon degeneration through apoptotic pathways. Genetic deletion of DLK (dual leucine zipper kinase, MAP3K12) or pharmacological inhibition by GNE-3511 or GNE-8505 was found to have benefits in mouse models of Alzheimers and ALS; however, there is no previous study that uses DLK inhibitors in epilepsy models. Therefore, the aim of our study is to suppress the DLK/JNK pathway with the DLK inhibitor GNE-3511 in the temporal lobe epilepsy model induced by pilocarpine and to determine the effect of this inhibition on cognitive and behavioural defects, as well as epileptogenesis. Open field, elevated plus maze, and Morris water maze tests were used to assess locomotor activity, anxiety and learning and memory, respectively. Following decapitation the hippocampi were removed and, histopathological and biochemical analyses were performed. Both treatment groups had less anxiety and locomotor activity as well as decreased impairment in memory and learning performance compared to SE group (p<0.001). Both doses of GNE-3511 prevented the spontaneous recurrent seizures in a dose dependent manner with respect to the SE group (p<0.01 and p<0.001, respectively). Histological examination of the hippocampus revealed a neuroprotective effect of both doses of treatment in the CA1 area and dentate gyrus (p<0.0001). Thus, DLK inhibitor GNE-3511 was found to be effective in preventing epileptogenesis, neuronal loss and cognitive and behavioural deficits due to pilocarpine induced SE.