Authors :
Presenting Author: Keryma Acevedo, MD – Pontificia Universidad Católica de Chile
Tamara Marín, PhD – Pontificia Universidad Católica de Chile
Silvana Zanlungo, PhD – Pontificia Universidad Católica de Chile
Alejandra Alvarez, PhD – Pontificia Universidad Católica de Chile
Rationale:
Now a days we still have 30% of refractory epilepsies. Moreover, there is a paucity of treatments that can modulate the epileptogenic processes that are triggered after different indults in the brain. Recent studies show the activation of c-Abl kinase in the brain of patients with epilepsy. We have described that its inhibition reduces seizures in mice models. Neurotinib is a new and safe c-Abl inhibitor, with better brain penetration than classic inhibitors. We evaluated the participation of c-Abl in epileptogenesis and the role of Neurotinib as a possible treatment for epilepsy.
Methods:
A mouse model of epilepsy with spontaneous and recurrent seizures (SRS) was developed using kainate injections in the hippocampus. Then, mice were fed with a Neurotinib-supplemented diet for 2 months. During this period, the frequency and severity of SRS and cognitive impairment of the mice were evaluated. c-Abl activation, neuronal death, and neuroinflammation were analyzed in the cortex and hippocampus. Statistical analysis with Student’s t test.
Results:
75% of mice injected with kainate showed SRS approximately 17 days post-injection. We observed 15% of mortality. 36 mice were injected with kainate. Injections produced around 70% of neuronal loss in the CA3 subfield of the hippocampus when compared to the uninjected side. We found an increase in gliosis and c-Abl activation in the brain. Moreover, mice injected with kainate showed impaired cognitive function. Neurotinib treatment decreased the number of seizures by 70% and the duration of seizures by 50% in the 18 treated animals. In addition, we observed a 40% reduction in neuronal death in Neurotinib-treated mice as compared to kainate-injected mice treated with the control diet. Moreover, we found a decrease in c-Abl activation, and neuroinflammation in the cortex and hippocampus. Neurotinib treated mice had significant better cognitive outcomes (p < 0.05).