Authors :
Presenting Author: Alberto Musto, MD, PhD – Macon & Joan Brock Virginia Health Sciences at Old Dominion University
Abheek Ritvik, MS – Macon & Joan Brock Virginia Health Sciences at Old Dominion University
Yali Kong, PhD – Macon & Joan Brock Virginia Health Sciences at Old Dominion University
Rationale:
Neuroinflammation is recognized as a critical contributor to seizure susceptibility and progression to chronic epilepsy. CD40-CD40L system mediates neuroinflammation. Previously, we observed that the downregulation of CD40 limits SE, seizure susceptibility, neuroinflammation, and neuronal network hyperexcitability. On the other hand, we found that the deficit of CD40 activates neuroprotection signaling in the brain. CD40 recruits TRAF6 upon CD40L ligation, leading to downstream of NF-κB. We hypothesized that the CD40-TRAF6 signaling axis, known for its role in immune regulation and neuroinflammation, is implicated in seizure-induced damage. The goal was to investigate the role of CD40-TRAF6 signaling in epilepsy.
Methods:
Post-status epilepticus (PSE) and pentylenetetrazol (PTZ) models were used in adult C57BL/6 mice. Seizures monitored using Ethovision software were classified using Racine's score. Brain samples were collected at different time points after PSE or PTZ. CD40-CD40L activation (sCD40L) and CD40-TRAF-6 signaling, including markers for neuronal damage, were explored using molecular and histological techniques. In a group of mice, a CD40-TRAF6 inhibitor was administer at specific dosage of at a particular time prior to PTZ.
Results:
Preliminary results showed that in brains from chronic epilepsy, sCD40L (ng/ml) increased (Mean: 2.51; SEM +/- 0.8) compared to control (Mean: 0.9, SEM: =/-0.13 p< 0.05). CD40-TRAF6 inhibitor limited seizure severity (Racine's Score: CD40-TRAF6: Mean 3.75, SEM +/- 0.4 vs. VEH: Mean: 5, SEM: +/-0, p=0.04), reduced 50% generalized tonic-clonic seizures, (Racine's Score 5: TRAF6: 0.25; SEM: +/-.0.25 vs. VEH: 1, SEM: +/- 0; p=0.02) and 50% of mortality. Also, CD40-TRAF6 inhibitor provided neuroprotection. In addition, CD40-TRAF6 showed no sedation or locomotor abnormalities within two hours of administration.