Limiting CD40-TRAF6 signaling reduces seizures
Poster #: 193
Session/Time: B
Author:
Abheek Ritvik, MS
Mentor:
Alberto E. Musto, MD, PhD
Research Type: Clinical Research
Abstract
INTRODUCTION:
Neuroinflammation is recognized as a critical contributor to seizure susceptibility and progression to chronic epilepsy. CD40-CD40L system mediates neuroinflammation. Previously, we observed that downregulation of CD40 limits SE, seizure susceptibility, neuroinflammation and neuronal network hyperexcitability. CD40 recruits TRAF6 upon CD40L ligation, leading to downstream of NF-κB. We hypothesized that CD40-TRAF6 signaling axis, known for its role in immune regulation and neuroinflammation is implicated 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 mice. Seizures monitored by the Ethovision software using Racine's score. CD40-TRAF6 inhibitor (10 mg/kg) or vehicle was administered intraperitoneal two hours before PTZ. Brain samples were collected at different time points after PSE or PTZ. In a group of mice, CD40-TRAF-6 signaling, including markers for neuronal damage were analyzed using molecular and histological techniques.
RESULTS:
Preliminary results showed that in chronic epilepsy sCD40L increased in the brain compared to control. This outcome is associated with aberrant locomotion such as reduced activity and increased orofacial movement. CD40-TRAF6 inhibitor reduced seizure severity limited 50% of mortality and increased neuroprotection. In addition, CD40-TRAF6 showed no sedation or locomotor abnormalities within two hours of administration.
CONCLUSION:
The CD40L-CD40-TRAF6 signaling in epilepsy can promote neuroinflammation and neuronal damage, thereby creating epileptogenesis. Moreover, spontaneous behavior after PSE predicts seizures, along with the sCD40L as a biomarker for epileptogenesis. CD40-TRAF6 inhibitor showed potential antiseizure effects that can be explored in chronic models of epilepsy.
Neuroinflammation is recognized as a critical contributor to seizure susceptibility and progression to chronic epilepsy. CD40-CD40L system mediates neuroinflammation. Previously, we observed that downregulation of CD40 limits SE, seizure susceptibility, neuroinflammation and neuronal network hyperexcitability. CD40 recruits TRAF6 upon CD40L ligation, leading to downstream of NF-κB. We hypothesized that CD40-TRAF6 signaling axis, known for its role in immune regulation and neuroinflammation is implicated 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 mice. Seizures monitored by the Ethovision software using Racine's score. CD40-TRAF6 inhibitor (10 mg/kg) or vehicle was administered intraperitoneal two hours before PTZ. Brain samples were collected at different time points after PSE or PTZ. In a group of mice, CD40-TRAF-6 signaling, including markers for neuronal damage were analyzed using molecular and histological techniques.
RESULTS:
Preliminary results showed that in chronic epilepsy sCD40L increased in the brain compared to control. This outcome is associated with aberrant locomotion such as reduced activity and increased orofacial movement. CD40-TRAF6 inhibitor reduced seizure severity limited 50% of mortality and increased neuroprotection. In addition, CD40-TRAF6 showed no sedation or locomotor abnormalities within two hours of administration.
CONCLUSION:
The CD40L-CD40-TRAF6 signaling in epilepsy can promote neuroinflammation and neuronal damage, thereby creating epileptogenesis. Moreover, spontaneous behavior after PSE predicts seizures, along with the sCD40L as a biomarker for epileptogenesis. CD40-TRAF6 inhibitor showed potential antiseizure effects that can be explored in chronic models of epilepsy.