Role of Succinate Accumulation in Prolonged Febrile Seizure-Induced Neuronal Injury and Epileptic Seizures in...

Though succinate accumulation is a vital contributor to overexcitation and reactive oxygen species (ROS) production, whether it contributes to febrile seizures (FS) is unclear. We sought to mechanistically explore the role of succinate in prolonged FS.

Prolonged FS were induced by hyperthermic treatment in Sprague-Dawley pups. Inhibitors of succinate dehydrogenase (SDH), purine nucleotide cycle (PNC), and malate/aspartate shuttle (MAS) were administered, respectively. Succinate levels and oxidative stress damage were assessed, and epileptic seizures and learning and memory ability were assessed after hyperthermic treatment.

Succinate levels increased significantly, accompanied by oxidative stress injury, seizures, and learning and memory defects, following prolonged FS. Treatment with the SDH inhibitor reduced succinate levels, accompanied by reduced levels of oxidative stress injury, attenuated seizures, and learning and memory deficits. Treatment with inhibitors of MAS and PNC, respectively, played similar protective roles, accompanied by decreased succinate levels.

Increased succinate levels promote prolonged FS-induced oxidative stress injury and epileptogenesis. Reducing succinate accumulation may be a potential method for prolonged FS treatment. Moreover, elevated succinate levels may result from the reverse catalysis of SDH-targeting fumarate, which was produced from PNC and MAS.