Molecular alterations underlying epileptogenesis after prolonged febrile seizure and modulation by erythropoietin

• Published in: Epilepsia (Copenhagen) 2011-03, Vol.52 (3), p.541-550
• Main Authors: Jung, Keun‐Hwa, Chu, Kon, Lee, Soon‐Tae, Park, Kyung‐IL, Kim, Jin‐Hee, Kang, Kyung‐Muk, Kim, Soyun, Jeon, Daejong, Kim, Manho, Lee, Sang Kun, Roh, Jae‐Kyu
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Animals, Newborn; Anticonvulsants - pharmacology; Apoptosis; Apoptosis - genetics; Biological and medical sciences; Blood-Brain Barrier - drug effects; Brain; Brain - drug effects; Brain - pathology; CD11b Antigen - genetics; Cell Adhesion - genetics; Cell cycle; Cell Cycle - genetics; Children; Convulsions & seizures; Disease Models, Animal; Diseases of the nervous system; Edema; Electroencephalography - drug effects; Energy metabolism; Energy Metabolism - genetics; Epilepsy; Epileptogenesis; Erythropoietin; Erythropoietin - pharmacology; Febrile seizure; Fever; gamma -Aminobutyric acid; gamma-Aminobutyric Acid - genetics; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Inflammation; Ion Transport - genetics; Latent period; Medical sciences; Microglia; Nervous system (semeiology, syndromes); Neurology; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Rats; Rats, Sprague-Dawley; Risk factors; Seizures; Seizures, Febrile - genetics; Seizures, Febrile - physiopathology; Signal Processing, Computer-Assisted; Signal Transduction - genetics; Synapses - drug effects; Synapses - genetics; Synapses - pathology; Synaptogenesis
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.1528-1167.2010.02916.x

Summary Purpose:  Children who experience complex febrile seizures are at a higher risk of subsequent epileptic episodes, and they may require therapy. This issue can be resolved by interventional studies using molecular targets identified and defined in animal models. In the current study, the molecular changes in the rat brain after febrile seizures were examined throughout the latent period, and erythropoietin was administered as a potentially antiepileptogenic intervention. Methods:  The changes in the expressions of genes that were differentially regulated during the latent period after febrile seizures were categorized into the following four patterns: (1) continuously high (CH); (2) continuously low (CL); (3) rise and fall (RF); and (4) going‐up (GU). Erythropoietin was administered immediately after seizure cessation and then once daily for at most 7 days, and spontaneous recurrent seizures and cellular and molecular changes were investigated. Key Findings:  The CH genes were associated with cell cycle and adhesion, whereas the CL genes were related to energy metabolism. Within the category of RF, the largest changes were for genes involved in inflammation, apoptosis, and γ‐aminobutyric acid (GABA) signaling. The GU category included genes involved in ion transport and synaptogenesis. Along with an early rise in inflammatory genes, there were substantial increases in brain edema and activated microglia during the early latent period. Erythropoietin reduced the early inflammatory responses and modulated the molecular alterations after febrile seizures, thereby reducing the risk of subsequent spontaneous seizures. Significance:  Erythropoietin treatment may provide a new strategy for preventing epilepsy in susceptible individuals with atypical febrile seizures.