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


RESULTS
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.


CONCLUSIONS
Erythropoietin treatment may provide a new strategy for preventing epilepsy in susceptible individuals with atypical febrile seizures.
Stroke & Stem Cell Laboratory in Clinical Research Institute, Stem Cell Research Center, Department of Neurology, Seoul National University, Seoul, South Korea.
Keun-Hwa
KH
Jung
Kon
K
Chu
Soon-Tae
ST
Lee
Kyung-Il
KI
Park
Jin-Hee
JH
Kim
Kyung-Muk
KM
Kang
Soyun
S
Kim
Daejong
D
Jeon
Manho
M
Kim
Sang Kun
SK
Lee
Jae-Kyu
JK
Roh
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D039481:CD11b Antigen / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects; D004734:Energy Metabolism / Q000235:genetics; D004921:Erythropoietin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D017136:Ion Transport / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D003294:Seizures, Febrile / Q000235:genetics* / Q000503:physiopathology*; D012815:Signal Processing, Computer-Assisted; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000235:genetics
D000927:Anticonvulsants; D039481:CD11b Antigen; D004921:Erythropoietin; D005680:gamma-Aminobutyric Acid