title: Decreased interaction between FoxO3a and Akt correlates with seizure-induced neuronal death.
abstract: Status epilepticus (SE) leads to neurodegeneration which likely contributes to the development of chronic temporal lobe epilepsy (TLE). Therefore, neuroprotection following SE is considered as a promising strategy for preventing chronic TLE, but molecular changes that occur following SE still remain unclear. The Forkhead homeobox type O (FoxO) family of Forkhead transcription factors mediates cell death in several pathological conditions, but the role of FoxO in the excitotoxic effects of kainic acid (KA) remains largely unknown. The present study examined how FoxO3a and its interaction with other proteins changed in response to excitotoxic stimuli in the mouse hippocampus after SE. Mice were given intraperitoneal injection of kainate and seizure behavior was monitored for 2h to ensure SE. Western blot analyses, co-immunoprecipitation experiments, sub-cellular fractionation and double immunofluorescence analyses were used to determine changes in levels of FoxO3a, Akt, Bim, cleaved caspase-3 and phospho-FoxO3a or phospho-Akt, and their interactions at 6 or 24h after KA treatment. We found that SE activated FoxO3a and increased levels of Bim or cleaved caspase-3, and decreased levels of phospho-FoxO3a or phospho-Akt in the hippocampus. In addition, we noted extensive hippocampal cell death at 24h after KA treatment, evidenced by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL), fluoro-jade B or anti-active caspase-3 staining. Furthermore, co-immunoprecipitation experiments revealed that phospho-Akt interaction with FoxO3a was significantly lowered in the hippocampus at 24h after KA treatment, paralleling enhanced Bim levels and Bim interaction with Bcl-xL. Moreover, double immunofluorescence analyses showed increased co-localization of FoxO3a or Bim and TUNEL in the hippocampi at 24h after KA treatment. Identifying molecular mechanism underlying SE-induced neuronal death can provide a novel strategy to protect against seizure-induced neuronal injury. We found that Akt-FoxO3a signaling relates to seizure-induced neuronal death, providing insight into neuroprotection following SE.
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Yoon Sook
authors: YS
authors: Kim
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Mee Young
authors: MY
authors: Choi
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Dong Hoon
authors: DH
authors: Lee
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Byeong Tak
authors: BT
authors: Jeon
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Gu Seob
authors: GS
authors: Roh
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Hyun Joon
authors: HJ
authors: Kim
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Sang Soo
authors: SS
authors: Kang
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea.
authors: Gyeong Jae
authors: GJ
authors: Cho
authors: Department of Anatomy and Neurobiology, School of Medicine, Institute of Health Science, Medical Research Center, Gyeongsang National University, 816-15 Jinju-daero, Jinju, Gyeongnam 660-751, South Korea. Electronic address: choiws@gnu.kr.
authors: Wan Sung
authors: WS
authors: Choi
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D018690:Excitatory Amino Acid Agonists; C496506:Foxa3 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051543:Hepatocyte Nuclear Factor 3-gamma; D051058:Oncogene Protein v-akt; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase; D007608:Kainic Acid
keywords: Akt; Apoptosis; Bim; FoxO3a; Kainic acid; Status epilepticus