A mitochondrial division inhibitor, Mdivi-1, inhibits mitochondrial fragmentation and attenuates kainic acid-induced hippocampal cell death.
Kainic acid (KA)-induced excitotoxicity promotes cytoplasmic calcium accumulation, oxidative stress, and apoptotic signaling, leading to hippocampal neuronal death. Mitochondria play a critical role in neuroinflammation and the oxidative stress response. Mitochondrial morphology is disrupted during KA-induced seizures; however, it is not clear whether mitochondrial fission or fusion factors are involved in KA-induced neuronal death.



We investigated the effect of Mdivi-1, a chemical inhibitor of the mitochondrial fission protein Drp1, on mitochondrial morphology and function in KA-injected mice. Mdivi-1 pretreatment significantly reduced seizure activity and increased survival rates of KA-treated mice. Mdivi-1 was protective against mitochondrial morphological disruption, and it reduced levels of phosphorylated Drp1 (Ser616) and Parkin recruitment to mitochondria. By contrast, levels of mitochondrial fusion factors did not change. Mdivi-1 also reduced KA-induced neuroinflammation and glial activation.



We conclude that inhibition of mitochondrial fission attenuates Parkin-mediated mitochondrial degradation and protects from KA-induced hippocampal neuronal cell death.
Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, 15, 816 Beon-gil, Jinju-daero, Jinju, Gyeongnam, 660-751, Republic of Korea. hwajin1@gmail.com.
Hwajin
H
Kim
Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, 15, 816 Beon-gil, Jinju-daero, Jinju, Gyeongnam, 660-751, Republic of Korea.
Jong Youl
JY
Lee
Division of Metabolic Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Republic of Korea.
Keon Jae
KJ
Park
Division of Metabolic Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Osong, Republic of Korea.
Won-Ho
WH
Kim
Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, 15, 816 Beon-gil, Jinju-daero, Jinju, Gyeongnam, 660-751, Republic of Korea. anaroh@gnu.ac.kr.
Gu Seob
GS
Roh
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D034281:Dynamins / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D008813:Mice, Inbred ICR; D008840:Microfilament Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology; D063306:Mitophagy / Q000187:drug effects* / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D011897:Random Allocation; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D050884:HSP72 Heat-Shock Proteins; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D052999:Quinazolinones; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C486391:Dnm1l protein, mouse; D034281:Dynamins; D007608:Kainic Acid
Drp1; Mitochondrial fission; Neuroinflammation; Neuronal cell death