Abstract
BackgroundKainic 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.ResultsWe 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.ConclusionsWe conclude that inhibition of mitochondrial fission attenuates Parkin-mediated mitochondrial degradation and protects from KA-induced hippocampal neuronal cell death.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0270-y) contains supplementary material, which is available to authorized users.
Highlights
Kainic acid (KA)-induced excitotoxicity promotes cytoplasmic calcium accumulation, oxidative stress, and apoptotic signaling, leading to hippocampal neuronal death
We demonstrated that phosphorylation of Drp1 (p-Drp1) levels were significantly increased in mitochondria isolated from the hippocampus of KAinjected mice and in co-localized CA3 neurons in KAinjected mice, whereas Mitochondrial division inhibitor-1 (Mdivi-1) pretreatment inhibited the increase of p-Drp1 expression
We showed that Mdivi-1 inhibited the increase of heat shock protein 72 (Hsp72) expression in mitochondria isolated from the hippocampus of KA-induced seizure mice, suggesting that Mdivi-1 prevents Parkin-mediated mitochondrial degradation
Summary
Kainic acid (KA)-induced excitotoxicity promotes cytoplasmic calcium accumulation, oxidative stress, and apoptotic signaling, leading to hippocampal neuronal death. Mitochondrial morphology is disrupted during KA-induced seizures; it is not clear whether mitochondrial fission or fusion factors are involved in KA-induced neuronal death. Kainic acid (KA) is a powerful neurotoxic analog of glutamate that induces excitotoxic neuronal death in the hippocampus [1, 2] through the accumulation of multiple cellular stress responses [3]. Mitochondria are cellular organelles that play a crucial role in ATP energy production, calcium homeostasis, and inflammation in the central nervous system. Mitochondrial dysfunction is found in many neurodegenerative diseases, and pathology is related to mitochondrial calcium overload, synaptic energy failure, inflammation, and oxidative stress [4, 5]. Mitochondrial fission facilitates movement of mitochondria to distal axons to supply ATP energy for proper synaptic function and prevents neuronal atrophy [10]
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