title: Inhibition of Drp1 provides neuroprotection in vitro and in vivo.
abstract: Impaired regulation of mitochondrial dynamics, which shifts the balance towards fission, is associated with neuronal death in age-related neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. A role for mitochondrial dynamics in acute brain injury, however, has not been elucidated to date. Here, we investigated the role of dynamin-related protein 1 (Drp1), one of the key regulators of mitochondrial fission, in neuronal cell death induced by glutamate toxicity or oxygen-glucose deprivation (OGD) in vitro, and after ischemic brain damage in vivo. Drp1 siRNA and small molecule inhibitors of Drp1 prevented mitochondrial fission, loss of mitochondrial membrane potential (MMP), and cell death induced by glutamate or tBid overexpression in immortalized hippocampal HT-22 neuronal cells. Further, Drp1 inhibitors protected primary neurons against glutamate excitotoxicity and OGD, and reduced the infarct volume in a mouse model of transient focal ischemia. Our data indicate that Drp1 translocation and associated mitochondrial fission are key features preceding the loss of MMP and neuronal cell death. Thus, inhibition of Drp1 is proposed as an efficient strategy of neuroprotection against glutamate toxicity and OGD in vitro and ischemic brain damage in vivo.
authors.affiliation: Institut für Pharmakologie und Klinische Pharmazie, Fachbereich Pharmazie, Philipps-Universität Marburg, Karl-von-Frisch-Strasse 1, Marburg 35032, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Grohm
authors.forename: S-W
authors.initials: SW
authors.lastname: Kim
authors.forename: U
authors.initials: U
authors.lastname: Mamrak
authors.forename: S
authors.initials: S
authors.lastname: Tobaben
authors.forename: A
authors.initials: A
authors.lastname: Cassidy-Stone
authors.forename: J
authors.initials: J
authors.lastname: Nunnari
authors.forename: N
authors.initials: N
authors.lastname: Plesnila
authors.forename: C
authors.initials: C
authors.lastname: Culmsee
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D002460:Cell Line; D004195:Disease Models, Animal; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport
chemical_list: D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C486391:Dnm1l protein, mouse; D034281:Dynamins