title: Reactive oxygen species initiate a metabolic collapse in hippocampal slices: potential trigger of cortical spreading depression.
abstract: Excessive accumulation of reactive oxygen species (ROS) underlies oxidative damage. We find that in hippocampal slices, decreased activity of glucose-based antioxidant system induces a massive, abrupt, and detrimental change in cellular functions. We call this phenomenon metabolic collapse (MC). This collapse manifested in long-lasting silencing of synaptic transmission, abnormal oxidation of NAD(P)H and FADH2 associated with immense oxygen consumption, and massive neuronal depolarization. MC occurred without any preceding deficiency in neuronal energy supply or disturbances of ionic homeostasis and spread throughout the hippocampus. It was associated with a preceding accumulation of ROS and was largely prevented by application of an efficient antioxidant Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl). The consequences of MC resemble cortical spreading depression (CSD), a wave of neuronal depolarization that occurs in migraine, brain trauma, and stroke, the cellular initiation mechanisms of which are poorly understood. We suggest that ROS accumulation might also be the primary trigger of CSD. Indeed, we found that Tempol strongly reduced occurrence of CSD in vivo, suggesting that ROS accumulation may be a key mechanism of CSD initiation.
authors.affiliation: 1] INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France [2] Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Malkov
authors.affiliation: INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France.
authors.forename: Anton I
authors.initials: AI
authors.lastname: Ivanov
authors.affiliation: 1] INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France [2] Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.
authors.forename: Irina
authors.initials: I
authors.lastname: Popova
authors.affiliation: 1] INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France [2] Laboratory of Neurobiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
authors.forename: Marat
authors.initials: M
authors.lastname: Mukhtarov
authors.affiliation: INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France.
authors.forename: Olena
authors.initials: O
authors.lastname: Gubkina
authors.affiliation: 1] INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France [2] Insitute of Biophysics and Cell Engineering, Minsk, Belarus.
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Waseem
authors.affiliation: INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France.
authors.forename: Piotr
authors.initials: P
authors.lastname: Bregestovski
authors.affiliation: INSERM UMR1106, Institut de Neurosciences des Systèmes, Marseille, France.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Zilberter
mesh_terms: D000818:Animals; D001927:Brain Diseases / Q000378:metabolism* / Q000473:pathology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D005182:Flavin-Adenine Dinucleotide / Q000031:analogs & derivatives / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D009249:NADP / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D009435:Synaptic Transmission
chemical_list: D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D005182:Flavin-Adenine Dinucleotide; C058805:1,5-dihydro-FAD; D009249:NADP; C001803:tempol