title: Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation.
abstract: Repetitive inhibition of oxidative phosphorylation is an established model of neurodegeneration. In contrast, a single mild treatment can be neuroprotective-chemical preconditioning. Repetitive chemical inhibition of oxidative phosphorylation may thus be a tool to study deterioration and improvement of cellular hypoxic tolerance and subsequent differential regulation of cellular responses in the same model. We investigated murine hippocampal function upon repetitive intraperitoneal injections of 3-nitropropionate (3-NP; 20 mg/kg body weight), an inhibitor of mitochondrial complex II. With a 2-day interval of repetitive in vivo treatment with 3-NP, posthypoxic recovery of population spike amplitude was below control. In contrast, even after nine in vivo treatments with 3-NP at 4-day intervals, an almost complete recovery of population spike amplitude was observed. Nerve growth factor (NGF) as assessed by ELISA and expression of beta-amyloid precursor protein (APP) mRNA increased upon nine treatments at 2-day intervals, but remained at control levels with 4-day intervals. In contrast, brain-derived neurotrophic factor (BDNF) as assessed by ELISA increased with the latter treatment. Expression of mRNA for adenosine-A1 and -A3 receptors and endothelial and neuronal nitric oxide synthase remained at control level for both treatment intervals. We conclude that the time interval between mild, subclinical repetitive inhibition of oxidative phosphorylation determines hippocampal neuronal impairment and integrity and modulates NGF and BDNF differently. Decreased hypoxic tolerance and increased APP expression upon repetitive inhibition of oxidative phosphorylation at short time intervals may thus trigger a vicious cycle and be a cofactor for neuronal dysfunction in cerebral hypoxia and neurodegenerative diseases.
authors.affiliation: Department of Psychiatry, Free University, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Hellweg
authors.forename: C A F
authors.initials: CA
authors.lastname: von Arnim
authors.forename: M
authors.initials: M
authors.lastname: Büchner
authors.forename: R
authors.initials: R
authors.lastname: Huber
authors.forename: M W
authors.initials: MW
authors.lastname: Riepe
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics; D009574:Nitro Compounds; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018047:Receptors, Purinergic P1 / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D009414:Nerve Growth Factors; D009574:Nitro Compounds; D011422:Propionates; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D019001:Nitric Oxide Synthase; C015392:3-nitropropionic acid