title: Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors.
abstract: Ketones have previously shown beneficial effects in models of neurodegenerative disorders, particularly against associated mitochondrial dysfunction and cognitive impairment. However, evidence of a synaptic protective effect of ketones remains lacking. We tested the effects of ketones on synaptic impairment induced by mitochondrial respiratory complex (MRC) inhibitors using electrophysiological, reactive oxygen species (ROS) imaging and biochemical techniques. MRC inhibitors dose-dependently suppressed both population spike (PS) and field potential amplitudes in the CA1 hippocampus. Pre-treatment with ketones strongly prevented changes in the PS, whereas partial protection was seen in the field potential. Rotenone (Rot; 100 nmol/L), a MRC I inhibitor, suppressed synaptic function without altering ROS levels and PS depression by Rot was unaffected by antioxidants. In contrast, antioxidant-induced PS recovery against the MRC II inhibitor 3-nitropropionic acid (3-NP; 1 mmol/L) was similar to the synaptic protective effects of ketones. Ketones also suppressed ROS generation induced by 3-NP. Finally, ketones reversed the decreases in ATP levels caused by Rot and 3-NP. In summary, our data demonstrate that ketones can preserve synaptic function in CA1 hippocampus induced by MRC dysfunction, likely through an antioxidant action and enhanced ATP generation.
authors.affiliation: Barrow Neurological Institute and St. Joseph's Hospital & Medical Center, Phoenix, Arizona 85013, USA. doyoung.kim@chw.edu
authors.forename: Do Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Johana
authors.initials: J
authors.lastname: Vallejo
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000090:Acetoacetates / Q000494:pharmacology; D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D002374:Catalase / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors*; D006861:Hydrogen Peroxide / Q000633:toxicity; D066298:In Vitro Techniques; D007659:Ketones / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
chemical_list: D000090:Acetoacetates; D045222:Electron Transport Chain Complex Proteins; D007659:Ketones; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D012402:Rotenone; C016635:acetoacetic acid; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D002374:Catalase; C015392:3-nitropropionic acid; D020155:3-Hydroxybutyric Acid