Effects of memantine on mitochondrial function.
Because NMDA complex and mitochondrial function are related, we hypothesized memantine would influence mitochondrial function. We addressed this in vitro by studying the effects of chronic and acute memantine exposures on mitochondrial function. For acute exposure experiments, mitochondria were isolated from NT2 cells and assayed for electron transport chain (ETC) enzyme function and peroxide production in buffers containing up to 60uM memantine. For chronic exposure experiments, NT2 cells were maintained for at least two weeks in medium containing up to 60uM memantine, following which we assayed cells or their mitochondria for ETC enzyme activities, cytochrome oxidase protein levels, oxidative stress, calcium levels, and mitochondrial DNA levels. The ability of the NMDA receptor antagonist aminophosphonovaleric acid (APV) to modify memantine's mitochondrial effects was evaluated. Acute and chronic memantine similarly affected complex I (increased at high concentrations) and IV (decreased at high concentrations) V(max) activities. APV did not alter the effects of chronic memantine exposure on citrate synthase and complex IV. We detected a lower mitochondrial peroxide production rate with acute exposure, and an increased mitochondrial peroxide production rate with chronic exposure. Micromolar memantine concentrations affect mitochondria, some of these effects are directly mediated, and acute and chronic effects may differ.
McAllister
Jenna
J
Department of Neurology, University of Virginia School of Medicine, 800394 McKim Hall, Charlottesville, VA 22908, United States.
Ghosh
Sangeeta
S
Berry
Diana
D
Park
Melissa
M
Sadeghi
Sina
S
Wang
Kai Xuan
KX
Parker
W Davis
WD
Swerdlow
Russell H
RH
D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D008559:Memantine / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D016194:Receptors, N-Methyl-D-Aspartate; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D002118:Calcium; D008559:Memantine