Effects of memantine on mitochondrial function

Abstract

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 60 uM memantine. For chronic exposure experiments, NT2 cells were maintained for at least two weeks in medium containing up to 60 uM 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) Vmax 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.

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

“…In a vitro study, which evaluated the effects of memantine on mitochondrial function, McAllister et al (2008) demonstrated that acute and chronic memantine treatments similarly affected complex I (increased at high concentrations) and IV (decreased at high concentrations) activities and were detected a lower mitochondrial peroxide production rate with chronic exposure. In the present study, we showed that creatine kinase activity increased with memantine at low concentrations (5 mg/kg) and decreased at high concentrations (20 mg/kg) after acute treatment.…”

“…Additionally, clinical studies suggest that administration of memantine ameliorates depressive symptoms in patients suffering from major depression (Muhonen et al 2009;Ferguson and Shingleton 2007). Moreover, memantine alters mitochondrial function (McAllister et al 2008). Furthermore, glutamate neurotoxicity is associated with mitochondrial dysfunction (Almeida et al 1998).…”

Recent insights into the mode of action of memantine and ketamine

“…Multiple other sites of action have been reported for each drug (e.g., [26,71,72]). For example, memantine inhibits multiple acetylcholine receptors subtypes [73-76] and 5-HT 3 serotonin receptors [10,77], whereas ketamine binds to dopamine D2 and 5-HT 2 serotonin receptors [12,78] and to HCN1 channels [79].…”

The Intermediate Conductance Calcium-activated Potassium Channel KCa3.1 Regulates Vascular Smooth Muscle Cell Proliferation via Controlling Calcium-dependent Signaling

“…Intracellular Ca 2ϩ Measurement-To measure [Ca 2ϩ ] i in VSMCs after 48 h of treatment (24), cells were incubated with Fluo-4 AM (10 M; Invitrogen) for 25 min at room temperature. Fluorescence images were captured and analyzed using an inverted epifluorescence microscope (Nikon TE200) with a 40ϫ Plan Fluor objective, a high speed wavelength switcher (Lambda DG-4 from Sutter Instrument), a PC-controlled digital CCD camera (Hamamatsu C4742-95), and MetaMorph software (Universal Imaging).…”