Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death.
Dimebon, a drug currently being evaluated in multiple Phase III Alzheimer's disease trials, has previously been shown to have effects on isolated mitochondria at muM concentrations. Here the effects of nM concentrations of Dimebon on mitochondrial function were investigated both in primary mouse cortical neurons and human neuroblastoma cells (SH-SY5Y). Under non-stress conditions nM concentrations of Dimebon increased succinate dehydrogenase activity (MTT-assay), mitochondrial membrane potential (DeltaPsim), and cellular ATP levels. Dimebon treatment had no effect on mitochondria DNA content, implying that mitochondrial biogenesis was not induced. Under stress conditions, mitochondria in Dimebon-treated neurons showed increased resistance to elevated intracellular calcium concentrations, thus, maintaining their DeltaPsim throughout the experiment, in contrast to control neurons, which rapidly lost their DeltaPsim. Moreover, we show that serum-starved differentiated SH-SY5Y cells treated with Dimebon had an increased survival rate as compared to untreated cells. In conclusion, these data demonstrate that Dimebon enhances mitochondrial function both in the absence and presence of stress and Dimebon-treated cells are partially protected to maintain cell viability.
Zhang
Shouting
S
KI-Alzheimer's Disease Research Center, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), Novum, Stockholm, Sweden.
Hedskog
Louise
L
Petersen
Camilla A Hansson
CA
Winblad
Bengt
B
Ankarcrona
Maria
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001798:Blood Proteins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics; D018628:Gene Dosage / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
D001798:Blood Proteins; D004272:DNA, Mitochondrial; D007211:Indoles; D018696:Neuroprotective Agents; C025615:glucosylated serum protein; D014212:Tretinoin; D000255:Adenosine Triphosphate; C010119:latrepirdine; D002118:Calcium