title: Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability.
abstract: Latrepirdine/Dimebon is a small-molecule compound with attributed neurocognitive-enhancing activities, which has recently been tested in clinical trials for the treatment of Alzheimer's and Huntington's disease. Latrepirdine has been suggested to be a neuroprotective agent that increases mitochondrial function, however the molecular mechanisms underlying these activities have remained elusive. We here demonstrate that latrepirdine, at (sub)nanomolar concentrations (0.1 nM), activates the energy sensor AMP-activated protein kinase (AMPK). Treatment of primary neurons with latrepirdine increased intracellular ATP levels and glucose transporter 3 translocation to the plasma membrane. Latrepirdine also increased mitochondrial uptake of the voltage-sensitive probe TMRM. Gene silencing of AMPKα or its upstream kinases, LKB1 and CaMKKβ, inhibited this effect. However, studies using the plasma membrane potential indicator DisBAC2(3) demonstrated that the effects of latrepirdine on TMRM uptake were largely mediated by plasma membrane hyperpolarization, precluding a purely 'mitochondrial' mechanism of action. In line with a stabilizing effect of latrepirdine on plasma membrane potential, pretreatment with latrepirdine reduced spontaneous Ca(2+) oscillations as well as glutamate-induced Ca(2+) increases in primary neurons, and protected neurons against glutamate toxicity. In conclusion, our experiments demonstrate that latrepirdine is a potent activator of AMPK, and suggest that one of the main pharmacological activities of latrepirdine is a reduction in neuronal excitability.
authors.affiliation: 1] Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland [2] Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Weisová
authors.forename: S P
authors.initials: SP
authors.lastname: Alvarez
authors.forename: S M
authors.initials: SM
authors.lastname: Kilbride
authors.forename: U
authors.initials: U
authors.lastname: Anilkumar
authors.forename: B
authors.initials: B
authors.lastname: Baumann
authors.forename: J
authors.initials: J
authors.lastname: Jordán
authors.forename: T
authors.initials: T
authors.lastname: Bernas
authors.forename: H J
authors.initials: HJ
authors.lastname: Huber
authors.forename: H
authors.initials: H
authors.lastname: Düssmann
authors.forename: J H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors; D002531:Cerebellum / Q000166:cytology; D020868:Gene Silencing; D051274:Glucose Transporter Type 3 / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051381:Rats
chemical_list: D051274:Glucose Transporter Type 3; D007211:Indoles; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; C010119:latrepirdine