Type

Other / n/a

Authors

Jochen HM Prehn
Heiko Düssmann
Heinrich J Huber
Tytus Bernas
Joaquin Jordán
B Baumann
Ujval Anilkumar
Seán M Kilbride
S P Alvarez
Petronela Weisova

Subjects

Biochemistry

Topics
bioenergetics amp activated protein kinase glutamate excitotoxicity ca2 homeostasis mitochondria physics physiology plasma membrane potential

Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability. (2013)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Jochen HM Prehn, Heiko Düssmann, Heinrich J Huber, Tytus Bernas, Joaquin Jordán, B Baumann, Ujval Anilkumar, Seán M Kilbride, S P Alvarez, Petronela Weisova

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45
 
3
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
4
Tytus Bernas
Royal College of Surgeons in Ireland
Total Publications: 8
 
5
Ujval Anilkumar
Royal College of Surgeons in Ireland
Total Publications: 14
 
6
Petronela Weisova
Royal College of Surgeons in Ireland
Total Publications: 10