Type

Journal Article

Authors

J H M Prehn
H Düssmann
H J Huber
T Bernas
J Jordán
B Baumann
U Anilkumar
S M Kilbride
S P Alvarez
P Weisová

Subjects

Biochemistry

Topics
rats membrane potentials pharmacology indoles glutamic acid calcium calmodulin dependent protein kinase kinase adenosine triphosphate animals metabolism neurons nootropic agents mice cerebellum cytology amp activated protein kinases drug effects neuroprotective agents gene silencing protein serine threonine kinases latrepirdine glucose transporter type 3 antagonists inhibitors mitochondria neocortex

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 -> PubMed

Full list of authors on original publication

J H M Prehn, H Düssmann, H J Huber, T Bernas, J Jordán, B Baumann, U Anilkumar, S M Kilbride, S P Alvarez, P Weisová

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